NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of antineoplastons as treatments for people with cancer. The summary includes a brief history of the development of antineoplastons; a review of laboratory, animal, and human studies; and possible side effects associated with antineoplaston use.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

Antineoplastons are an experimental cancer therapy developed by S.R. Burzynski, MD, PhD. Chemically, antineoplastons are a mixture of amino acid derivatives, peptides, and amino acids found in human blood and urine.[1–4] The developer originally isolated antineoplastons from human blood and later found the same peptides in urine. Urine was subsequently used because it was less expensive and easier to obtain. Since 1980, antineoplastons have been synthesized from commercially available chemicals at the Burzynski Research Institute.[2,4]

According to the developer, antineoplastons are part of a biochemical surveillance system in the body and work as “molecular switches.” For the developer, cell differentiation is the key to cancer therapy. At the molecular level, abnormal cells that are potential cancer cells need to be “switched” to normal mode. Antineoplastons are the surveillance system that directs cancer cells into normal channels of differentiation. According to statements published by the developer, people with cancer lack this surveillance system because they do not have an adequate supply of antineoplastons.[1–3]

The notion of controlling tumor growth through a naturally occurring biochemical mechanism in the body that directs cancer cells into normal channels of differentiation is one of the theoretical foundations of antineoplaston therapy. In a complex organism like the body, cells are continuously differentiating. Groups of abnormal cells can arise under the influence of carcinogenic factors from outside or inside the body. The body must have a mechanism for dealing with these abnormal cells, or the organism will not live very long. The proposed components in the body that correct the differentiation problems of abnormal cells and send them into normal pathways have been given the name “antineoplastons” by the developer.[2]

The developer defines antineoplastons as “substances produced by the living organism that protect it against development of neoplastic growth by a nonimmunological process which does not significantly inhibit the growth of normal tissues.”[2]

The developer originally hypothesized the existence of antineoplastons by applying the cybernetic theory of information exchange in autonomous systems to the study of peptides in the blood.[2] The living cell is an autonomous cybernetic system connected to, and receiving, information from its environment through an energy pathway and an information pathway. It was postulated that a regulator within such a system would control the transfer of information and the expenditure of energy. Peptides were considered the information carriers in the body. Hypothesizing that peptides were the carriers of differentiation information to the cells, the developer began looking for peptides in the blood of cancer patients that might correct abnormal differentiation.[1–3,5]

To begin the search for antineoplastons, the developer used human blood, separating and removing the peptides found there. Later it was discovered that the same peptide fractions existed in human urine. Each peptide fraction was tested in vitro against various normal and neoplastic cell lines to gauge its effect on DNA synthesis and growth. The fractions that had little or no inhibitory effect on normal cells but a substantial inhibitory effect on neoplastic cell lines were separated into two classes: those that were effective against a specific cell line and those that were active against a broad array of neoplastic cell lines. Those with a broad spectrum of activity were grouped together and called “antineoplaston A.” Peptide fractions with specific antineoplastic activity were not investigated further.[2]

Antineoplaston A was further purified and yielded antineoplastons A1, A2, A3, A4, and A5. These mixtures of 7 to 13 peptides were patented in 1985.[6] In vitro tissue culture studies and in vivo toxicity studies in animal models were performed for antineoplastons A1 through A5. According to the developer, each individual fraction had a higher level of antitumor activity and lower toxicity level than antineoplaston A.[2]

Phase I trials of this antineoplaston group in patients with various advanced cancers showed A2 as contributing to the highest tumor response rate, so it was selected for further study.[2]

The active compound in A2 was found to be 3-phenylacetylamino-2,6-piperinedione, which was named antineoplaston A10.[7] From antineoplaston A10, three other compounds have been derived:

Other antineoplastons (A3, A4, A10-1, AS5) were added to this group after further studies.[2–4]

There have been no independent analyses of which amino acids comprise the antineoplastons used in any of the reported studies.

Antineoplastons are administered by different methods. Antineoplaston A has been given intravenously, intramuscularly, rectally, topically, intrapleurally, and by bladder instillation.[8] Presently, antineoplastons A10, AS2-5, AS2-1, A2, A3, and A5 are given orally or by injection.[8–20]

Critical opposition to antineoplaston therapy and its developer have appeared in the published literature.[4] A basic criticism of the developer’s work is that although he has put forth a theory of peptides inducing cell differentiation, there is no published evidence that he has experimentally tested the hypothesis that information-bearing peptides could normalize cancer cells. Although some articles attempt to demonstrate that antineoplastons (specifically, antineoplaston A10) can bind to DNA at certain sites, this is an extrapolation from three-dimensional molecular models of DNA and A10 and does not demonstrate that this binding actually occurs.[21–23]

Other criticism focuses on the form of antineoplastons. Although the active fraction, antineoplaston A10, is insoluble in aqueous solutions, the developer has stated that it is present in body fluids.[4]

Antineoplastons AS2-5 and AS2-1 are derived from A10. Antineoplaston AS2-5 is PAG, and AS2-1 is a 4:1 mixture of PA and PAG. Because it is a strong acid, PA would exhibit cytotoxicity in vitro if in high enough concentration and not in neutralized form.[4]

The active component of antineoplaston A10 is 3-phenylacetylamino-2,6-piperidinedione. Reagents necessary for the synthesis of this antineoplaston compound are readily available internationally from any chemical supply company.[24] The developer retains patents on antineoplaston compounds and their use when administered pharmaceutically to inhibit the growth of neoplastic cells.[6,25]

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). The FDA’s IND process is confidential, and the existence of an IND application can be disclosed only by an applicant.

Although several possible mechanisms of action and theories about the activity of antineoplastons have been proposed, specifically for antineoplaston A10, none of the theories has been conclusively demonstrated.

One theoretical mechanism of action proposes that antineoplaston A10 is specifically capable of intercalating with DNA at specific base pairs and thereby might interfere with carcinogens binding to the DNA helix. This interweaving of A10 into the DNA helix may be capable of interfering with DNA replication, transcription, or translation.[21,23] The theory is based on the manipulation of molecular models of DNA and A10; however, no published evidence of the creation of this actual molecule or evidence of the properties ascribed to it exists in the medical literature.

Another theoretical mechanism of action is based on the structural similarities of antineoplaston A10 to other experimental anticancer drugs such as carmustine and 5-cinnamoyl-6-aminouracil. A10 has been proposed to bind to chromatin and, therefore, relate to other anticancer drugs such as doxorubicin that interact directly with DNA.[21,26,27]

At the cellular level, two other mechanisms of action have been proposed to explain inhibition of tumor growth. One theory involves the activity of PAG, a component of some antineoplastons. PAG appears to compete with glutamine for access to the glutamine membrane transporter and may inhibit the incorporation of glutamine into the proteins of neoplastic cells. Because glutamine is essential for the cell cycle transition from G1 to S phase where DNA replication occurs, antineoplastons may arrest cell cycle progression and stop cell division.[28] Another theory proposes that phenylacetic acid, also a component of several antineoplastons, inhibits methylation of nucleic acids in cancer cells. The hypomethylation of DNA in cancer cells may lead to terminal differentiation and prevention of tumor growth or progression.[28] In one in vitro study, human colon cancer cells were exposed to antineoplaston AS2-1 at high concentration and reported to normalize hypermethylation status at the promoter region of various tumor suppressor genes that are silenced in colon cancer.[29] However, this effect was noted at an AS2-1 concentration of 2 mg/mL, which is approximately four times higher than the mean steady state concentration previously reported in cancer patients treated with AS2-1,[20] and thus the clinical relevance of these findings is questionable.

References

1. Burzynski SR: Antineoplastons: biochemical defense against cancer. Physiol Chem Phys 8 (3): 275-9, 1976. [PUBMED Abstract]
2. Burzynski SR: Antineoplastons: history of the research (I). Drugs Exp Clin Res 12 (Suppl 1): 1-9, 1986. [PUBMED Abstract]
3. Burzynski SR: Potential of antineoplastons in diseases of old age. Drugs Aging 7 (3): 157-67, 1995. [PUBMED Abstract]
4. Green S: ‘Antineoplastons’. An unproved cancer therapy. JAMA 267 (21): 2924-8, 1992. [PUBMED Abstract]
5. Burzynski SR: The present state of antineoplaston research (1). Integr Cancer Ther 3 (1): 47-58, 2004. [PUBMED Abstract]
6. Burzynski SR: Purified Antineoplaston Fractions and Methods of Treating Neoplastic Disease. US Patent 4558057. December 10, 1985. Washington, DC: US Patent and Trademark Office, 1985. Available online. Last accessed September 8, 2016.
7. Revelle LK, D’Avignon DA, Wilson JA: 3-[(Phenylacetyl)amino]-2,6-piperidinedione hydrolysis studies with improved synthesis and characterization of hydrolysates. J Pharm Sci 85 (10): 1049-52, 1996. [PUBMED Abstract]
8. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977. [PUBMED Abstract]
9. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995. [PUBMED Abstract]
10. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986. [PUBMED Abstract]
11. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986. [PUBMED Abstract]
12. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986. [PUBMED Abstract]
13. Burzynski SR, Kubove E, Burzynski B: Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp Clin Res 16 (7): 361-9, 1990. [PUBMED Abstract]
14. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987. [PUBMED Abstract]
15. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987. [PUBMED Abstract]
16. Burzynski SR, Kubove E: Initial clinical study with antineoplaston A2 injections in cancer patients with five years’ follow-up. Drugs Exp Clin Res 13 (Suppl 1): 1-11, 1987. [PUBMED Abstract]
17. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995. [PUBMED Abstract]
18. Tsuda H, Sata M, Kumabe T, et al.: Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncol Rep 5 (3): 597-600, 1998 May-Jun. [PUBMED Abstract]
19. Kumabe T, Tsuda H, Uchida M, et al.: Antineoplaston treatment for advanced hepatocellular carcinoma. Oncol Rep 5 (6): 1363-7, 1998 Nov-Dec. [PUBMED Abstract]
20. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999. [PUBMED Abstract]
21. Lehner AF, Burzynski SR, Hendry LB: 3-Phenylacetylamino-2,6-piperidinedione, a naturally-occurring peptide analogue with apparent antineoplastic activity, may bind to DNA. Drugs Exp Clin Res 12 (Suppl 1): 57-72, 1986. [PUBMED Abstract]
22. Hendry LB, Muldoon TG, Burzynski SR, et al.: Stereochemical modelling studies of the interaction of antineoplaston A10 with DNA. Drugs Exp Clin Res 13 (Suppl 1): 77-81, 1987. [PUBMED Abstract]
23. Michalska D: Theoretical investigations on the structure and potential binding sites of antineoplaston A10 and experimental findings. Drugs Exp Clin Res 16 (7): 343-9, 1990. [PUBMED Abstract]
24. Choi BG, Seo HK, Chung BH, et al.: Synthesis of Mannich bases of antineoplaston A10 and their antitumor activity. Arch Pharm Res 17 (6): 467-9, 1994. [PUBMED Abstract]
25. Burzynski SR: Purified Antineoplaston Fractions and Methods of Treating Neoplastic Disease. US Patent 4559325. December 17, 1985. Washington, DC: US Patent and Trademark Office, 1985. Available online. Last accessed September 8, 2016.
26. Wood JC, Copland JA, Muldoon TG, et al.: 3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis. Proc Soc Exp Biol Med 197 (4): 404-8, 1991. [PUBMED Abstract]
27. Tsuda H: Inhibitory effect of antineoplaston A-10 on breast cancer transplanted to athymic mice and human hepatocellular carcinoma cell lines. The members of Antineoplaston Study Group. Kurume Med J 37 (2): 97-104, 1990. [PUBMED Abstract]
28. Sołtysiak-Pawłuczuk D, Burzyński SR: Cellular accumulation of antineoplaston AS21 in human hepatoma cells. Cancer Lett 88 (1): 107-12, 1995. [PUBMED Abstract]
29. Ushijima M, Ogata Y, Tsuda H, et al.: Demethylation effect of the antineoplaston AS2-1 on genes in colon cancer cells. Oncol Rep 31 (1): 19-26, 2014. [PUBMED Abstract]

As noted in the General Information section, Burzynski first proposed antineoplastons as a naturally occurring biochemical defense against cancer in 1976 as a result of his study of cybernetic systems and information theory. The search for information-bearing peptides in body fluids led him to separate peptides from human blood and subsequently from human urine. He called these substances antineoplastons and categorized them according to their general and specific anticarcinogenic potential. In 1980, the developer characterized the chemical structures of antineoplastons and began preparing them synthetically rather than isolating them from human urine. Preparations now used in clinical studies to treat cancer are antineoplastons A10, AS2-5, AS2-1, A2, A3, and A5.

From 1991 to 1995, the National Cancer Institute (NCI) initiated phase II clinical trials of antineoplastons A10 and AS2-1. Protocols for two phase II clinical trials were originally developed by investigators from several cancer centers, with review and input from both the developer and NCI. The National Institutes of Health (NIH), Office of Alternative Medicine, now known as the National Center for Complementary and Integrative Health, provided funding for the trials. Three centers (Memorial Sloan-Kettering Cancer Center, the Mayo Clinic, and the Warren Grant Magnuson Clinical Center at NIH) began accruing participants for these NCI-sponsored studies in 1993. However, by August 1995 only nine patients had entered the trials. Despite efforts by the developer, NCI staff, and investigators to reach agreement on proposed changes to increase patient accrual and dose, these agreements could not be reached, and the studies were closed prematurely in August 1995.[1,2]

The developer and investigators in Japan have reported several case series showing varying results using antineoplastons as a clinical therapy against several different types of cancer, alone or in combination with standard chemotherapy.[3–14] These studies are described in more detail in the Human/Clinical Studies section of this summary. Most of these studies were phase I trials or their equivalent; therefore, the only objective of these trials was safety.

Other uses of antineoplastons suggested by the developer include treatment of conditions such as Parkinson’s disease, sickle cell anemia, and thalassemia.[15]

References

1. Burzynski SR: Efficacy of antineoplastons A10 and AS2-1. Mayo Clin Proc 74 (6): 641-2, 1999. [PUBMED Abstract]
2. Hammer MR, Jonas WB: Managing social conflict in complementary and alternative medicine research: the case of antineoplastons. Integr Cancer Ther 3 (1): 59-65, 2004. [PUBMED Abstract]
3. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977. [PUBMED Abstract]
4. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995. [PUBMED Abstract]
5. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986. [PUBMED Abstract]
6. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986. [PUBMED Abstract]
7. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986. [PUBMED Abstract]
8. Burzynski SR, Kubove E, Burzynski B: Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp Clin Res 16 (7): 361-9, 1990. [PUBMED Abstract]
9. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987. [PUBMED Abstract]
10. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987. [PUBMED Abstract]
11. Burzynski SR, Kubove E: Initial clinical study with antineoplaston A2 injections in cancer patients with five years’ follow-up. Drugs Exp Clin Res 13 (Suppl 1): 1-11, 1987. [PUBMED Abstract]
12. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995. [PUBMED Abstract]
13. Tsuda H, Sata M, Kumabe T, et al.: Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncol Rep 5 (3): 597-600, 1998 May-Jun. [PUBMED Abstract]
14. Kumabe T, Tsuda H, Uchida M, et al.: Antineoplaston treatment for advanced hepatocellular carcinoma. Oncol Rep 5 (6): 1363-7, 1998 Nov-Dec. [PUBMED Abstract]
15. Burzynski SR: Potential of antineoplastons in diseases of old age. Drugs Aging 7 (3): 157-67, 1995. [PUBMED Abstract]

In vitro studies using a variety of human cell lines have been used to assess the effectiveness of antineoplastons as antineoplastic agents. Burzynski states that antineoplaston A is species-specific because it had no therapeutic effect when the human preparation was tested on animal tumor systems. Although this finding limits the usefulness of animal model testing, the developer has suggested that a “marked” therapeutic effect was produced in a xenograft bearing human tumor tissue.[1] This claim is made only for antineoplaston A. Other formulations of antineoplastons have not been tested in animal models.

Japanese scientists have tested antineoplastons A10 and AS2-1 in vitro for cell growth inhibition and progression in several human hepatocellular cell lines.[2,3] Tests were performed in a dose-dependent manner at concentrations varying from 0.5 to 8 µg/mL for A10 and AS2-1, and growth inhibition was generally observed at 6 to 8 µg/mL. This dose level is considered excessively high and generally reflects a lack of activity. Growth inhibition of one of the cell lines (KIM-1) was observed at low concentration for a mixture of cisplatin (CDDP) and A10, but this result was probably caused by the cisplatin, which was effective at concentrations of 0.5 to 2.0 μg/mL when tested alone.[4] AS2-1 was reported to induce apoptosis in three of the cell lines at concentrations of 2 and 4 μg/mL.

Antineoplaston A10 was also shown to inhibit prolactin or interleukin-2 stimulation of mitogenesis in a dose-dependent manner in rat Nb2 lymphoma cell line. The addition of A10 (1–12 mM) to prolactin-stimulated cells inhibited growth but was reversible when A10 was removed, suggesting a cytostatic rather than cytotoxic mechanism of action. A10 also showed no toxicity in a chromium release assay. DNA synthesis was also inhibited by A10.[5]

The ability of antineoplaston A3, isolated from urine and not an analog, to inhibit the growth of the HBL-100 human breast cancer cell line in vitro was investigated in a study that also examined the toxicity of A3 in Swiss white mice. Antineoplaston A3 inhibited colony formation in a dose-dependent manner over a dose range of 0.05, 0.1, 0.2, and 0.4 µg/mL.[6]

A somewhat different approach to the use of A10 was taken by researchers in Egypt. Taking the developer’s initial ideas about the presence of A10 in the urine of patients, this study looked for the amount of A10 in the urine of 31 breast cancer patients and compared this to the amount in 17 healthy controls. They found significantly (P < .001) less A10 in the urine of breast cancer patients than in controls, suggesting that the amount of A10 in urine has a potential use as a screening tool.[7]

The same researchers looked at the immunomodulating potential of A10 by examining the inhibition of neutrophil apoptosis induced by A10 in vitro. Neutrophils from 28 breast cancer patients and 28 controls were obtained from blood samples. Urine samples were obtained from the same patients and tested for the presence of A10. Cancer patients had significantly (P < .001) higher levels of neutrophil apoptosis and significantly lower levels of A10. Neutrophil apoptosis was assessed by adding A10 at a dose of 10 µg/mL to the cellular suspensions of 42 breast cancer patients. Nontreated samples were used as controls. A10 was found to significantly inhibit neutrophil apoptosis (P < .0001).[8]

In a 2014 study done in Japan, human colon cancer cells were exposed to antineoplaston AS2-1 at high concentration and reported to normalize hypermethylation status at the promoter region of various tumor suppressor genes that are silenced in colon cancer.[9] However, this effect was noted at an AS2-1 concentration of 2 mg/mL, which is approximately four times higher than the mean steady state concentration previously reported in cancer patients treated with AS2-1,[10] and thus the clinical relevance of these findings is questionable.

Several analogs of antineoplaston A10 have been synthesized and their antineoplastic activity tested against various cell lines. These include aniline mustard analogs of antineoplaston A10 and Mannich bases of antineoplaston A10.[11,12] These analogs showed improved in vitro antitumor activity over that of antineoplaston A10.

References

1. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977. [PUBMED Abstract]
2. Tsuda H: Inhibitory effect of antineoplaston A-10 on breast cancer transplanted to athymic mice and human hepatocellular carcinoma cell lines. The members of Antineoplaston Study Group. Kurume Med J 37 (2): 97-104, 1990. [PUBMED Abstract]
3. Tsuda H, Iemura A, Sata M, et al.: Inhibitory effect of antineoplaston A10 and AS2-1 on human hepatocellular carcinoma. Kurume Med J 43 (2): 137-47, 1996. [PUBMED Abstract]
4. Tsuda H, Sugihara S, Nishida H, et al.: The inhibitory effect of the combination of antineoplaston A-10 injection with a small dose of cis-diamminedichloroplatinum on cell and tumor growth of human hepatocellular carcinoma. Jpn J Cancer Res 83 (5): 527-31, 1992. [PUBMED Abstract]
5. Wood JC, Copland JA, Muldoon TG, et al.: 3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis. Proc Soc Exp Biol Med 197 (4): 404-8, 1991. [PUBMED Abstract]
6. Lee SS, Mohabbat MO, Burzynski SR: In vitro cancer growth inhibition and animal toxicity studies of antineoplaston A3. Drugs Exp Clin Res 13 (Suppl 1): 13-6, 1987. [PUBMED Abstract]
7. Badria F, Mabed M, Khafagy W, et al.: Potential utility of antineoplaston A-10 levels in breast cancer. Cancer Lett 155 (1): 67-70, 2000. [PUBMED Abstract]
8. Badria F, Mabed M, El-Awadi M, et al.: Immune modulatory potentials of antineoplaston A-10 in breast cancer patients. Cancer Lett 157 (1): 57-63, 2000. [PUBMED Abstract]
9. Ushijima M, Ogata Y, Tsuda H, et al.: Demethylation effect of the antineoplaston AS2-1 on genes in colon cancer cells. Oncol Rep 31 (1): 19-26, 2014. [PUBMED Abstract]
10. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999. [PUBMED Abstract]
11. Choi BG, Kim OY, Chung BH, et al.: Synthesis of antineoplaston A10 analogs as potential antitumor agents. Arch Pharm Res 21 (2): 157-63, 1998. [PUBMED Abstract]
12. Hendry LB, Chu CK, Copland JA, et al.: Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes. J Steroid Biochem Mol Biol 48 (5-6): 495-505, 1994. [PUBMED Abstract]

No phase III, randomized, controlled trials of antineoplastons as a treatment for cancer have been conducted. Publications have taken the form of case reports, phase I clinical trials, toxicity studies, and phase II clinical trials. Phase I toxicity studies are the first group discussed below. The studies are categorized by the antineoplaston investigated. The second group of studies involves patients with various malignancies. Table 1 is a summary of dose regimens for all human studies. Table 2 summarizes the following clinical trials and appears at the end of this section.

Phase I Toxicity Studies for Specific Antineoplastons

The studies discussed below are phase I toxicity studies in patients with various types of malignancies, including bladder cancer, breast cancer, and leukemias. The studies are listed by the antineoplastons administered. The effect of a specific antineoplaston under investigation is difficult to ascertain because of the confounding effect of previous therapies. Unless specifically noted, all studies were conducted by the developer and his associates at his research institute.

Antineoplaston A

A 1977 article reported on 21 patients with advanced cancer or leukemia who were treated with antineoplaston A and followed for up to 9 months. Patients ranged in age from 14 to 75 years and had cancers of various types. Eight patients received no previous therapies, and 13 patients had been previously treated with chemotherapy and radiation therapy.[1] Antineoplaston A was administered intravenously (IV), intramuscularly (IM), rectally, by bladder instillation, intrapleurally, and by application to the skin. Tolerance to antineoplaston A depended on the method of administration and the type of neoplasm.

Fever and chills, the main side effects, occurred only after IV or IM administration at the beginning of treatment. Fever lasted for a few hours, followed by subnormal temperatures and lowered blood pressure. Premedication with salicylates, adrenocorticotrophic hormone, or corticosteroids were used to treat the fever or suppress it. Only patients with chronic lymphocytic leukemia, transitional cell carcinoma of the bladder, metastatic adenocarcinoma of the rectum, squamous cell carcinoma of the cervix, and synovial sarcoma reacted with fever to low doses of antineoplaston A. No severe adverse reactions were reported, even when patients were treated with very high doses of the formulation (refer to Table 1). No toxicities were reported in any patient. Platelet and white blood cell counts were elevated after a month of treatment but gradually returned to normal.

Four patients obtained complete tumor response (two cases of bladder cancer, one case of breast cancer, and one case of acute lymphocytic leukemia); four patients obtained partial tumor response (two cases of chronic lymphocytic leukemia, one case of rectosigmoid adenocarcinoma, and one case of synovial sarcoma); six patients had stable disease; and two patients discontinued treatment. There were five deaths during the study that were not attributed to antineoplaston A toxicity.[1]

Antineoplaston A10

In 1986, a toxicity study of antineoplaston A10 reported on 18 patients with 19 malignancies. Patients ranged in age from 19 to 70 years. Only patients who completed 6 or more weeks of antineoplaston A10 injections were included in the results. Six of the 18 patients received other antineoplastons in addition to A10. Four patients were administered additional drugs such as antibiotics, analgesics, and anticonvulsants.[2]

Treatment duration ranged from 52 to 640 days. No major toxicities were reported. As with the antineoplaston A study described above, chills and fever were reported in nine patients and occurred only once during the course of treatment. Other side effects noted were muscle and joint pain, abdominal pain, nausea, dizziness, and headache. Partial remission occurred in one patient with chondrosarcoma, and mixed response was obtained in three other cases. Eight patients attained stable disease, and six patients had disease progression. Ten patients discontinued treatment during the study; no reasons were reported. Ten of the 18 patients had died by the time of study publication, 4 years after the start of the study.[2]

Antineoplaston AS2-1

A 1986 study examined the toxicity of injectable antineoplaston AS2-1.[3] Twenty patients ranging in age from 17 to 74 years received antineoplaston injections for 21 malignancies. Patients were followed for 5 years. Eight patients received antineoplaston AS2-1 alone. The remaining 12 received other antineoplastons in combination with AS2-1 at different times during treatment.

Side effects associated with AS2-1 treatment included nausea and vomiting, rash, moderate blood pressure elevation, mild electrolyte imbalance, and slightly lowered white blood cell count. Although complete remission was reported in six cases (one case each of stage IV lymphocytic lymphoma, glioma, myelocytic leukemia, intraductal carcinoma of the breast, stage IA uterine cervix carcinoma, and metastatic breast carcinoma), one patient with breast carcinoma could not be considered evaluable for response because she had undergone radical mastectomy and had no measurable disease at the beginning of treatment with AS2-1; the cervical cancer patient had received prior radiation therapy, which could not be ruled out as producing a beneficial effect.

Partial remissions were reported in two cases, one each of stage III lung adenocarcinoma and chronic myelogenous leukemia in blastic phase. The patient with lung cancer had received prior radiation therapy; both patients developed disease progression and had died by the time of study publication. Seven cases were reported as having stable disease, and six patients had disease progression. Ten patients discontinued antineoplaston therapy during the study: two who were in complete remission, one in partial remission, and seven with stable disease.[3]

Antineoplastons A10 and AS2-1

A 1998 case series from Japan discussed three patients enrolled in a phase I study of antineoplastons A10 and AS2-1. Diagnoses included one case of breast cancer metastatic to the lung, one case of an anaplastic astrocytoma/thalamic glioma, and one case of large cell lung carcinoma (stage IIIB). All patients also received chemotherapy and radiation therapy.[4]

In the patient with metastatic breast cancer, A10 was added to a variety of chemotherapeutics. Rapid tumor growth was followed by the addition of antineoplaston AS2-1 and additional chemotherapy to the treatment regimen. Two weeks following this treatment, a chest x-ray showed marked reduction in size and number of metastatic tumors, and tumor sizes decreased further over the next 5 months.[4]

The patient with anaplastic astrocytoma received antineoplaston AS2-1 in addition to other chemotherapy and radiation. An MRI 6 weeks after diagnosis showed a 50% reduction in tumor diameters.[4]

The third patient with metastatic lung cancer received antineoplaston A10 in addition to chemotherapy followed by radiation. Although initially diagnosed as inoperable, after 1 month of this treatment the patient was reconsidered and underwent a middle and lower lobectomy. Follow-up showed the patient in good condition, and a computed tomography (CT) scan had confirmed no trace of tumor postoperatively.[4]

The addition of other therapies to the administration of antineoplastons is a confounding factor in assessing the results of antineoplaston treatment.

Antineoplaston AS2-5

In a 1986 study, antineoplaston AS2-5 injections were administered to 13 patients with 15 various malignancies (two patients each had two different malignancies).[5] All patients had stage IV disease and ranged in age from 20 to 64 years. Only patients who had an expected survival longer than 1 month were eligible for the study.

In addition to antineoplaston AS2-5 injections, two patients also received injections of antineoplaston AS2-1, and one patient received antineoplaston A10 after surgical intervention for a recurrence. Patients received other drugs such as antibiotics, analgesics, anti-inflammatory agents, anti-emetics, bronchial dilators, diuretics, corticosteroids, antihistamines, and uricosuric agents.

Side effects included chills and fever in two patients; swelling of the joints, bone pain, and redness of hands and feet in one patient; increase in platelet count in one patient; and an increase in plasma globulin in one patient.

Two patients were classified as having achieved complete remission, four patients were classified as having stable disease, six had disease progression, and one patient had a mixed response. During the study, eight patients discontinued treatment and were lost to follow-up, and three patients died. At the time of study publication, one patient who was given A10 after surgical intervention for recurrence was reported to be free of cancer for a period of slightly more than 4 years.[5]

Antineoplaston A2

In a 1987 study, 15 patients received antineoplaston A2 through intravenous subclavian catheter. Minor side effects were noted in four patients: fever, chills, and muscle pain. Of the 15 patients, 9 had objective response to treatment: complete tumor response in 7 and partial tumor response in 2. Five patients had stable disease, and one had disease progression. Follow-up showed three patients with complete response were cancer-free 5 years after treatment, and three patients were known to have survived for 4 years from the beginning of the study. Three patients were followed for 2 years, at which time they discontinued AS2-1 therapy. Five patients died within 2 years of the start of the study, and one patient was lost to follow-up.[6]

Antineoplaston A3

In 1987, 24 patients with 25 various malignancies participated in a retrospective nonconsecutive case series study of antineoplaston A3. Patients who had more than 6 weeks’ anticipated survival and who continued the treatment for more than 6 weeks were eligible. Antineoplaston A3 was administered through subclavian vein catheter in 23 patients. One patient received IM injections. Length of treatment was 44 to 478 days. Side effects, which occurred only once during treatment, included fever and chills in four patients, vertigo in two patients, headache in two patients, flushing of the face in one patient, nausea in one patient, and tachycardia in one patient. In addition, there was an increase in platelets, white blood cell counts, and reticulocyte counts. Tumor response was complete in five patients, and partial response was seen in five patients. Stable disease was reported in nine patients, while six patients had disease progression. One patient received radiation therapy before entering the study, so tumor response cannot be attributed solely to A3. Six patients discontinued treatment during the study; no reasons were reported.[7]

Antineoplaston A5

In 1987, patients with a variety of advanced malignancies participated in a retrospective selective case series study of antineoplaston A5. Patients ranged in age from 43 to 71 years. Only patients who were expected to survive for at least 6 weeks and who continued the treatment for at least 6 weeks were eligible. Patients received A5 through IV subclavian vein catheter. Treatment lasted from 47 to 130 days. Side effects included chills and fever in five patients, arthralgia in one patient, and premature heart beats and chest pressure in one patient. An increase in platelets and white blood cell counts were noted, as was hypertrophy of the epidermis. One patient had complete tumor response, and there were two partial responses. Stable disease was reported in seven patients. Disease progression occurred in four patients.[8]

Studies of Specific Malignancies Treated with Antineoplastons

Brain tumors

A 1995 phase I study from Japan investigated the use of antineoplastons in conjunction with radiochemotherapy and surgical resection in patients with malignant brain tumors.[9] Nine patients were diagnosed with the following brain tumors: three cases of glioblastoma, two cases of anaplastic astrocytoma, one pontine glioma, one medulloblastoma, one metastatic brain tumor, and one case of multiple brain metastases. All patients received some form of chemotherapy and radiation, with the exception of the patient with multiple brain metastases. Most patients underwent surgical resection of the tumor, with the exception of the cases of pontine glioma, multiple brain metastases, and metastatic brain tumor. Patients with glioma were treated with remission maintenance therapy. Nimustine or ranimustine was administered over intervals of several months; at 2-week intervals, the patients received interferon-beta and an antineoplaston. The study does not indicate which antineoplastons were used.[9]

One complete response was achieved in a patient with anaplastic astrocytoma. This response was seen within 4 weeks and lasted for 6 months, at which time the patient developed recurrence in another part of the brain. Two patients (one case of pontine glioma and one case of metastatic brain tumor) achieved a partial response. In two patients, no change in disease status was reported, while four patients had disease progression. Adverse effects of antineoplaston therapy included itchy skin rash, stiff finger joints, flatulence, and mild myelosuppression.[9]

A multicenter phase II study conducted by the departments of Oncology and Neurology at the Mayo Clinic attempted to assess the pharmacokinetics, toxicity, and efficacy of antineoplastons A10 and AS2-1.[10] Slow patient accrual caused the trial to be closed early. Nine adult patients with anaplastic oligoastrocytoma, anaplastic astrocytoma, or glioblastoma multiforme that had recurred after radiation therapy received escalating doses of A10 and AS2-1, to a target daily dose of 1.0 g/kg for A10 and 0.4 g/kg for AS2-1. Six of the patients experienced a second tumor recurrence, while the remaining three patients experienced their first tumor recurrence.[10]

Of the nine patients enrolled in the trial, six could be evaluated for objective tumor response in accordance with the protocol. At the time of study publication, all patients had died. The median survival time was 5.2 months and the mean survival time was 7.2 months. All patients except one died of tumor progression. The remaining patient died of sepsis related to complications from chemotherapy, which was administered after antineoplaston treatment was discontinued.[10]

None of the six assessable patients showed evidence on computed tomography (CT) scan or magnetic resonance imaging (MRI) of tumor regression associated with antineoplaston treatment; however, all nine patients showed evidence of tumor progression. Antineoplaston treatment was administered for 6 to 66 days, after which treatment was discontinued. Toxicity caused three patients to discontinue treatment and subsequent scans of these patients showed tumor progression. The mean time to treatment failure (progression or unacceptable toxicity) was 29 days.[10]

Burzynski has stated that the results of this study were inconclusive because (1) the duration of treatment was too short and (2) researchers used a dosing regimen known to be ineffective against brain tumors as large as those of the study participants.[11] However, in response, the study authors have stated that all patients in this study received treatment until either tumor progression or unacceptable toxic effects occurred.[11] The National Cancer Institute and the Burzynski Institute agreed to the dosage regimen and study plan before the study was initiated, and the tumor size in seven of the nine patients was within the specified limits.[11]

Steady-state plasma concentrations of phenylacetate and phenylacetylglutamine were measured during antineoplaston treatment in this study (refer to Table 1). High serum concentrations of phenylacetate were associated with central nervous system toxic effects.[11] Treatment-related neurologic toxicity included excessive somnolence, somnolence plus confusion, and increased frequency of underlying focal motor seizures. MRI scans also revealed increased cerebral edema in two patients. One of the nine patients had findings suggestive of a diffuse metabolic encephalopathic process; this patient and one other had antineoplaston treatment interrupted and received dexamethasone for their symptoms, which resolved within 48 hours. These patients resumed their treatment with a 25% decrease in dose and had no recurrence of neurologic toxicity. Another patient manifested persistent confusion that stopped after discontinuation of antineoplastons. Other toxicities included nausea and vomiting, headache, myalgia, and edema. These effects were reported as usually mild to moderate, except for headache, which was severe in two patients. The patient who experienced persistent confusion also developed severe cutaneous erythema, pruritus, and facial edema, at which time treatment was permanently discontinued. Another patient had treatment discontinued because of edema of the extremities and face that was unresponsive to diuretics. The edema resolved after discontinuation of antineoplastons.[10]

A phase II study also conducted by the developer and his associates at his clinic reported on 12 patients with recurrent and diffuse intrinsic brain stem glioma. Of the ten patients who were evaluable, two achieved complete tumor response, three had partial tumor response, three had stable disease, and two had progressive disease. Patients ranged in age from 4 to 29 years. Treatment with escalating intravenous bolus injections of antineoplastons A10 and AS2-1 continued for 6 months. The average dose of A10 was 11.3 g/kg daily, and the average dose of AS2-1 was 0.4 g/kg daily. Adverse effects included skin allergy, anemia, fever and hypernatremia, agranulocytosis, hypocalcemia, hypoglycemia, numbness, tiredness, myalgia, and vomiting.[12]

A similar study of 12 pediatric patients with recurrent and progressive brain tumors was conducted by the developer and his associates at his clinic. Six patients were diagnosed with pilocytic astrocytoma, four had low-grade glioma, one had grade 2 astrocytoma, and one had visual pathway glioma. Both A10 and AS2-1 were administered intravenously and later orally, for an average duration of 16 months. The average dose of A10 was 7.95 g/kg daily, and the average dose of AS2-1 was 0.33 g/kg daily. Injections were discontinued after the patients showed stable disease or partial or complete tumor response. The patients then received oral administration of A10 and AS2-1 for an average duration of 19 months. Average doses for both A10 and AS2-1 were 0.28 g/kg daily. Of the 12 patients, one was nonevaluable, three were still in the study at the time of publication, and two achieved complete response. The remaining six patients requested removal from the study.[13]

Another study by the developer and associates reported on the long-term survival of high-risk pediatric patients with central nervous system primitive neuroectodermal tumors treated with a combination of AS2-1 and A10 for an average duration of 20 months (range, 1.2–67 months). The average dose of A10 was 10.3 g/kg daily, and the average dose of AS2-1 was 0.38 g/kg daily. Of 13 patients (age range, 1–11 years) with recurrent or high-risk disease given intravenous infusions of the antineoplaston combination, six patients survived more than 5 years from the start of antineoplaston therapy, and three of these six survived more than 7 years. These three patients received no chemotherapy or radiation after their initial partial tumor resection and before treatment with antineoplastons. A complete response was seen in two of the long-term survivors.[14] Reported adverse effects included fever, granulocytopenia (reversible), and anemia.

A 2006 report from the developer and associates summarizes the results from four phase II trials of antineoplaston treatment for high-grade, recurrent, and progressive brainstem glioma. Two of the 18 patients in this report were included in a previously published study.[15] Patients were treated with a combination of AS2-1 and A10 for an average of 216 days (range, 1.53–18.36 months). Doses of A10 ranged from 0.78 g/kg daily to 19.44 g/kg daily; doses of AS2-1 ranged from 0.2 g/kg daily to 0.52 g/kg daily.

Complete responses were observed in two cases, partial response in two cases, stable disease in seven cases, and progressive disease in seven cases. Reversible anemia, the only reported adverse effect, occurred in three patients. Survival from the start of antineoplaston treatment ranged from 2.6 months to 68.4 months among the newly reported cases.[16]

Prostate cancer

A phase II clinical trial using antineoplaston AS2-1 in conjunction with low-dose diethylstilbestrol (DES) was conducted by the developer and his associates in 14 patients with hormonally refractory prostate cancer.[17] Thirteen patients were diagnosed with stage IV prostate cancer, and one patient was diagnosed with stage II prostate cancer. Ages ranged from 54 to 88 years. Previous therapy included prostatectomy, orchiectomy, radiation therapy, and treatment with DES, luteinizing hormone-releasing hormone agonists, flutamide, aminoglutethimide, and immunotherapy. Patients all showed disease progression after initial response to treatment. During the study, all 14 patients received oral AS2-1 in doses ranging from 97 to 130 mg/kg daily and DES in doses ranging from 0.01 to 0.02 mg/kg daily. Patients exhibited few significant side effects.

Overall, there were two complete remissions, three partial remissions, seven cases of stable disease, and two cases of disease progression. All patients were known to be alive 2 years after the beginning of the study. The two patients who showed disease progression discontinued AS2-1 treatment.[17] The use of DES in conjunction with AS2-1 is a confounding factor in interpreting any results of tumor response.

Hepatocellular (liver) cancer

A case report from Japan discussed two patients with advanced hepatocellular carcinoma who received antineoplaston A10 in addition to other treatments. Although both patients died—one from hemorrhagic pancreatic necroses and the other from hepatic failure brought on by esophageal varices—both appeared to tolerate A10 with few serious side effects. CT scans indicated that one patient exhibited inhibition of tumor growth and slight shrinkage of the tumor after oral administration and infusion of A10.[18]

Comment on Studies

No randomized controlled trials examining the use of antineoplastons in patients with cancer have been reported in the literature. Existing published data have taken the form of case reports or series, phase I clinical trials, and phase II clinical trials, conducted mainly by the developer of the therapy and his associates. While these publications have reported successful remissions with the use of antineoplastons, other investigators have been unable to duplicate these results [10] and suggest that interpreting effects of antineoplaston treatment in patients with recurrent gliomas may be confounded by pre-antineoplaston treatment and imaging artifacts.[11,14,16] Reports originating from Japan on the effect of antineoplaston treatment on brain and other types of tumors have been mixed, and in some Japanese studies the specific antineoplastons used are not named.[9] In many of the reported studies, several or all patients received concurrent or recent radiation therapy, chemotherapy, or both, confounding interpretability.

Table 1 summarizes the dose ranges of antineoplastons used in the studies discussed above.

Table 1. Dose Ranges for Clinical Studies of Antineoplastons

Reference	Cancer Types (No. Patients)	Antineoplaston	Dose	Administration	Treatment Duration
bi-wk = bi-weekly; d = day; DES = diethylstilbestrol; h = hour; IM = intramuscular; IV = intravenous; mo = month; No. = number; U = unit; wk = week.
aB indicates a study by Burzynski and associates.
Single-Antineoplaston Therapy
[1]Ba	Various advanced cancers or leukemia (12)	A	A was measured in units, the amount of preparation A that produces a cytostatic effect in 100 mL of breast cancer cell line MDA-MB-231 determined by the stable number of cells counted after 24 h of incubation and persisting for at least an additional 48 h. Dose differed by type of administration.	IV: Range from 0.6 U/m²/24 h to 33 U/m²/24 h daily for 1 mo. IM: Range from 0.6 U/m²/24 h to 20 U/m²/24 h for up to 8 mo bi-wk. Rectal: Range from 15 U/m²/24 h to 23 U/m²/24 h daily divided into 2 or 3 doses/12–8 h post–IM treatment. Bladder instillation: Continuous infusion of 2.3 U/m²/24 h for 3 wk. Intrapleurally: 2 U to 4 U/injection. Highest tolerated dose: IV: 33 U/m²/24 h after initial febrile reaction subsided. IM: 10 U/m²/24 h.	IV: 1 mo; IM: bi-wk for up to 8 wk Rectal: daily Bladder Instillation: 3 wk Intrapleural: once/wk
[6]Ba	Various advanced cancers (15)	A2	Highest dose: 147 mg/kg/24 h (A2 formulations: 50 mg/mL and 100 mg/mL)	IV: daily divided doses every 6 h or every 12 h.	52–358 d
[7]Ba	Various advanced cancers (23)	A3	Highest dose: 76 mg/kg/24 h		44–478 d
[8]Ba	Various advanced cancers (15)	A5	Highest dose range: 44 to 154 mg/kg/24 h	IV: daily divided doses	47–130 d
[2]Ba	Various advanced cancers (18)	A10	Highest dose range: 70.0 to 2,210.5 mg/kg/24 h	IV: gradual increase every 3–6 h from 100 mg/mL to highest dose.	52–640 d
			Typical dose range: 206.9 to 387 mg/kg/24 h
[3]	Various advanced cancers	AS2-1	Highest dose: 160 mg/kg/24 h	IV: every 6 h	38–872 d
[5]	Various advanced cancers	AS2-5	Highest dose: 167.6 mg/kg/24 h	IV: daily divided doses	41–436 d
Combinations
[17]Ba	Hormonally refractive prostate (14)	AS2-1 and DES	AS2-1 dose range: 97 to 130 mg/kg/24 h	Oral	64–425 d
			DES dose range: 0.01 to 0.02 mg/kg/24 h
[9]	Various brain tumors (9)	AS2-1/A10	Highest dose range: 7 to 10 g/d	Oral and IV
[18]	Hepatocellular (3)	AS2-1/A10 (1 patient)	3 to 10 g/d	IV	7–120 d (approx)
[10]	Recurrent glioma (9)	A10/AS2-1	Target dose: A10: 1.0 g/kg/24 h; AS2-1: 0.4 g/kg/24 h.	IV: daily divided doses	9–66 d
			Steady-state plasma concentrations at target dose: phenylacetate, 177 ± 101 μg/mL; phenylacetylglutamine: 301 ± 102 μg/mL
[13]Ba	Pediatric recurrent progressive multicentric glioma (11)	A10/AS2-1	Formulation dose: A10: 300 mg/mL; AS2-1: 80 mg/mL A10 and AS2-1	IV injection gradually increasing dose until max dose is reached. Oral administration by capsules followed.	IV: Average 16 mo; Oral: 19 mo
			Max dose range: A10: 5.29 g/kg/d to 16.13 g/kg/d
			Max dose range: AS2-1: 0.21 g/kg/d to 0.58 g/kg/d
[12]Ba	Recurrent diffuse intrinsic brain stem glioma (12)	A10/AS2-1	Formulation dose: A10: 300 mg/mL; AS2-1: 80 mg/mL	IV injection of gradually increasing dose until max dose is reached.	Average 6 mo
			A10 max dose range: 5.29 g/kg/d to 16.13 g/kg/d
			AS2-1 max dose range: 0.21 g/kg/d to 0.58 g/kg/d
[14]Ba	Primitive neuroectodermal tumor (13)	A10/AS2-1	Formulation dose: A10: 300 mg/mL; AS2-1: 80 mg/mL	IV injection of gradually increasing dose until max dose is reached.	Average 20 mo
			Average dose: A10: 10.3 g/kg/d; AS2-1: 0.38 g/kg/d
			Max dose: A10: 25 g/kg/d; AS2-1: 0.6 g/kg/d
[16]Ba	Recurrent diffuse intrinsic brain stem glioma	A10/AS2-1	Average max dose: A10: 13.37g/kg/d; AS2-1: 0.49 g/kg/d	IV injection of gradually increasing dose until max dose is reached.	Average 5 mo

Table 2 summarizes the clinical trials used in the studies discussed above.

Table 2. Antineoplastons Clinical Trials

Reference Citations	Type of Study	Type(s) of Antineoplaston	Type(s) of Cancer	No. of Patients	Strongest Benefit Reported	Concurrent Therapy
ALL = acute lymphoblastic leukemia; No. = number; NSLCC = non-small cell lung cancer; pt/pts = patient/patients.
aReported at 9 months of follow-up; patient with breast cancer had undergone radical mastectomy, radiation therapy, and chemotherapy and had subsequent metastases to ribs surgically resected prior to treatment with antineoplastons.
bOne patient with bladder cancer had surgery for removal of necrotic tumor.
cReported at 5 years of follow-up; patient with stage IA cervical cancer received prior radiation therapy; patient with breast cancer received prior radical mastectomy and had no measurable disease at the initiation of antineoplaston treatment.
dOne patient received 5-fluorouracil.
eReported at 5 years of follow-up; patient with stage II laryngeal cancer was reported to be in complete remission 730 days after beginning of treatment, but was lost to follow-up at time of study publication and his status was unknown; patient with stage III NSCLC was reported to be in complete remission after 62 days of treatment, but subsequently developed cervical lymph node recurrence and lobular breast carcinoma. Both were treated surgically and patient received antineoplaston A10; at the time of study publication, the patient was reported to have been free of both cancers for more than 4 years.
fReported at 4 years of follow-up; 10 patients had died at the time of study publication.
gPatients reported to be in complete remission more than 5 years after beginning treatment; the patient with colon cancer had undergone previous resection and was reported to have maintained complete remission during A3 treatment, however, developed recurrence with metastases after discontinuation of treatment. This patient subsequently received other antineoplaston formulations and chemotherapy.
hLength of follow-up not specified.
iReported at 2 years of follow-up; at the time of study publication, one patient was reported to have been in complete remission for 17 months and off treatment for 16 months; the other patients were reported to have been disease-free for 9 months prior to study publication and to be continuing antineoplastons but not DES.
jDES
kLength of follow-up not specified.
lSurgery, chemotherapy, radiation, and biological response modifiers (beta-interferon).
mAuthors reported on the outcome of 46 tumors for complete or partial response and provided survival information for patients.
nChemotherapy and radiation.
oSurgery, chemotherapy, radiation, and interferon.
pBoth patients had died by the time of study publication.
qChemotherapy.
rAt the time of study publication, all patients had died.
sSurgery, chemotherapy, radiation, and interferon.
tBoth patients had died by the time of study publication.
uChemotherapy.
vAt the time of study publication, all patients had died.
[1]	Nonconsecutive case series	A	Various types	21	Complete remission (2 grade III bladder cancers, stage IV breast cancer, ALL)a	Nob
[3]	Nonconsecutive case series	AS2-1 (8 pts)	Various types, most in advanced stages	20	Complete remission (stage IA cervical, intraductal breast carcinoma, stage IV lymphocytic lymphoma)c	Nod
		AS2-1 plus other antineoplaston formulations (12 pts)
[5]	Nonconsecutive case series	AS2-5 (11 pts)	Various types, advanced stages	13	Complete remission (stage II laryngeal, stage III NSCLC)e	No
		AS2-5 plus AS2-1 (2 pts)
[2]	Nonconsecutive case series	A10 (12 pts)	Various types, most in advanced stages	18	Partial remission (one case stage IB chondrosarcoma)f	No
		A10 plus other antineoplaston formulations (6 pts)
[7]	Nonconsecutive case series	A3	Various types, advanced stages	24	Complete remission (bladder carcinoma, basal cell epithelioma, and colon cancer)g	No
[8]	Nonconsecutive case series	A5	Various types, advanced stages	15	Complete remission (grade III mixed bladder cancer)h	Not specified
[17]	Consecutive case series (phase II trial)	AS2-1	Prostate cancer, hormone refractory (13 stage IV, 1 stage II)	14	Complete remission (2 pts)i	Yesj
[9]	Nonconsecutive case series/case reports	AS2-1, A10	Brain tumors	9	Partial response (1 pontine glioma, 1 metastatic brain tumor)k	Yesl
[19]	Phase I clinical trial	A10, AS2-1 (randomly chosen)	Various types, advanced stages	42m	Complete response (3 tumors)k	Yesn
[4]	Case reports	A10, AS2-1	Various types	3	Reduction in tumor size (stage IV breast, stage IIIB NSCLC)	Yeso
[18]	Case reports	A10, AS2-1	Advanced hepatocellular carcinoma	2	Slight shrinkage of tumor thrombus in the portal vein p	Yesq
[10]	Phase II clinical trial	A10, AS2-1	Recurrent brain tumor (anaplastic astrocytoma or glioblastoma multiforme)	9 (6 pts were assessable for efficacy)	Noner	No
[13]	Phase II study	A10, AS2-1	Recurrent and progressive multicentric glioma in children	12	Complete response 2	No
					Nonevaluable 1
[12]	Phase II study	A10, AS2-1	Recurrent diffuse intrinsic brain stem glioma	12	Complete response 2	No
[4]	Case reports	A10, AS2-1	Various types	3	Reduction in tumor size (stage IV breast, stage IIIB NSCLC)	Yess
[18]	Case reports	A10, AS2-1	Advanced hepatocellular carcinoma	2	Slight shrinkage of tumor thrombus in the portal veint	Yesu
[10]	Phase II clinical trial	A10, AS2-1	Recurrent brain tumor (anaplastic astrocytoma or glioblastoma multiforme)	9 (6 assessable for efficacy)	Nonev	No
[13]	Phase II study	A10, AS2-1	Recurrent and progressive multicentric glioma in children	12	Complete response 2	No
					Nonevaluable 1
[12]	Phase II study	A10, AS2-1	Recurrent diffuse intrinsic brain stem glioma	12	Complete response 2	No
[14]	Phase II study	A10, AS2-1	Primitive neuroectodermal tumor	13	Complete response 3	No
[16]	Summary of data, phase II trials	A10, AS2-1	Recurrent diffuse intrinsic brainstem glioma	18 (2 previously reported in [13])	Complete response 1 (1 previously reported)	No

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977. [PUBMED Abstract]
2. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986. [PUBMED Abstract]
3. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986. [PUBMED Abstract]
4. Tsuda H, Sata M, Kumabe T, et al.: Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncol Rep 5 (3): 597-600, 1998 May-Jun. [PUBMED Abstract]
5. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986. [PUBMED Abstract]
6. Burzynski SR, Kubove E: Initial clinical study with antineoplaston A2 injections in cancer patients with five years’ follow-up. Drugs Exp Clin Res 13 (Suppl 1): 1-11, 1987. [PUBMED Abstract]
7. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987. [PUBMED Abstract]
8. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987. [PUBMED Abstract]
9. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995. [PUBMED Abstract]
10. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999. [PUBMED Abstract]
11. Burzynski SR: Efficacy of antineoplastons A10 and AS2-1. Mayo Clin Proc 74 (6): 641-2, 1999. [PUBMED Abstract]
12. Burzynski SR, Lewy RI, Weaver RA, et al.: Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic brain stem glioma: a preliminary report. Drugs R D 4 (2): 91-101, 2003. [PUBMED Abstract]
13. Burzynski SR, Weaver RA, Lewy RI, et al.: Phase II study of antineoplaston A10 and AS2-1 in children with recurrent and progressive multicentric glioma : a preliminary report. Drugs R D 5 (6): 315-26, 2004. [PUBMED Abstract]
14. Burzynski SR, Weaver RA, Janicki T, et al.: Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1. Integr Cancer Ther 4 (2): 168-77, 2005. [PUBMED Abstract]
15. Burzynski SR, Conde AB, Peters A, et al.: A retrospective study of antineoplastons A10 and AS2-1 in primary brain tumors. Clin Drug Investig 18 (1): 1-10, 1999.
16. Burzynski SR, Janicki TJ, Weaver RA, et al.: Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma. Integr Cancer Ther 5 (1): 40-7, 2006. [PUBMED Abstract]
17. Burzynski SR, Kubove E, Burzynski B: Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp Clin Res 16 (7): 361-9, 1990. [PUBMED Abstract]
18. Kumabe T, Tsuda H, Uchida M, et al.: Antineoplaston treatment for advanced hepatocellular carcinoma. Oncol Rep 5 (6): 1363-7, 1998 Nov-Dec. [PUBMED Abstract]
19. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995. [PUBMED Abstract]

Adverse effects of antineoplaston therapy have ranged from mild and short-lasting symptoms to severe neurologic toxicity necessitating discontinuation of therapy in some patients.[1]

Table 3 summarizes the adverse effects in the referenced studies.

Table 3. Adverse Effects

Adverse Effect	Reference
aThe most severe adverse effects occurred in this study, which reported neurologic toxic effects such as excessive somnolence, somnolence plus confusion, and increased frequency of underlying focal motor seizures; increased cerebral edema; and persistent confusion. In addition, the study reported myalgia, severe cutaneous erythema, pruritus, and anasarca of the extremities and face.
Anemia	[2,3]
Blood pressure elevation	[4,5]
Dizziness or vertigo	[6,7]
Excess abdominal gas	[4,8]
Fever and chills	[2,5–7,9–11]
General malaise with and without anorexia	[2,4]
Headaches	[1,4,6,7]
Hypocalcemia and hypercalcemia	[2,5]
Increased thickness of epidermis associated with skin peeling and faster-than-usual growth of nails	[11]
Maculopapular or itchy skin rash	[2,4,5,8]
Mild myelosuppression	[5,8,12]
Nausea and vomiting	[1,2,5–7]
Neurocortical toxicity, severe	[1]a
Numbness	[2]
Palpitations, tachycardia, or pressure in the chest with irregular heartbeat	[4,11,1,7]
Peripheral edema, facial edema, cerebral edema	[1,4]
Swelling, pain, or stiffness of small joints	[4,8,10,11]

References

1. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999. [PUBMED Abstract]
2. Burzynski SR, Lewy RI, Weaver RA, et al.: Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic brain stem glioma: a preliminary report. Drugs R D 4 (2): 91-101, 2003. [PUBMED Abstract]
3. Burzynski SR, Janicki TJ, Weaver RA, et al.: Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma. Integr Cancer Ther 5 (1): 40-7, 2006. [PUBMED Abstract]
4. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995. [PUBMED Abstract]
5. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986. [PUBMED Abstract]
6. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986. [PUBMED Abstract]
7. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987. [PUBMED Abstract]
8. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995. [PUBMED Abstract]
9. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977. [PUBMED Abstract]
10. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986. [PUBMED Abstract]
11. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987. [PUBMED Abstract]
12. Burzynski SR, Weaver RA, Janicki T, et al.: Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1. Integr Cancer Ther 4 (2): 168-77, 2005. [PUBMED Abstract]

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the “levels of evidence“) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

Antineoplaston therapy has been studied as a complementary and alternative therapy for cancer. Case reports, phase I toxicity studies, and some phase II clinical studies examining the effectiveness of antineoplaston therapy have been published. For the most part, these publications have been authored by the developer of the therapy, Dr. S.R. Burzynski, in conjunction with his associates at the Burzynski Clinic. Although these studies often report remissions, other investigators have not been successful in duplicating these results. (Refer to the Human/Clinical Studies section of this summary for more information.) The evidence for use of antineoplaston therapy as a treatment for cancer is inconclusive. Controlled clinical trials are necessary to assess the value of this therapy.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis of integrative, alternative, and complementary therapies for cancer, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of antineoplastons in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Antineoplastons. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/antineoplastons-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389311]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What are antineoplastons?

   Antineoplastons are chemical compounds found in urine and blood. They are made up of amino acids (the building blocks of protein) and peptides (compounds made of two or more amino acids). When used in research, antineoplastons are made from chemicals in the laboratory.

2. How are antineoplastons given?

   Antineoplastons are given by mouth or by injection (shot).

3. Have any laboratory or animal studies been done using antineoplastons?

   In laboratory studies, tumor cells are used to test a substance to find out if it is likely to have any anticancer effects. In animal studies, tests are done to see if a drug, procedure, or treatment is safe and effective in animals. Laboratory and animal studies are done before a substance is tested in people.

   Laboratory and animal studies have tested the effects of antineoplastons in laboratory experiments. See the Laboratory/Animal/Preclinical Studies section of the PDQ health professional summary on Antineoplastons for information on laboratory and animal studies done using antineoplastons.

4. Have any studies of antineoplastons been done in people?

   No phase III, randomized, controlled trials of antineoplastons as a treatment for cancer have been done. Phase I clinical trials, phase II clinical trials, and case reports have been reported.

   Cancer patients have been studied and treated with antineoplastons at the clinic where antineoplastons were first made. A few trials and case studies have been done outside of the clinic. Cancer types studied include breast, bladder, cervical, prostate, liver, lung, brain, leukemia, and lymphoma.

   Some patients in the studies received standard treatments and the antineoplastons. In those cases, it is not known if responses and side effects were caused by antineoplaston therapy, the other treatments, or both.

   (See the PDQ health professional summary on Antineoplastons for information on clinical trial results.)

5. Have any side effects or risks been reported from antineoplastons?

   Side effects from antineoplastons include the following:

   • Anemia (lower than normal number of red blood cells).
   • Abnormal levels of calcium in the blood.
   • High blood pressure.
   • Irregular heartbeat.
   • Headaches.
   • Dizziness.
   • Fever and chills.
   • Nausea and vomiting.
   • Anorexia.
   • Gas.
   • Dry or itchy skin rash.
   • Numbness.
   • Tiredness or sleepiness.
   • Swelling caused by excess fluid in body tissues.
   • Swelling, pain, or stiffness in small joints.
   • Confusion.
   • Seizures.
   • Swelling near the brain.

   The most severe side effects from antineoplastons occurred in a phase II trial in brain tumor patients that included sleepiness, confusion, seizures, and swelling near the brain.

6. Are antineoplastons approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment?

   Antineoplastons are not approved by the U. S. Food and Drug Administration (FDA) for the prevention or treatment of any disease. The FDA gave the developer permission to run clinical trials of antineoplaston therapy at his own clinic. In the United States, antineoplaston therapy can be obtained only in clinical trials at the developer’s clinic.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the use of antineoplastons in the treatment of people with cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Antineoplastons. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/antineoplastons-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389445]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of 714-X as a treatment for people with cancer. The summary includes a brief history of the development of 714-X; a review of laboratory, animal, and clinical research; and possible side effects of 714-X use.

This summary contains the following key information:

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

714-X was developed more than 30 years ago in a privately funded laboratory in Quebec, Canada, where it continues to be produced. The primary component of 714-X is naturally derived camphor that is chemically modified by the introduction of ammonia chloride moiety. Numerous trace elements have also been found in batches of 714-X.[1,2]

The private laboratory markets 714-X worldwide through its own distribution company.[1] In Canada, this compound is legally available on compassionate grounds only and must be obtained through a physician. [1,2] Because the production of 714-X is not regulated, there is no guarantee that rigorous quality control procedures are followed to ensure manufacturing consistency or product safety. The U.S. Food and Drug Administration (FDA) has not approved 714-X for use as a treatment for cancer or any other medical condition. In addition, the FDA has placed an import ban on 714-X.

Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. The IND application process is confidential, and information about an IND can be disclosed only by the applicants. No investigators have announced that they have applied for an IND to study 714-X as a treatment for cancer.

714-X is usually administered by injection near lymph nodes in the groin. It can also be administered nasally, using a nebulizer. Nasal administration is used for follow-up treatment and for the treatment of patients with lung or oral cancers. The producers of 714-X do not recommend intravenous or oral administration. A usual treatment cycle consists of a single daily injection for 21 days followed by a 2- to 3-day rest period. Between 6 and 12 treatment cycles have been recommended by the producers. The producers of 714-X advise a 50% reduction in dose for pediatric patients who weigh less than 30 kg (66 lb).[1,2]

It has been suggested that 714-X is more effective if administered early in the disease process and before surgery, chemotherapy, or radiation therapy. The producers claim, however, that 714-X can also be used in conjunction with conventional treatments. It has been further suggested that the use of alcohol and treatment with nonconventional therapies such as shark or bovine (i.e., cow) cartilage (and other angiogenesis inhibitors), vitamin B₁₂ supplements, and vitamin E supplements be avoided during 714-X treatment.[1,2]

References

1. 714X Technical Data. Rock Forest, Canada: CERBE Distribution, Inc. Available online. Last accessed April 7, 2016.
2. Kaegi E: Unconventional therapies for cancer: 6. 714-X. Task Force on Alternative Therapeutic of the Canadian Breast Cancer Research Initiative. CMAJ 158 (12): 1621-4, 1998. [PUBMED Abstract]

Little documentation exists regarding the development of 714-X and its mechanism of action. It appears to have been developed in the 1960s on the basis of earlier studies that used a high-magnification dark-field microscope called a somatoscope.[1,2] With dark-field microscopes, researchers are able to examine living cells in samples of fresh blood and tissue taken from healthy individuals and individuals with serious diseases, including cancer.

The developer of 714-X states that the study of living cells (as opposed to the dead cells examined with a conventional light microscope or an electron microscope) led to the theory that microorganisms distinct from bacteria, viruses, and fungi exist normally in the blood and play a role in the development of cancer. These microorganisms, which are called somatids, are said to exist in multiple forms, some of which appear only in individuals affected by degenerative or malignant diseases. The forms associated with degenerative diseases or cancer reportedly secrete growth hormones and toxic substances that disrupt normal cellular metabolism and damage the immune system. In this compromised environment, cells that have become cancerous are allowed to proliferate. It was also suggested that cancer cells trap nitrogen, thereby depriving the rest of the body of the nitrogen needed for normal cellular metabolism. In addition, it was proposed that cancer cells secrete a toxic substance, cocancerogenic K factor, that further inhibits the immune system.[1,2]

The producers of 714-X state that cancer can be diagnosed, and its development and spread can be predicted, by studying blood samples with the somatoscope. No evidence has been published in peer-reviewed scientific journals to support these proposals, and the somatidian theory of cancer development is not widely accepted.

714-X reportedly works by protecting, stabilizing, and reactivating the patient’s immune system so that the body can defend itself against cancer cell growth and metastasis.[1–3] 714-X is said to accomplish this, in part, by helping to increase the “fluidity” of lymph.[3] In addition, the camphor component of 714-X is purportedly attracted to cancer cells, where the added nitrogen is released, thus preventing malignant cells from depleting the nitrogen required by normal cells (including immune system cells) for proper metabolism and function.[1,2]

References

1. Kaegi E: Unconventional therapies for cancer: 6. 714-X. Task Force on Alternative Therapeutic of the Canadian Breast Cancer Research Initiative. CMAJ 158 (12): 1621-4, 1998. [PUBMED Abstract]
2. Hess DJ: Germ warfare: the case for bacteria as carcinogen. In: Hess DJ: Can Bacteria Cause Cancer? Alternative Medicine Confronts Big Science. New York University Press, 1997, pp 7-48.
3. 714X Technical Data. Rock Forest, Canada: CERBE Distribution, Inc. Available online. Last accessed April 7, 2016.

No laboratory study of the safety and/or effectiveness of 714-X has been published in scientific literature. A few animal experiments have been conducted, but the results of these experiments have not been reported in peer-reviewed scientific journals. The animal studies utilized a lymphosarcoma tumor model in rats and lymphoma tumor models in dogs and cows. 714-X was not found to be effective as an anticancer treatment in these studies.[1]

A few laboratory and animal studies have suggested that camphor is able to enhance the response of the immune system to vaccine administration and to increase the sensitivity of tumor cells to radiation therapy.[2–6] In one series of studies, investigators used camphor vapors as a conditioned stimulus to promote an immune response.[2–5] These studies demonstrated that mice exposed to camphor vapors at the same time they received an antilymphoma vaccine showed decreased growth of transplanted lymphoma cells and increased survival when they were re-exposed to camphor vapors plus the vaccine or to camphor vapors alone, in comparison with mice re-exposed to only the vaccine.[2,3] These investigators also demonstrated that exposure to camphor vapors led to an increase in natural killer cells [4] and an increase in tumor-specific cytotoxic T cells.[5] Another study reported that breast adenocarcinoma cells transplanted under the skin of mice responded better to local radiation therapy when small doses of camphor were administered by intraperitoneal injection before the radiation treatment.[6]

Finally, researchers examined nine compounds, including a camphor-containing compound, for their ability to inhibit the activity of estrone sulfatase, an enzyme involved in the production of estrone, which is a precursor of the various forms of estrogen. Estrogens are thought to promote the growth of hormone-dependent breast cancer cells. The camphor-containing compound showed only modest inhibition of estrone sulfatase activity in human breast cancer cells grown in vitro.[7]

References

1. Kaegi E: Unconventional therapies for cancer: 6. 714-X. Task Force on Alternative Therapeutic of the Canadian Breast Cancer Research Initiative. CMAJ 158 (12): 1621-4, 1998. [PUBMED Abstract]
2. Hiramoto RN, Hiramoto NS, Rish ME, et al.: Role of immune cells in the Pavlovian conditioning of specific resistance to cancer. Int J Neurosci 59 (1-3): 101-17, 1991. [PUBMED Abstract]
3. Ghanta VK, Hiramoto NS, Solvason HB, et al.: Conditioning: a new approach to immunotherapy. Cancer Res 50 (14): 4295-9, 1990. [PUBMED Abstract]
4. Ghanta VK, Hiramoto NS, Solvason HB, et al.: Conditioned enhancement of natural killer cell activity, but not interferon, with camphor or saccharin-LiCl conditioned stimulus. J Neurosci Res 18 (1): 10-5, 1987. [PUBMED Abstract]
5. Ghanta VK, Hiramoto NS, Soong SJ, et al.: Conditioning of the secondary cytotoxic T-lymphocyte response to YC8 tumor. Pharmacol Biochem Behav 50 (3): 399-403, 1995. [PUBMED Abstract]
6. Goel HC, Roa AR: Radiosensitizing effect of camphor on transplantable mammary adenocarcinoma in mice. Cancer Lett 43 (1-2): 21-7, 1988. [PUBMED Abstract]
7. Howarth NM, Purohit A, Reed MJ, et al.: Estrone sulfonates as inhibitors of estrone sulfatase. Steroids 62 (4): 346-50, 1997. [PUBMED Abstract]

No clinical studies (i.e., clinical trials, case series, or case reports) have been reported in peer-reviewed scientific journals to support the safety or the efficacy of 714-X. A number of anecdotal reports and testimonials have been published in newspapers and other nonmedical literature. The producers of 714-X state that they have tried to document the long-term experience of patients treated with this compound, but they have encountered difficulty in obtaining information from patients and their health care providers.[1]

References

1. Kaegi E: Unconventional therapies for cancer: 6. 714-X. Task Force on Alternative Therapeutic of the Canadian Breast Cancer Research Initiative. CMAJ 158 (12): 1621-4, 1998. [PUBMED Abstract]

It is claimed that 714-X is nontoxic in the manufacturer-recommended dose range.[1,2] The only described side effects of treatment with this compound are local redness, tenderness, and swelling at injection sites.[2]

References

1. 714X Technical Data. Rock Forest, Canada: CERBE Distribution, Inc. Available online. Last accessed April 7, 2016.
2. Kaegi E: Unconventional therapies for cancer: 6. 714-X. Task Force on Alternative Therapeutic of the Canadian Breast Cancer Research Initiative. CMAJ 158 (12): 1621-4, 1998. [PUBMED Abstract]

To assist readers in evaluating the results of human/clinical studies of integrative, alternative, and complementary therapies for cancer, a scoring system has been devised that allows studies of individual treatments to be ranked according to the strength of their evidence (i.e., their level of evidence). Not all studies, however, are given a level of evidence score. To be eligible, a study must:

Evidence from studies that do not meet these requirements is considered extremely weak. In addition to scoring individual studies, a summary of the evidence is usually made.

Because no study of the use of 714-X in humans has been reported in a peer-reviewed scientific journal, no level of evidence analysis is possible for this treatment. Therefore, at this time, the use of 714-X as a treatment for cancer cannot be recommended outside the context of well-designed clinical trials.

For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of 714-X in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ 714-X. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/714-x-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389421]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is 714-X?

   The main ingredient in 714-X is made by combining chemicals with camphor, a natural substance that comes from the wood and bark of the camphor tree. Ammonia and salt are added to camphor to make 714-X.

2. What is the history of the discovery and use of 714-X as a complementary and alternative treatment for cancer?

   714-X was developed in the 1960s in Canada, where it is still being made. Patients in Canada can get 714-X only from a doctor, for compassionate use (giving a treatment to patients before it is approved, because they have a life-threatening disease and there is no drug or other therapy to treat the disease). 714-X is used in Mexico and some western European countries. It is not approved by the US Food and Drug Administration (FDA) for use in the United States (see Question 8).

3. What is the theory behind the claim that 714-X is useful in treating cancer?

   The development of 714-X was based on the theory that there are tiny living things in the blood called somatids. According to this theory, some types of somatids are found only in the blood of people who have cancer or other serious diseases. These types of somatids are said to make growth hormones that cause cells to grow without control. The makers of 714-X state that by looking at the number and type of somatids in the blood, doctors can see if cancer is starting to form or can diagnose cancer and predict where the cancer will spread.

   The theory states that cancer cells trap nitrogen needed by normal cells and make a toxic substance that weakens the immune system. 714-X is reported to help the body fight cancer cells in these ways:

   • The camphor in 714-X is said to prevent cancer cells from taking nitrogen from the body’s normal cells.
   • 714-X is also said to help the immune system by increasing the flow of lymph, the colorless fluid that travels through the body carrying white blood cells that help fight infection and disease.

   Some research studies are published in scientific journals. Most scientific journals have experts who review research reports before they are published, to make sure that the evidence and conclusions are sound. This is called peer review. Studies published in peer-reviewed scientific journals are considered to be better evidence. No studies have been published in peer-reviewed scientific journals to support the theory of somatids in the development of cancer. Research on the use of 714-X as a cancer treatment is discussed in Question 5 and Question 6.

4. How is 714-X administered?

   714-X is usually given by injection near the lymph nodes in the groin. In some patients with lung or oral cancer, 714-X can be sprayed into the nose using a nebulizer (a device that turns liquid into a fine spray). The makers of 714-X do not recommend injecting it into a vein (intravenously) or taking it by mouth.

   The makers of 714-X suggest the following:

   • 714-X is more effective if given early in the disease, before chemotherapy or radiation therapy is begun.
   • 714-X can be used along with conventional treatments.
   • Vitamin B ₁₂ supplements, vitamin E supplements, shark cartilage, and alcohol should not be used during treatment with 714-X.
5. Have any preclinical (laboratory or animal) studies been conducted using 714-X?

   Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be useful in humans. Animal tumor models are used to learn how a cancer may progress and to test new treatments. These preclinical studies are done before any testing in humans is begun.

   No laboratory studies of the safety and/or effectiveness of 714-X have been published in a peer-reviewed scientific journal. A few animal experiments have been done, but the results of these experiments have not been reported in scientific journals. The animal studies used a lymphosarcoma tumor model in rats and lymphoma tumor models in dogs and cows. 714-X was not found to be effective against cancer in these studies.

6. Have any clinical trials (research studies with people) of 714-X been conducted?

   No clinical trials or other studies with cancer patients have been published in peer-reviewed scientific journals to support the safety or effectiveness of 714-X. A number of anecdotal reports (incomplete descriptions of the medical and treatment history of one or more patients) and testimonials (personal reports from people who claim to have been helped or cured by the product) have been published in newspapers and other nonmedical literature. The National Cancer Institute (NCI) reviewed the records of some cancer patients who used 714-X. This review was done to decide if NCI should begin a clinical trial of the product. Not enough information was available to support recommending a trial.

7. Have any side effects or risks been reported from 714-X?

   The makers of 714-X claim that it is not harmful to humans. The reported side effects of treatment with 714-X are redness, tenderness, and swelling at the injection site.

8. Is 714-X approved by the FDA as a cancer treatment in the United States?

   The FDA has not approved 714-X for use in the United States.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the use of 714-X in the treatment of people with cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ 714-X. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/714-x-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389214]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of PC-SPES as a treatment in people with cancer. The summary includes a brief history of PC-SPES research, the results of clinical trials, and possible adverse effects of PC-SPES. Included in this summary is a discussion of the contamination of PC-SPES and its withdrawal from avenues of distribution.

This summary contains the following key information:

Note: Separate PDQ summaries on Prostate Cancer, Nutrition, and Dietary Supplements and Prostate Cancer Treatment are also available.

PC-SPES is a patented herbal mixture that was sold as a dietary supplement and used as a complementary and alternative medicine (CAM) treatment for prostate cancer. It is a combination of the following eight herbs:

With the exception of saw palmetto, the herbs in PC-SPES have been used individually or in combination in Traditional Chinese Medicine (TCM) for a variety of health problems, including those of the prostate, for hundreds of years.[1,2]

PC-SPES is an herbal product that resulted from a collaboration between a chemist at the New York Medical College in Valhalla, New York, and a Chinese herbalist and doctor of TCM in China. Their idea was to combine TCM with the scientific techniques of Western laboratory research. In the United States, a series of in vitro and in vivo laboratory studies was started on the mixture of herbs used in TCM specially formulated to treat prostate problems. Researchers published the results of these studies, which showed promising anticancer activity from PC-SPES.[3–11]

Considerable research has been conducted on the anticancer properties of the eight individual botanicals in PC-SPES.

Baikal skullcap (Scutellaria baicalensis)—Chinese name huang qin—contains baicalin and wogonin, two active flavones. Baicalin converts to baicalein, which is another active flavone. In vitro, baicalin and baicalein inhibit cell growth of AD LNCaP and JCA-1 AI human prostate cancer cell lines,[12,13] as well as inducing apoptosis in human LNCaP cells.[14] Baicalin also shows antimutagenic and antioxidant activity in vitro as well as free radical scavenging ability.[15–20]

Licorice (Glycyrrhiza glabra or Glycyrrhiza uralensis)—Chinese name gan cao—contains the very active flavonoid licochalcone A, which has demonstrated in vitro estrogenic activity.[21] This botanical shows a broad range of anticancer activity in vitro. It enhances the cytotoxicity of commonly used anticancer drugs and induces apoptosis in MCF-7 human breast cancer and HL-60 promyelocytic leukemia cell lines.[21–24]

Reishi mushroom (Ganoderma lucidum [Curtis: fr.] Karst.)—Chinese name ling zhi— has been shown to aid in the recovery of leukocyte counts in irradiated mice in a dose-dependent manner. It contains the polysaccharide G009, which has demonstrated antioxidant behavior against HL-60 cells in vitro and dose-dependent inhibition of lipid peroxidation in rat brain cells in vitro.[25–29]

Isatis (Isatis indigotica)—Chinese name da qing ve—contains active agents in each part of the plant.[2] TCM has different names for the medicinals coming from the leaf, stem, and root and uses these plant products for different purposes. Indirubin, an active ingredient, and its analogs have demonstrated inhibition of cyclin-dependent kinases in human mammary carcinoma cell line MCF-7 in vitro.[30]

Ginseng (Panax ginseng or Panax pseudoginseng var. notoginseng)—Chinese name tianqi—contains ginsenosides and saponins. Of the 30 ginsenosides that have been isolated from Panax ginseng, only the 20(S)-protopanaxadiol type R3 has inhibited cell growth and suppressed PSA expression, androgen receptor and 5-alpha-reductase activity, and PCNA production in vitro.[31–33]

Chrysanthemum flowers (Dendranthema morifolium)—Chinese name ju hua—contain triterpene diols and triols. Arnidiol exhibited cytotoxicity in vitro against 58 of the 60 human cancer cell lines developed by the National Cancer Institute (NCI) Developmental Therapeutics Program.[34]

The botanical rabdosia rubescens (Isodon rubescens)—Chinese name dong ling cao—has two very active agents, oridonin and rubesencin b. Oridonin inhibits DNA synthesis in vitro,[1] and rubesencin b inhibited cell growth in cancer cell lines in vitro and in a mouse model.[35]

Saw palmetto (Serenoa repens) is the only botanical in PC-SPES that is not used in TCM. There is strong evidence from human trials that saw palmetto has some activity against benign prostatic hypertrophy (BPH), including improved urine flow and less erectile dysfunction when compared with placebo or finasteride. S. repens also exhibits antiestrogenic activity in placebo-controlled BPH trials. In LNCaP cells, S. repens produced apoptosis in vitro.[36–40]

Exactly how PC-SPES works in the body is still unknown. The presence of adulterants and varying amounts of the active agents in each lot of PC-SPES complicates the interpretation of any results from studies that might lead to an explanation of its mechanisms of action. More studies of the individual components of the mixture and testing of a standard formulation that is free of adulterants are needed before any conclusions can be reached about the level of cytotoxicity, antineoplasticity, or estrogenicity of PC-SPES.

The National Center for Complementary and Integrative Health (NCCIH) stopped funding to studies of PC-SPES after the drug contamination was detected and made public, although the laboratory studies were later resumed.

Although manufacturers are selling supplements purporting to be substitutes, the only company that had a license from the patent holder to manufacture PC-SPES is no longer in business, and the product cannot be legally manufactured in the United States without the patent holder’s permission. PC-SPES is not legally available in the United States.

References

1. Huang KC, Williams WM: The Pharmacology of Chinese Herbs. 2nd ed. CRC Press, 1998.
2. Zhu YP: Chinese Materia Medica: Chemistry, Pharmacology, and Applications. Harwood Academic, 1998.
3. Halicka HD, Ardelt B, Juan G, et al.: Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC SPES. Int J Oncol 11: 437-48, 1997.
4. Hsieh T, Chen SS, Wang X, et al.: Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 42 (3): 535-44, 1997. [PUBMED Abstract]
5. Chenn S: In vitro mechanism of PC SPES. Urology 58 (2 Suppl 1): 28-35; discussion 38, 2001. [PUBMED Abstract]
6. Hsieh TC, Wu JM: Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol 20 (3): 583-8, 2002. [PUBMED Abstract]
7. Chen S, Ruan Q, Bedner E, et al.: Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Prolif 34 (5): 293-304, 2001. [PUBMED Abstract]
8. Kubota T, Hisatake J, Hisatake Y, et al.: PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo . Prostate 42 (3): 163-71, 2000. [PUBMED Abstract]
9. Darzynkiewicz Z, Traganos F, Wu JM, et al.: Chinese herbal mixture PC SPES in treatment of prostate cancer (review). Int J Oncol 17 (4): 729-36, 2000. [PUBMED Abstract]
10. Marks LS, DiPaola RS, Nelson P, et al.: PC-SPES: herbal formulation for prostate cancer. Urology 60 (3): 369-75; discussion 376-7, 2002. [PUBMED Abstract]
11. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001. [PUBMED Abstract]
12. Huerta S, Arteaga JR, Irwin RW, et al.: PC-SPES inhibits colon cancer growth in vitro and in vivo. Cancer Res 62 (18): 5204-9, 2002. [PUBMED Abstract]
13. Schwarz RE, Donohue CA, Sadava D, et al.: Pancreatic cancer in vitro toxicity mediated by Chinese herbs SPES and PC-SPES: implications for monotherapy and combination treatment. Cancer Lett 189 (1): 59-68, 2003. [PUBMED Abstract]
14. Chan FL, Choi HL, Chen ZY, et al.: Induction of apoptosis in prostate cancer cell lines by a flavonoid, baicalin. Cancer Lett 160 (2): 219-28, 2000. [PUBMED Abstract]
15. Okita K, Li Q, Murakamio T, et al.: Anti-growth effects with components of Sho-saiko-to (TJ-9) on cultured human hepatoma cells. Eur J Cancer Prev 2 (2): 169-75, 1993. [PUBMED Abstract]
16. Matsuzaki Y, Kurokawa N, Terai S, et al.: Cell death induced by baicalein in human hepatocellular carcinoma cell lines. Jpn J Cancer Res 87 (2): 170-7, 1996. [PUBMED Abstract]
17. Kimura Y, Matsushita N, Okuda H: Effects of baicalein isolated from Scutellaria baicalensis on interleukin 1 beta- and tumor necrosis factor alpha-induced adhesion molecule expression in cultured human umbilical vein endothelial cells. J Ethnopharmacol 57 (1): 63-7, 1997. [PUBMED Abstract]
18. Hsieh TC, Lu X, Chea J, et al.: Prevention and management of prostate cancer using PC-SPES: a scientific perspective. J Nutr 132 (11 Suppl): 3513S-3517S, 2002. [PUBMED Abstract]
19. Ikezoe T, Chen SS, Heber D, et al.: Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest. Prostate 49 (4): 285-92, 2001. [PUBMED Abstract]
20. Hsu SL, Hsieh YC, Hsieh WC, et al.: Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules. Eur J Pharmacol 425 (3): 165-71, 2001. [PUBMED Abstract]
21. Gao Z, Huang K, Yang X, et al.: Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochim Biophys Acta 1472 (3): 643-50, 1999. [PUBMED Abstract]
22. Armanini D, Bonanni G, Palermo M: Reduction of serum testosterone in men by licorice. N Engl J Med 341 (15): 1158, 1999. [PUBMED Abstract]
23. Rafi MM, Vastano BC, Zhu N, et al.: Novel polyphenol molecule isolated from licorice root (Glycrrhiza glabra) induces apoptosis, G2/M cell cycle arrest, and Bcl-2 phosphorylation in tumor cell lines. J Agric Food Chem 50 (4): 677-84, 2002. [PUBMED Abstract]
24. Rafi MM, Rosen RT, Vassil A, et al.: Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 20 (4): 2653-8, 2000 Jul-Aug. [PUBMED Abstract]
25. Wang ZY, Nixon DW: Licorice and cancer. Nutr Cancer 39 (1): 1-11, 2001. [PUBMED Abstract]
26. Bao XF, Wang XS, Dong Q, et al.: Structural features of immunologically active polysaccharides from Ganoderma lucidum. Phytochemistry 59 (2): 175-81, 2002. [PUBMED Abstract]
27. Chen WC, Hau DM, Lee SS: Effects of Ganoderma lucidum and krestin on cellular immunocompetence in gamma-ray-irradiated mice. Am J Chin Med 23 (1): 71-80, 1995. [PUBMED Abstract]
28. Hsu HY, Lian SL, Lin CC: Radioprotective effect of Ganoderma lucidum (Leyss. ex. Fr.) Karst after X-ray irradiation in mice. Am J Chin Med 18 (1-2): 61-9, 1990. [PUBMED Abstract]
29. Lee JM, Kwon H, Jeong H, et al.: Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum. Phytother Res 15 (3): 245-9, 2001. [PUBMED Abstract]
30. Marko D, Schätzle S, Friedel A, et al.: Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 84 (2): 283-9, 2001. [PUBMED Abstract]
31. Liu WK, Xu SX, Che CT: Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 67 (11): 1297-306, 2000. [PUBMED Abstract]
32. Yun TK, Lee YS, Lee YH, et al.: Anticarcinogenic effect of Panax ginseng C.A. Meyer and identification of active compounds. J Korean Med Sci 16 (Suppl): S6-18, 2001. [PUBMED Abstract]
33. Surh YJ, Na HK, Lee JY, et al.: Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax ginseng C.A. Meyer. J Korean Med Sci 16 (Suppl): S38-41, 2001. [PUBMED Abstract]
34. Ukiya M, Akihisa T, Tokuda H, et al.: Constituents of Compositae plants III. Anti-tumor promoting effects and cytotoxic activity against human cancer cell lines of triterpene diols and triols from edible chrysanthemum flowers. Cancer Lett 177 (1): 7-12, 2002. [PUBMED Abstract]
35. Jing JY, Reed E: Preliminary study of the effect of selected Chinese natural drugs on human ovarian cancer cells. Oncol Rep 2: 571-5, 1995.
36. Marks LS, Hess DL, Dorey FJ, et al.: Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. Urology 57 (5): 999-1005, 2001. [PUBMED Abstract]
37. Di Silverio F, D’Eramo G, Lubrano C, et al.: Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur Urol 21 (4): 309-14, 1992. [PUBMED Abstract]
38. Di Silverio F, Monti S, Sciarra A, et al.: Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate 37 (2): 77-83, 1998. [PUBMED Abstract]
39. Iguchi K, Okumura N, Usui S, et al.: Myristoleic acid, a cytotoxic component in the extract from Serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells. Prostate 47 (1): 59-65, 2001. [PUBMED Abstract]
40. Wilt T, Ishani A, Mac Donald R: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev (3): CD001423, 2002. [PUBMED Abstract]

In 1997, the herbal formula for PC-SPES was patented in the United States.[1] A company, BotanicLab (Brea, California), was formed to produce, distribute, and sell the product. PC-SPES was sold through the BotanicLab website (the website was taken down after PC-SPES was recalled) and through selected distributors. Anecdotal information about the product and its positive effects was widely circulated on the Internet through websites that informed prostate cancer patients about new developments in treatment. At the same time, the published papers were being read by the scientific community, and the findings were presented at various conferences. As a result, clinicians and researchers began looking at PC-SPES as one of the first viable treatments to come out of the alternative medicine community.

The manufacturing process for PC-SPES has been described by the manufacturer as follows: extracts of raw plant material were obtained from the specified plants, which were grown in particular geographic regions in China and harvested at certain times of the year to reduce the natural variation inherent in any biological product. The extracts were shipped to the United States, where high-performance liquid chromatography (HPLC) was used to monitor the key active compounds—which are believed to be directly related to the clinical effects—for batch-to-batch reproducibility. Activity-related biomarkers were kept in a constant concentration from lot to lot. A commercial testing laboratory (Truesdail Laboratory; Tustin, California) was used to guarantee that each batch was free from contamination with heavy metals, pesticides, microorganisms and products, and prescription drugs. Each lot was standardized by an anticancer bioassay for an effective dose of 50% in vitro inhibition of cell growth using human LNCaP cells for androgen-dependent (AD) prostate cancer and DU-145 cells for androgen-independent (AI) prostate cancer. The powder was then encapsulated, bottled, labeled, and sterilized at the BotanicLab facility.[2]

In 2001, allegations that PC-SPES contained the synthetic estrogen diethylstilbestrol (DES) started to appear on e-mail listservs used by prostate cancer patients and in online newsletters. Prostate cancer patients who were taking PC-SPES noticed that their recent medication was not as effective as the previous batches.[3] A sample of PC-SPES submitted to a testing laboratory by BotanicLab in August 2001 found no DES. BotanicLab posted the letter from the laboratory on their website, claiming that PC-SPES contained no DES. However, in other tests of six different lots of PC-SPES received from two different sources in August 2001, Rocky Mountain Instrumental Laboratory found varying amounts of DES in three lots. More tests done by the California Department of Health Services in February 2002 did not find DES but did find warfarin, a prescription drug used as a blood thinner.[4]

The presence of a synthetic estrogen such as DES was suspected early in the clinical use of PC-SPES after reports in the literature discussed the mixture’s estrogen-like ability to lower prostate-specific antigen (PSA) levels in AD prostate cancer patients. In addition, the side effects of treatment were similar to those of estrogen therapy. [5–7] In one study, patients who showed the most response to PC-SPES were also those who were the most responsive to DES.[8,9] The same study also attempted to find out whether DES or similar compounds were present in PC-SPES. Transcriptional activation assays in yeast strain PL3 Saccharomyces cerevisiae using an ethanolic extract of PC-SPES showed estrogenic activity similar to 1nM estradiol. In addition, ovariectomized CD-1 mice showed substantially increased uterine weights. HPLC, gas chromatography, and mass spectrometry did not reveal the presence of DES but rather that of a compound with similar chemical characteristics. The authors of the report concluded that PC-SPES contains estrogenic compounds that are distinct from DES or other synthetic estrogens.[9]

A definitive evaluation of PC-SPES analyzed specific lots of PC-SPES capsules manufactured from 1996 to 2001.[10] In addition to using HPLC to isolate, identify, and quantify the synthetic drugs and active phytoestrogens, this study also identified components using proton nuclear magnetic resonance, gas chromatography/mass spectrometry, and mass spectra analysis. Tests showed the presence of the synthetic drugs indomethacin (a nonsteroidal anti-inflammatory drug not previously reported in the literature or found in other testing), DES, and warfarin. Testing was also done for concentrations of the two naturally occurring phytosterols, licochalcone A and baicalin. Test results indicated a history of rising and falling levels of contamination by the three synthetic drugs and a recent rise in the naturally occurring phytochemicals in PC-SPES. Lots of PC-SPES manufactured in 1996 through mid-1999 contained indomethacin ranging from 1.07 mg/g to 13.19 mg/g and DES ranging from 107.28 µg/g to 159.27 µg/g and were 2 to 6 times more antineoplastic and up to 50 times more estrogenic than lots manufactured after the spring of 1999. In vitro testing of ethanolic extracts of PC-SPES against LNCaP, PC-3, and DU-145 prostate cancer cell lines showed a decrease in both antineoplasticity and estrogenicity in lots of PC-SPES manufactured in June 1998 through August 2001, which correlated with the amount of DES and indomethacin contamination.[10] Another in vitro test of suspected lots of PC-SPES manufactured from 2000 to 2001 also showed the presence of DES.[11]

Although the laboratory testing showed that certain lots of the mixture contained indomethacin, warfarin, and DES, the amount of DES present may not have accounted for all of the estrogenic effect of PC-SPES. There is some evidence that the mixture acts differently from DES at the molecular level.[12,13] In addition, its anticancer effects on both AI prostate cancer and AD prostate cancer may point to a mechanism other than estrogen-like activity.[10,14,15] The in vitro activity of PC-SPES against cancer cells other than prostate also gives rise to the speculation that its estrogen-like qualities might not account for all of the mixture’s anticancer activity.[16,17]

References

1. Chen S, Wang X: Herbal Composition for Treating Prostate Carcinoma. US Patent 5665393. September 9, 1997. Washington, DC: US Patent and Trademark Office, 1997. Available online. Last accessed April 12, 2016.
2. Marks LS, DiPaola RS, Nelson P, et al.: PC-SPES: herbal formulation for prostate cancer. Urology 60 (3): 369-75; discussion 376-7, 2002. [PUBMED Abstract]
3. PSA Rising: Prostate Cancer Survivor News, Info and Support. New York, NY: PSA Rising, 2005. Available online. Last accessed April 12, 2016.
4. Ko R, Wilson RD, Loscutoff S: PC-SPES. Urology 61 (6): 1292, 2003. [PUBMED Abstract]
5. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001. [PUBMED Abstract]
6. Oh WK, George DJ, Kantoff PW: Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: report of four cases. Cancer 94 (3): 686-9, 2002. [PUBMED Abstract]
7. de la Taille A, Hayek OR, Burchardt M, et al.: Role of herbal compounds (PC-SPES) in hormone-refractory prostate cancer: two case reports. J Altern Complement Med 6 (5): 449-51, 2000. [PUBMED Abstract]
8. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001. [PUBMED Abstract]
9. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998. [PUBMED Abstract]
10. Sovak M, Seligson AL, Konas M, et al.: Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 94 (17): 1275-81, 2002. [PUBMED Abstract]
11. Guns ES, Goldenberg SL, Brown PN: Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol. Can J Urol 9 (6): 1684-8; discussion 1689, 2002. [PUBMED Abstract]
12. Chen S, Ruan Q, Bedner E, et al.: Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Prolif 34 (5): 293-304, 2001. [PUBMED Abstract]
13. Bonham M, Arnold H, Montgomery B, et al.: Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma. Cancer Res 62 (14): 3920-4, 2002. [PUBMED Abstract]
14. Reynolds T: Contamination of PC-SPES remains a mystery. J Natl Cancer Inst 94 (17): 1266-8, 2002. [PUBMED Abstract]
15. Malkowicz SB: The role of diethylstilbestrol in the treatment of prostate cancer. Urology 58 (2 Suppl 1): 108-13, 2001. [PUBMED Abstract]
16. Huerta S, Arteaga JR, Irwin RW, et al.: PC-SPES inhibits colon cancer growth in vitro and in vivo. Cancer Res 62 (18): 5204-9, 2002. [PUBMED Abstract]
17. Schwarz RE, Donohue CA, Sadava D, et al.: Pancreatic cancer in vitro toxicity mediated by Chinese herbs SPES and PC-SPES: implications for monotherapy and combination treatment. Cancer Lett 189 (1): 59-68, 2003. [PUBMED Abstract]

Before the discovery of diethylstilbestrol (DES), warfarin, and indomethacin contamination, PC-SPES appeared to have some efficacy as an antineoplastic agent in laboratory and animal studies. These studies are presented below. Due to the fact that there was no standardization of the composition of PC-SPES or any knowledge of the amount of contamination of each lot used in testing, it is difficult to interpret the data from these studies.

In one study that attempted to measure the effects of the whole PC-SPES mixture versus that of individual herbs of PC-SPES on prostate-specific antigen (PSA) expression and cell growth, LNCaP cells were treated with ethanol extracts of PC-SPES and each of the eight herbs. The PC-SPES mixture reduced cell growth by 72% to 80%, while Dendranthema morifolium (Ramat.) Tzvelev (synonym Chrysanthemum morifolium) (chrysanthemum) produced the highest reduction of the herb group at 85%. Panax pseudoginseng var. notoginseng Hoo & tseng (Synonym Panax notoginseng [Burkill] F.H.Chen) was next at 80.9% reduction, followed by Glycyrrhiza uralensis Fisch ex DC. (73%). The lowest reduction in cell growth was exhibited by Serenoa repens (Bartr.) Small (14.5%). Scutellaria baicalensis Georgi, Serenoa repens, and Glycyrrhiza uralensis lowered PSA expression, but each of the other herbs increased PSA expression. The ability of individual herbs to reduce PSA expression was not uniform, but the PC-SPES mixture as a whole exhibited a uniform response. The varying results with the individual herbs and the positive response of the cells (i.e., increased cytotoxicity and reduced PSA expression) to the aggregate PC-SPES mixture may suggest that the botanicals in PC-SPES work in concert and that no individual herb can account for the overall effects of the mixture.[1]

In other studies, PC-SPES was found to inhibit clonal growth in three human prostate cancer cell lines: LNCaP, PC-3, and DU-145. Cell cycle analysis showed cell cycle arrest at the G2 phase.[2] Cell proliferation and reduced clonogenicity were observed in cancer cell lines other than those of prostate cancer: human breast carcinoma lines MCF-7 and T47-D, SK-N-MC neuroepithelioma, COLO 38 melanoma, U937 histiomonocytic lymphoma, and HL-60 and MOLT-4 leukemias. Cytotoxic and cytostatic effects of PC-SPES were common to all tumor cell lines tested.[3]

In another study evaluating regulation of PSA expression and androgen receptor (AR) activity, LNCaP prostate cancer cell lines showed downregulation of both proliferating cell nuclear antigen (PCNA) and PSA expression. PSA changes occurred concurrently with the decrease of PCNA. The results suggest that PC-SPES modulates cell growth by changing PCNA expression and may decrease PSA levels indirectly by suppressing AR expression.[4]

None of the studies above indicated lot number or year of manufacture of the PC-SPES used. Therefore, it is not possible to assess the amount of contamination of the mixtures used in the studies or whether the mixtures used were not in fact contaminated.

A 1998 study that evaluated estrogenic activity of extracts of PC-SPES, ginseng (Panax ginseng C.A. Meyer), saw palmetto, DES, and estrone (estradiol-17 beta) in vitro reported on the estrogenic response of ovariectomized CD-1 mice to PC-SPES extract as well as the response to PC-SPES capsules in eight prostate cancer patients who had received previous therapy. [5] This study used four samples of PC-SPES ordered in separate purchases from BotanicLab. No lot numbers were supplied in the study. Lot numbers from October 1996 through July 1998 were later tested for contamination and had DES levels of 114.74 μg/g to 159.27 μg/g, as well as the highest detected levels of indomethacin of the PC-SPES lots tested.[6] In vitro tests of PC-SPES extract or estradiol showed estrogenic activity similar to 1 nM estradiol on estrogen receptor Y253 yeast strain. Transcriptional activation assays in yeast strain PL3 Saccharomyces cerevisiae with ethanolic extract of PC-SPES exhibited estrogen-like effects. In the eight prostate cancer patients, serum testosterone concentrations decreased during the use of PC-SPES and increased within 3 weeks after treatment was discontinued. PSA levels decreased in all eight patients. Side effects in all eight patients were similar to those seen after treatment with estrogen: breast tenderness and loss of libido. One patient had superficial venous thrombosis. In addition to baicalin, two other compounds purified from PC-SPES, isoliquiritigenin and wogonin, have been shown to reduce PSA levels and downregulate AR.[7]

By incorporating PC-SPES into the rat diet, researchers conducting an in vivo study showed antitumor effects using a Dunning R3327 rat prostate cancer model. Levels of 0.05% and 0.025% of dietary PC-SPES were fed to the rats over a 6-week period. No toxicity was seen, nor was there a difference in the food intake of the rats during this time. Pulmonary tumors were induced by intradermal injections of MAT-LyLu cells, which are particularly resistant to many forms of treatment. Tumor incidence was inhibited in a dose-dependent manner, and the rate of tumor growth showed the same dose-dependent response.[8,9]

In another study, which used male BNX nu/nu immunodeficient nude mice, PC-SPES was also administered orally, but in suspension. The mice received 300 rad of whole-body irradiation, after which they were inoculated with either PC-3 or DU-145 prostate cancer cell lines. Treatment with PC-SPES began the day after injection. Results showed that PC-SPES suppressed the growth of DU-145 tumors compared with tumor growth in the control group. Cytological analysis showed apoptosis in the treated group that was not apparent in the control group.[10]

In two other studies, clinical studies of patients were initiated along with in vitro and in vivo research. The results of these two patient groups are discussed in the Human/Clinical Trials section of this summary. The first study, preceding more extensive research, examined in vitro activity of PC-SPES against LNCaP, LNCaP-bcl-2, PC-3, and DU-145 cells lines. Results showed that PC-SPES was active in suppressing both hormone-sensitive and hormone-insensitive prostate cancer cell lines. In the subsequent study, research was conducted in vitro on the ability of PC-SPES to induce apoptosis in androgen-independent (AI) prostate cancer cell lines, and in vivo on the effect of oral PC-SPES on the growth of xenografted PC-3 tumors in immunodeficient male mice. Mice in the treatment arm—in which treatment was started 1 week after implantation—showed a significant decrease in tumor weight when compared with mice in the control arm. PC-SPES showed activity against both androgen-sensitive and AI prostate cancer in the patients and suppressed tumor growth in AI tumors in mice.[10–12] In both studies, the patients were given capsules manufactured between 1996 and 1999, a time when contamination levels of DES were highest.[6]

Another study in rats demonstrated that PC-SPES (one lot contaminated with DES and one lot without DES) caused some decrease in the activity of a liver enzyme involved in drug metabolism (CYP3A).[13]

References

1. Hsieh TC, Lu X, Chea J, et al.: Prevention and management of prostate cancer using PC-SPES: a scientific perspective. J Nutr 132 (11 Suppl): 3513S-3517S, 2002. [PUBMED Abstract]
2. Kubota T, Hisatake J, Hisatake Y, et al.: PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo . Prostate 42 (3): 163-71, 2000. [PUBMED Abstract]
3. Ko R, Wilson RD, Loscutoff S: PC-SPES. Urology 61 (6): 1292, 2003. [PUBMED Abstract]
4. Hsieh TC, Wu JM: Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol 20 (3): 583-8, 2002. [PUBMED Abstract]
5. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998. [PUBMED Abstract]
6. Sovak M, Seligson AL, Konas M, et al.: Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 94 (17): 1275-81, 2002. [PUBMED Abstract]
7. Chen S, Gao J, Halicka HD, et al.: Down-regulation of androgen-receptor and PSA by phytochemicals. Int J Oncol 32 (2): 405-11, 2008. [PUBMED Abstract]
8. Tiwari RK, Geliebter J, Garikapaty VP, et al.: Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 14 (4): 713-9, 1999. [PUBMED Abstract]
9. Geliebter J, Mittelman A, Tiwari RK: PC-SPES and prostate cancer. J Nutr 131 (1): 164S-166S, 2001. [PUBMED Abstract]
10. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000. [PUBMED Abstract]
11. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001. [PUBMED Abstract]
12. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999. [PUBMED Abstract]
13. Wadsworth T, Poonyagariyagorn H, Sullivan E, et al.: In vivo effect of PC-SPES on prostate growth and hepatic CYP3A expression in rats. J Pharmacol Exp Ther 306 (1): 187-94, 2003. [PUBMED Abstract]

One published randomized cross-over study of patients with androgen-independent (AI) prostate cancer who initially received either 960 mg of PC-SPES 3 times a day or 3 mg of diethylstilbestrol (DES) once a day before crossing over to the other regimen; when disease progression occurred, there were reports of data demonstrating the presence and levels of adulterants in the four lots of PC-SPES used in this trial. The lots were manufactured by BotanicLab (Brea, California). The study was halted and chemical analyses of the lots were performed. The analyses showed that all four lots of PC-SPES contained amounts of DES ranging from 0.1 μg/g to 32.7μg/g, and that one lot contained varying amounts of ethinyl estradiol. The authors concluded that the presence of these adulterants rendered their results inconclusive.[1]

Several nonrandomized clinical studies published between 1999 and 2003 described the results of clinical trials conducted before adulterants had been conclusively identified in PC-SPES lots and before it was known that there was significant variation in naturally occurring active agents, such as baicalein and licochalcone-A, in the lots. These studies, many of which enrolled small numbers of patients, did not identify the source of the lots that were used in the trials, nor did they identify where patients acquired PC-SPES.

In addition to the confounding effects of adulterants on the clinical trial results discussed below, the fact that an optimal dose of PC-SPES remains undetermined and that dose varies among these studies makes it difficult to compare their findings.

In a retrospective study of 23 consecutive patients with AI disease, charts were evaluated for patients’ responses to PC-SPES and the occurrence of any toxicity. There is no report of where the patients acquired their PC-SPES or what lots were used. Patients were all seen between February and November in 1999. Patients ranged in age from 51 to 88 years, with a median age of 70 years. All had previous initial androgen ablation for a period of 6 months to 144 months. Ten patients had received chemotherapy, 13 had not. More than half of the patients with AI showed a post-therapy prostate-specific antigen (PSA) decline of 50% or greater. Median time to PSA progression was 6 months. The side effects were similar to those of estrogen therapy (gynecomastia and impotence). Other side effects were nausea/vomiting and diarrhea and to a lesser extent, allergic reactions, leg cramps, and leg swelling.[2]

In a prospective clinical trial of 16 men with stage D3 metastatic prostate cancer in which all patients had failed therapy and had disease progression, the effects of PC-SPES on pain, quality of life, and side effects were assessed. Previous therapy was either orchidectomy or a luteinizing hormone–releasing agonist with or without antiandrogen. Hormonal therapy was continued throughout the trial to avoid the known withdrawal effect of antiandrogen on PSA levels. There was a significant decrease in pain scores such that the 14 patients on analgesics required an average of 40% less analgesics while taking PC-SPES. PC-SPES treatment was associated with improved function and emotional and physical well-being. PSA levels declined significantly after PC-SPES therapy (>50%). Side effects were breast tenderness, deep venous thrombosis, and mild dyspepsia.[3,4]

In a study of 70 patients, 37 with androgen-dependent (AD) disease and 33 with AI disease, the AD cohort was treated with PC-SPES only after an initial treatment with prostatectomy, radiation, cryotherapy, and/or hormonal therapy. Median duration of PSA response was greater than 57 weeks. All patients in the AD cohort had PSA declines within a range of 80% to 100%, and two patients with bone metastases showed improvement on radiographic analysis. Within the AI cohort, 54% (19 of 35) had a PSA decrease of greater than 50%, with median time to nadir of 10 weeks and a median duration of 18 weeks. Eight of the 16 patients who had received ketoconazole therapy prior to PC-SPES also obtained a decrease of greater than 50% in their PSA values. Testosterone levels within the AD group decreased to castrate levels (<50 ng/mL) in 94% of patients (31 of 33), and libido (25 of 25) and potency (15 of 15) were lost in all patients who entered the study. Side effects were hot flashes, gynecomastia/gynecodynia, and thromboembolic effects in 3 of 70 patients. Although the results of this trial were promising for the treatment of both AI and AD prostate cancer, it is not possible to assess what was responsible for these effects. This trial used PC-SPES from one single lot, but the published study does not indicate the lot number. The research was completed before 2000. No attempt was made to assess the possible contamination of the product.[3,5]

A prospective clinical series assessed the ability of PC-SPES to lower serum PSA levels in 33 prostate cancer patients. The patients had either refused conventional therapy or had failed previous cryosurgery, radiation therapy, and/or hormonal therapy. No overt signs of disease progression were found in any of the patients. At 2 months, PSA levels had decreased by a mean of 52% in 27 of the 31 patients and had increased in two patients. Of the five patients who had hormone–refractory disease, all had decreased serum PSA levels.[3,6]

In a continuation of the previous study, a total of 69 patients with either AI or AD disease were separated into three study groups. Group one (n = 43) had undergone previous therapy, including hormonal; group two (n = 22) developed AI after treatment; and group three (n = 4) had not undergone previous therapy. The study assessed PC-SPES activity in suppressing PSA levels. Patients were given three capsules of PC-SPES 3 times per day. PSA levels and side effects were observed for 24 months.[7]

In group one, 82% of patients (32 of 39) had a decrease in PSA levels, with 20 patients having a decrease of greater than 50% at 2 months’ follow-up; the decrease lasted for 24 months in two patients. In group two (AI patients), 90% (19 of 21) had a decrease in PSA at their 2-month follow-up, with 66% (14 of 21) having a decrease of greater than 50% in PSA levels. At 24 months, two patients had a decrease of 20% to 50% in pretreatment PSA levels. In group three, 50% (2 of 4) had a decrease of greater than 50% in PSA levels at 2 months, and the remaining two patients had an increase at 2 and 6 months. Eighty-two percent of study patients had a decreased PSA level after 2 months of therapy. Side effects included nipple tenderness (42%), gynecomastia (8%), hot flashes, and deep venous thrombosis.[7] In both Germany and the United Kingdom, PC-SPES–like formulations have been studied. A phase I trial of PC-Spes2 in the United Kingdom encountered tolerability problems due to diarrhea.[8]

References

1. Oh WK, Kantoff PW, Weinberg V, et al.: Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 22 (18): 3705-12, 2004. [PUBMED Abstract]
2. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001. [PUBMED Abstract]
3. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001. [PUBMED Abstract]
4. Pfeifer BL, Pirani JF, Hamann SR, et al.: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85 (4): 481-5, 2000. [PUBMED Abstract]
5. Small EJ, Frohlich MW, Bok R, et al.: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18 (21): 3595-603, 2000. [PUBMED Abstract]
6. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999. [PUBMED Abstract]
7. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000. [PUBMED Abstract]
8. Shabbir M, Love J, Montgomery B: Phase I trial of PC-Spes2 in advanced hormone refractory prostate cancer. Oncol Rep 19 (3): 831-5, 2008. [PUBMED Abstract]

Adverse effects of PC-SPES treatment were similar to those of hormonal drugs. The percentages indicate the approximate low-to-high range of side effects reported in the studies. It is difficult to compile accurate numbers from all studies reporting side effects because they are not consistently reported. Some studies concatenated categories of side effects, some did not report specific numbers or percentages, and some reported a few side effects while not reporting others. The following references indicate the studies from which the percentages come:

References

1. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001. [PUBMED Abstract]
2. Oh WK, George DJ, Kantoff PW: Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: report of four cases. Cancer 94 (3): 686-9, 2002. [PUBMED Abstract]
3. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000. [PUBMED Abstract]
4. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999. [PUBMED Abstract]
5. Small EJ, Frohlich MW, Bok R, et al.: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18 (21): 3595-603, 2000. [PUBMED Abstract]
6. Pfeifer BL, Pirani JF, Hamann SR, et al.: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85 (4): 481-5, 2000. [PUBMED Abstract]
7. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998. [PUBMED Abstract]
8. Moyad MA, Pienta KJ, Montie JE: Use of PC-SPES, a commercially available supplement for prostate cancer, in a patient with hormone-naive disease. Urology 54 (2): 319-23; discussion 323-4, 1999. [PUBMED Abstract]

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

The lack of consistent composition of PC-SPES due to varying concentrations of adulterants makes it difficult to determine the effects of PC-SPES in humans; therefore, no level of evidence analysis is possible for this treatment. At this time, the use of PC-SPES as a treatment for cancer cannot be recommended outside the context of well-designed clinical trials.

For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of PC-SPES in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ PC-SPES. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/pc-spes-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389352]

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This cancer information summary provides an overview of the use of various foods and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. This summary includes the history of research, reviews of laboratory and animal studies, and results of clinical trials on the following foods or dietary supplements:

Each type of dietary supplement or food will have a dedicated section in the summary, and new topics will be added over time. Note: A summary on PC-SPES is also available.

Prostate cancer is the most common noncutaneous cancer affecting men in the United States. On the basis of data from 2018 to 2021, it is estimated that 12.8% of U.S. men will be diagnosed with prostate cancer during their lifetimes.[1]

Many studies suggest that complementary and alternative medicine (CAM) use is common among prostate cancer patients, and the use of vitamins, supplements, and specific foods is frequently reported by these patients. For example, the Prostate CAncer Therapy Selection (PCATS) study was a prospective study that investigated men’s decision-making processes about treatment following a diagnosis of local-stage prostate cancer. As part of this study, patients completed surveys regarding CAM use, and more than half of the respondents reported using one or more CAM therapies, with mind-body modalities and biologically based treatments being the most commonly used.[2]

International studies have reported similar findings. A Swedish study published in 2011 found that, overall, participants with prostate cancer were more likely to have used supplements than were healthy population-based control subjects. Supplement use was even more common among patients with the healthiest dietary patterns (e.g., high consumption of fatty fish and vegetables).[3] In a Canadian study, CAM use was reported among 39% of recently diagnosed prostate cancer patients, and the most commonly used forms of CAM were herbals, vitamins, and minerals. Within those categories, saw palmetto, vitamin E, and selenium were the most popular. The two most popular reasons for choosing CAM were to boost the immune system and to prevent recurrence.[4] According to another Canadian study, approximately 30% of survey respondents with prostate cancer reported using CAM treatments. In that study, vitamin E, saw palmetto, and lycopene were most commonly used.[5] A British study published in 2008 indicated that 25% of prostate cancer patients used CAM, with the most frequently reported interventions being low-fat diets, vitamins, and lycopene. The majority of CAM users in this study cited improving quality of life and boosting the immune system as the main reasons they used CAM.[6]

Vitamin and supplement use has also been documented in men at risk of developing prostate cancer. One study examined vitamin and supplement use in men with a family history of prostate cancer. At the time of the survey, almost 60% of the men were using vitamins or supplements. One-third of the men were using vitamins and supplements that were specifically marketed for prostate health or chemoprevention (e.g., selenium, green tea, and saw palmetto).[7] A 2004 study examined herbal and vitamin supplement use in men who attended a prostate cancer screening clinic. Men who attended the screening clinic completed questionnaires about supplement use. Of the respondents, analysis revealed that a reported 70% used multivitamins, and 21% used herbal supplements.[8]

A meta-analysis published in 2008 reviewed studies that reported vitamin and mineral supplement use among cancer survivors. The results showed that, among prostate cancer survivors, vitamin or mineral use ranged from 26% to 35%.[9]

Although many prostate cancer patients use CAM treatments, they do not all disclose their CAM use to treating physicians. According to results from the PCATS study, 43% of patients discussed their CAM use with a health care professional.[2] In two separate studies, 58% of respondents told their doctors about their CAM usage.[4,6]

How do prostate cancer patients decide whether or not to use CAM? A qualitative study published in 2005 described results from interviews with prostate cancer patients. The study identified differences in thinking patterns between CAM users and nonusers and suggested that no specific theme led patients to CAM; instead, patients were directed by a combination of ideas. For example, the perception of CAM as harmless was associated with the belief that conventional medicine resulted in many negative side effects.[10] Results of a 2003 qualitative study suggested that decision making about CAM treatments by prostate cancer patients depended on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.[11]

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be considered an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

For more information, see Prostate Cancer Prevention.

References

1. National Cancer Institute: SEER Stat Fact Sheets: Prostate. Bethesda, Md: National Cancer Institute. Available online. Last accessed October 22, 2024.
2. McDermott CL, Blough DK, Fedorenko CR, et al.: Complementary and alternative medicine use among newly diagnosed prostate cancer patients. Support Care Cancer 20 (1): 65-73, 2012. [PUBMED Abstract]
3. Westerlund A, Steineck G, Bälter K, et al.: Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. Ann Oncol 22 (4): 967-72, 2011. [PUBMED Abstract]
4. Eng J, Ramsum D, Verhoef M, et al.: A population-based survey of complementary and alternative medicine use in men recently diagnosed with prostate cancer. Integr Cancer Ther 2 (3): 212-6, 2003. [PUBMED Abstract]
5. Boon H, Westlake K, Stewart M, et al.: Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristics. Urology 62 (5): 849-53, 2003. [PUBMED Abstract]
6. Wilkinson S, Farrelly S, Low J, et al.: The use of complementary therapy by men with prostate cancer in the UK. Eur J Cancer Care (Engl) 17 (5): 492-9, 2008. [PUBMED Abstract]
7. Bauer CM, Ishak MB, Johnson EK, et al.: Prevalence and correlates of vitamin and supplement usage among men with a family history of prostate cancer. Integr Cancer Ther 11 (2): 83-9, 2012. [PUBMED Abstract]
8. Barqawi A, Gamito E, O’Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004. [PUBMED Abstract]
9. Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 26 (4): 665-73, 2008. [PUBMED Abstract]
10. Singh H, Maskarinec G, Shumay DM: Understanding the motivation for conventional and complementary/alternative medicine use among men with prostate cancer. Integr Cancer Ther 4 (2): 187-94, 2005. [PUBMED Abstract]
11. Boon H, Brown JB, Gavin A, et al.: Men with prostate cancer: making decisions about complementary/alternative medicine. Med Decis Making 23 (6): 471-9, 2003 Nov-Dec. [PUBMED Abstract]

Overview

This section contains the following key information:

• Calcium is required for certain metabolic functions such as vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion.
• Major sources of calcium in the United States are food and dietary supplements.
• Studies of the association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products.
• Some studies suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.
• Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk.

General Information and History

Calcium, the most abundant mineral in the body, is found in some foods, added to others, available as a dietary supplement, and present in some medicines (such as antacids). Calcium is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion, although less than 1% of total body calcium is needed to support these critical metabolic functions.[1] Serum calcium is very tightly regulated and does not fluctuate with changes in dietary intake; the body uses bone tissue as a reservoir for, and source of, calcium to maintain constant concentrations of calcium in blood, muscle, and intercellular fluids.[1]

The major sources of calcium in the U.S. population are food and dietary supplements.[2] According to recent National Health and Nutrition Examination Survey data, U.S. adults obtain 38% of their dietary calcium from milk and milk products, such as yogurt and cheese.[3] Nondairy sources include vegetables, such as Chinese cabbage, kale, and broccoli. Spinach provides calcium, but its bioavailability is poor. Most grains do not have high amounts of calcium unless they are fortified; however, they contribute calcium to the diet because they contain small amounts of calcium, and people consume them frequently. Foods fortified with calcium include many fruit juices and drinks, tofu, and cereals. In the United States, dietary supplements, including calcium supplements, are commonly used to prevent chronic diseases, including cancer.[1] Mean dietary calcium intakes for males aged 1 year and older ranged from 871 to 1,266 mg/day depending on life stage group (i.e., infant, adolescent, or adult). About 43% of the U.S. population uses dietary supplements containing calcium, which increases calcium intake by about 330 mg/day among supplement users.[1,2]

To evaluate the association between calcium intake and prostate cancer mortality and morbidity, it may be important to assess objective, biological markers of calcium, include data that account for nutritional and supplemental calcium intake, and control for other confounding factors. However, studies of the association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products. Although more than half of the U.S. population uses vitamin and mineral supplements (at an annual cost of over $11 billion), few studies include supplement use in the association of disease risk, including prostate cancer or mortality rates.[1,2] For more information, see Prostate Cancer Prevention.

Companies distribute calcium as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of calcium as a treatment for cancer.

Preclinical/Animal Studies

In vitro studies

Prostate cancer cells were treated with bovine milk, almond milk, soy milk, casein, or lactose in a 2011 study. Treatment with bovine milk resulted in growth stimulation of LNCaP prostate cancer cells. Growth of prostate cancer cells was not affected by treatment with soy milk, and treatment with almond milk resulted in growth inhibition.[4]

In vivo studies

One study investigated the effects of dietary calcium on prostate tumor progression in LPB-Tag transgenic mice. The animals consumed low (0.2%) or high (2.0%) calcium diets and were sacrificed at age 5, 7, or 9 weeks. Tumor weight and progression were similar in mice that were fed low- and high-calcium diets.[5]

A 2012 study examined the impact of dietary vitamin D and calcium on prostate cancer growth in athymic mice. The mice were injected with human prostate cancer cells and were randomly assigned to receive specific diets (e.g., high calcium/vitamin D or normal calcium/no vitamin D). The mice that received the normal calcium/vitamin D-deficient diet exhibited significantly greater (P < .05) tumor volumes than did mice that received the other diets.[6]

Human Studies

Epidemiological studies

Several epidemiological studies have found an association between high intakes of calcium, dairy foods, or both, and an increased risk of developing prostate cancer.[7–9] However, others have found only a weak relationship, no relationship, or a negative association between calcium intake and prostate cancer risk.[10–14] A 2022 prospective cohort study examined 28,737 men who belong to the Seventh-day Adventist church. These men had wide ranges of dairy and calcium intake. The study found that a higher intake of dairy foods or other potentially causal factors associated with dairy intake were associated with a higher risk of prostate cancer. This was not true for nondairy sources of calcium. On the basis of these studies, interpretation of the evidence is complicated by the difficulty of separating the effects of dairy products from the effects of calcium. Additionally, earlier epidemiological studies had several limitations. The association between dairy foods, calcium intake, and prostate cancer was limited to evidence from self-reported food frequency questionnaires of nutritional sources of calcium, with a focus on dairy foods.[14–16] Competing risk factors, such as other major nutrients in dairy (i.e., total fats, saturated fats, calories) and concomitant and confounding factors (i.e., age, body mass index, steroid hormones, and other metabolic events in the causal pathway) were not accounted for. Additionally, no objective markers of calcium, such as serum calcium, were obtained from these cohorts. Observational studies overall, however, suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.[11,12,17–19] Another analysis of 886 prostatectomy patients found an increased risk of being diagnosed with more aggressive disease in men with higher calcium intakes.[20] The hazard of disease recurrence after surgical treatment was increased in men with both very low and high calcium intakes. Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk and to elucidate potential biological mechanisms.

Interventional studies

In a randomized clinical trial published in 2005, 672 men received either 3 g of calcium carbonate (1,200 mg calcium) or placebo daily for 4 years and were followed for 12 years. During the first 6 years of the study, there were significantly fewer prostate cancer cases in the calcium group compared with the placebo group. However, this difference was no longer statistically significant at the 10-year evaluation.[21]

Meta-analyses

A meta-analysis published in 2005 reported that there may be an association between increased risk of prostate cancer and greater consumption of dairy products and calcium.[22]

A 2008 meta-analysis reviewed 45 observational studies and found no evidence of a link between dairy products and risk of prostate cancer.[23] A meta-analysis of cohort studies published between 1996 and 2006 found a positive association between milk and dairy product consumption and risk of prostate cancer.[24]

In a recent review, the U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews, conducted meta-analyses using Mantel-Haenszel fixed effects models for overall cancer incidence, cardiovascular disease incidence, and all-cause mortality. Vitamin D and/or calcium supplementation showed no overall effect on cancer incidence and mortality, including prostate cancer.[3] In a meta-analysis of the association of calcium without the coadministration of vitamin D, a reduced risk of prostate cancer was observed, although there were only a few events.[25]

In 2007, the World Cancer Research Fund/American Institute for Cancer Research reported that there was probable evidence that diets high in calcium increase the risk of prostate cancer and that there is limited suggestive evidence that milk and dairy products also increase the risk.[26] Since publication, 18 additional studies that evaluated dairy or calcium intake and the risk of prostate cancer have been published. A 2015 meta-analysis of this literature concluded that high intakes of dairy products, milk, low-fat milk, cheese, total dietary calcium, and dairy calcium may increase prostate cancer risk.[27] Supplemental calcium and nondairy calcium were not associated with an increased risk, although supplemental calcium was associated with an increased risk of fatal prostate cancer. The authors suggested that this association needs additional study.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Ross AC, Taylor CL, Yaktine AL, et al., eds.: Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press, 2011. Also available online. Last accessed May 26, 2022.
2. Lampe JW: Dairy products and cancer. J Am Coll Nutr 30 (5 Suppl 1): 464S-70S, 2011. [PUBMED Abstract]
3. Fortmann SP, Burda BU, Senger CA, et al.: Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality, 2013. Available online. Last accessed May 27, 2022.
4. Tate PL, Bibb R, Larcom LL: Milk stimulates growth of prostate cancer cells in culture. Nutr Cancer 63 (8): 1361-6, 2011. [PUBMED Abstract]
5. Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [PUBMED Abstract]
6. Ray R, Banks M, Abuzahra H, et al.: Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res 32 (3): 727-31, 2012. [PUBMED Abstract]
7. Butler LM, Wong AS, Koh WP, et al.: Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res 70 (12): 4941-8, 2010. [PUBMED Abstract]
8. Kurahashi N, Inoue M, Iwasaki M, et al.: Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men. Cancer Epidemiol Biomarkers Prev 17 (4): 930-7, 2008. [PUBMED Abstract]
9. Raimondi S, Mabrouk JB, Shatenstein B, et al.: Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case-control study. Prostate 70 (10): 1054-65, 2010. [PUBMED Abstract]
10. Park Y, Mitrou PN, Kipnis V, et al.: Calcium, dairy foods, and risk of incident and fatal prostate cancer: the NIH-AARP Diet and Health Study. Am J Epidemiol 166 (11): 1270-9, 2007. [PUBMED Abstract]
11. Giovannucci E, Liu Y, Stampfer MJ, et al.: A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (2): 203-10, 2006. [PUBMED Abstract]
12. Koh KA, Sesso HD, Paffenbarger RS, et al.: Dairy products, calcium and prostate cancer risk. Br J Cancer 95 (11): 1582-5, 2006. [PUBMED Abstract]
13. Ahn J, Albanes D, Peters U, et al.: Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (12): 2623-30, 2007. [PUBMED Abstract]
14. Orlich MJ, Mashchak AD, Jaceldo-Siegl K, et al.: Dairy foods, calcium intakes, and risk of incident prostate cancer in Adventist Health Study-2. Am J Clin Nutr 116 (2): 314-324, 2022. [PUBMED Abstract]
15. Park SY, Murphy SP, Wilkens LR, et al.: Calcium, vitamin D, and dairy product intake and prostate cancer risk: the Multiethnic Cohort Study. Am J Epidemiol 166 (11): 1259-69, 2007. [PUBMED Abstract]
16. Pettersson A, Kasperzyk JL, Kenfield SA, et al.: Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death. Cancer Epidemiol Biomarkers Prev 21 (3): 428-36, 2012. [PUBMED Abstract]
17. Mitrou PN, Albanes D, Weinstein SJ, et al.: A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). Int J Cancer 120 (11): 2466-73, 2007. [PUBMED Abstract]
18. Kesse E, Bertrais S, Astorg P, et al.: Dairy products, calcium and phosphorus intake, and the risk of prostate cancer: results of the French prospective SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) study. Br J Nutr 95 (3): 539-45, 2006. [PUBMED Abstract]
19. Rohrmann S, Platz EA, Kavanaugh CJ, et al.: Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study. Cancer Causes Control 18 (1): 41-50, 2007. [PUBMED Abstract]
20. Binder M, Shui IM, Wilson KM, et al.: Calcium intake, polymorphisms of the calcium-sensing receptor, and recurrent/aggressive prostate cancer. Cancer Causes Control 26 (12): 1751-9, 2015. [PUBMED Abstract]
21. Baron JA, Beach M, Wallace K, et al.: Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 14 (3): 586-9, 2005. [PUBMED Abstract]
22. Gao X, LaValley MP, Tucker KL: Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 97 (23): 1768-77, 2005. [PUBMED Abstract]
23. Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [PUBMED Abstract]
24. Qin LQ, Xu JY, Wang PY, et al.: Milk consumption is a risk factor for prostate cancer in Western countries: evidence from cohort studies. Asia Pac J Clin Nutr 16 (3): 467-76, 2007. [PUBMED Abstract]
25. Bristow SM, Bolland MJ, MacLennan GS, et al.: Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br J Nutr 110 (8): 1384-93, 2013. [PUBMED Abstract]
26. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: World Cancer Research Fund/American Institute for Cancer Research, 2007. Also available online. Last accessed February 5, 2025.
27. Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Am J Clin Nutr 101 (1): 87-117, 2015. [PUBMED Abstract]

Overview

This section contains the following key information:

• Green tea is produced by a process of steaming and drying the leaves from the Camellia sinensis (L.) plant.
• Some research results suggest that green tea may have a protective effect against cardiovascular diseases and against various forms of cancer, including prostate cancer.
• Catechins are phenolic compounds in tea that have been associated with many of green tea’s proposed health benefits.
• Green tea catechins (GTCs) include (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), but also include oligomeric proanthocyanidins derived from these catechin monomers.
• Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis. EGCG has been shown to act as an androgen antagonist and can suppress prostate cancer cell proliferation, suppress production of prostate-specific antigen (PSA) by prostate cancer cells, and demonstrate potent and selective proapoptotic activity in prostate cancer cell lines in vitro.
• Oral intake of either a GTC solution or EGCG alone was associated with significant reductions in tumor size, reduced multiplicity, and reduced development of prostate cancer in studies with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.
• In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world, and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States. Case-control and cohort studies, so far, have variously shown beneficial or neutral results, with the exception of one study that showed an increased risk of developing advanced prostate cancer with consumption of green tea.
• GTCs have been well tolerated in clinical studies that target healthy male subjects, men with precursor lesions, and men with prostate cancer. Side effects were reduced with a decaffeinated formulation and when green tea was consumed in nonfasting conditions. The most common side effects related to GTC were mild gastrointestinal symptoms.
• At least two randomized controlled trials have shown an overall decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HGPIN) treated with GTCs.

General Information and History

Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most-consumed beverage in the world.[1] Tea originates from the C. sinensis plant, and the process methods of the leaves determine the type of tea produced. Green tea is not fermented but is made by an enzyme deactivation step whereby intensive heat (i.e., roasting the freshly collected tea leaves in a wok or, historically, steaming the leaves) is applied to preserve the tea’s polyphenols (catechins) and freshness. In contrast, the enzyme-catalyzed polymerization and oxidation of catechins and other components produce darker-colored black tea.[2] Oolong, a third major type of tea, which is dark/black rather than green as a result of being partially fermented, contains partially oxidized catechins.[1]

In this summary, tea refers to the leaves of the C. sinensis plant or the beverage brewed from those leaves.

Some observational and interventional studies suggest that green tea may have a protective effect against cardiovascular disease,[3] and there is evidence that green tea may protect against various forms of cancer.[4] Many of the health benefits associated with tea have been attributed to polyphenols. GTCs include EGCG, EC, EGC, ECG, and oligomeric proanthocyanidins derived from these catechin monomers. Among these compounds, EGCG is the most abundant catechin in green tea and has been widely researched;[5] however, it is also classified as a promiscuous compound.[6] Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis.[5] Tea leaves also contain considerable amounts of oligomeric catechins, in particular, oligomeric proanthocyanidins. Together with the catechin monomers, they constitute the green tea polyphenols (GTPs). GTP composition and the ratio of monomeric to oligomeric catechins can vary widely, depending on processing and source of the tea leaves. Considering that EGCG and other monomeric catechins interfere with in vitro assays and exhibit a wide range of biological effects,[6,7] this indicates that the chemical factors responsible for the actual in vivo health benefits of green tea are mostly unknown.

Several companies distribute green tea as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of green tea as a treatment for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

Prostate cancer cells treated with EGCG (concentrations, 0–80 μM) demonstrated suppressed cell proliferation and decreased levels of PSA protein and mRNA in the presence or absence of androgen.[8]

In a 2011 study, human prostate cancer cells were treated initially with EGCG (concentrations, 1.5–7.5 μM) and then with radiation. The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced apoptosis, compared with radiation alone.[9]

In another study, prostate cancer cells treated with EGCG (0–50 μM) exhibited dose-dependent decreases in cellular proliferation and increases in extracellular signal-regulated kinase (ERK) 1/2 activity. To further examine the effect of EGCG on the ERK 1/2 pathway, cells were treated with EGCG (0–50 μM) and a mitogen-activated protein kinase (MEK) inhibitor or phosphoinositide-3 kinase (PI3K) inhibitor. Inhibition of MEK did not prevent ERK 1/2 upregulation, although the increase in ERK 1/2 after EGCG treatment was partially inhibited with the PI3K inhibitor. These findings suggest that EGCG may prevent prostate cancer cell proliferation by increasing the activity of ERK 1/2 via a MEK-independent, PI3K-dependent mechanism.[10]

According to a 2010 study, EGCG treatment (20–120 μM) resulted in changes in expression levels of 40 genes in prostate cancer cells, including a fourfold downregulation of inhibitor of DNA binding 2 (ID2; a protein involved in cell proliferation and survival). In addition, forced expression of ID2 in cells treated with 80 μM EGCG resulted in reduced apoptosis, suggesting that EGCG may cause cell death via an ID2-related mechanism.[11]

Advances in nanotechnology—nanochemoprevention—may result in more-effective administration of EGCG to men at risk of developing prostate cancer. Prostate cancer cells were treated with EGCG-loaded (100 μM EGCG) nanoparticles or free EGCG. Although both treatments decreased cell proliferation and induced apoptosis, the nanoparticle treatment had a greater effect at a lower concentration than did free EGCG. This finding suggests that using a nanoparticle delivery system for EGCG may increase its bioavailability and improve its chemopreventive actions.[12] In one study, EGCG (30 μM) was encapsulated in nanoparticles that contained polymers targeting prostate-specific membrane antigen (PSMA). Prostate cancer cells treated with this intervention exhibited decreases in proliferation; however, the intervention did not affect nonmalignant control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.[13]

Research also suggests that glutathione-S-transferase pi (GSTP1) may be a tumor suppressor and that hypermethylation of certain regions of this gene (i.e., CpG islands) may be a molecular marker of prostate cancer. Increased methylation leads to silencing of the gene. A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. Treatment of different types of prostate cancer cells with green tea polyphenols (1–10 μg/mL Polyphenon E) resulted in re-expression of GSTP1 by reversing hypermethylation and by reducing expression of methyl-CpG–binding domain proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.[14]

The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting histone deacetylases (HDACs). Class I HDACs are often overexpressed in various cancers, including prostate cancer. Treatment of human prostate cancer cells with green tea polyphenols (10–80 μg/mL Polyphenon E) resulted in decreased class I HDAC activity and increased expression of Bax, a proapoptotic protein.[15]

Owing to the high concentrations of tea polyphenols used in some of the in vitro experiments, results should be interpreted with caution. Studies in humans have indicated that blood levels of EGCG are 0.1 to 0.6 µM after consumption of two to three cups of green tea and that drinking seven to nine cups of green tea results in EGCG blood levels still lower than 1 μM.[16,17]

Animal studies

Animal models have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC–treated water (0.3% GTC solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer, whereas mice treated with GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors.[18] In another study, castrated mice were injected with prostate cancer cells and then treated daily with intraperitoneal injections of 1 mg EGCG or vehicle. Treatment with EGCG resulted in reductions in tumor volume and decreases in serum PSA levels compared with vehicle treatment.

In a 2011 study, EGCG was shown to be an androgen antagonist; when added to prostate cancer cells, EGCG physically interacted with the androgen receptor’s ligand-binding domain. In addition, mice implanted with tumor cells and treated with EGCG (intraperitoneal injections of 1 mg EGCG, 3/wk) exhibited less androgen receptor protein expression than did mice that were treated with vehicle.[19]

In a 2009 study, TRAMP mice were started on a green tea polyphenol intervention (0.1% green tea polyphenols in drinking water) at various ages (meant to represent different stages of prostate cancer development).[20] The results showed that, although all of the green tea–fed mice exhibited longer tumor-free survival than did water-fed control mice, there was an advantage for the mice that were fed with green tea the longest.[20] In one study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea/d) was initiated in TRAMP mice at age 12 or 28 weeks. EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks.[21]

Using the TRAMP mouse model,[22] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea/d) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by magnetic resonance imaging; decreased prostate weight (64% of baseline) and genitourinary weight (72%); inhibited serum insulin-like growth factor (IGF)-1; restored insulin-like growth factor–binding protein-3 (IGFBP-3) levels; and produced marked reduction in the protein expression of proliferating cell nuclear antigen in the GTP-fed TRAMP mice, compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and metastasis to distant organ sites. In another study, 119 male TRAMP mice and 119 C57BL/6J mice were treated orally with one of three doses of Polyphenon E (200, 500, or 1,000 mg/kg/d) in drinking water ad libitum, replicating human-achievable doses. Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals. In untreated 32-week-old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period.[23]

Animal safety studies

In a National Cancer Institute (NCI) Division of Cancer Prevention (DCP)–sponsored, 9-month, oral toxicity study, Polyphenon E was administered (200, 500, or 1,000 mg/kg/d) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to morbidity and mortality in all treatment groups. These studies have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tracts, livers, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. In the 13-week follow-up study, the no-observed-adverse-effect–level was greater than 600 mg/kg per day of Polyphenon E.[24] When the study was conducted in nonfasted dogs under the same testing conditions and dose levels, the results were unremarkable. Nonspecific toxicity and a tenfold reduction in the maximum tolerated dose in fasted beagle dogs compared with fed beagle dogs were seen using a purified GTC containing less than 77% EGCG.[25] However, in the follow-up NCI DCP–sponsored study, which compared fed dogs with fasted dogs using several Polyphenon E formulations, no deaths occurred, suggesting that fasting may have rendered the target organ systems more vulnerable to the effects of green tea extract.

In a study [23] of several doses of a standardized Polyphenon E targeting TRAMP mice, no liver or other toxicities were observed. Long-term (32 weeks) treatment with Polyphenon E (200, 500, and 1,000 mg/kg/d) was safe and well tolerated, with no evidence of toxicity in C57BL/6J mice. The C57BL/6J mice showed no differences in appearance or behavior, or changes in prostate and body weights after 32 weeks of treatment for all three doses of Polyphenon E. No discernible histopathological changes were observed in the liver, lung, or any prostate lobe of C57BL/6J mice treated with the three different doses of Polyphenon E.[23] Similarly, another preclinical study [26] did not observe liver or other toxicities with standardized EGCG at doses of up to 500 mg EGCG preparation/kg per day.

Human Studies

Epidemiological studies

The relationship between green tea intake and prostate cancer has been examined in several epidemiological studies.

Two meta-analyses examined the consumption of green tea and prostate cancer risk, with one meta-analysis including black tea.[27,28] For green tea, seven observational studies were identified, and most were from Asia. The results indicated a statistically significant inverse association between green tea consumption and prostate cancer risk in the three case-control studies, but no association was found in the four cohort studies. For black tea, no association was found between black tea consumption and prostate cancer risk.[27] The inconsistent results reported in these population studies may be attributed to confounding factors that include the following:[29–33]

• Consumption of salted or very hot tea.
• Geographical location.
• Tobacco use.
• Alcohol use.
• Other dietary differences.

In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[34] and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States.[34] Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[27,35] Currently, there are no epidemiological studies in other populations examining the association between green tea consumption and prostate cancer risk or protection from risk. With the increasing consumption of green tea worldwide, including by the U.S. population, emerging data from ongoing studies will further contribute to defining the cancer preventive activity of green tea or GTCs.

Interventional studies

Bioavailability

Phase I/II intervention studies have reported bioavailability of EGCG in plasma using single and repeated doses of EGCG, noting higher plasma EGCG concentrations in fasting conditions relative to fed conditions.[36–38] Studies using varying doses (400 mg, 800 mg EGCG) of GTCs and Polyphenon E administered in single and repeated dosing schedules for 3 to 6 weeks have reported median maximum concentrations of EGCG ranging from 68.8 ng/mL to 390.36 ng/mL (see Table 1).[38–40] Not all individuals in the treatment arms of these and other studies [31,41,42] had detectable levels of EGCG, indicating potential variation in individual absorption. Catechins other than EGCG were nondetectable or below quantifiable levels in the plasma in many trials.

Catechin tissue levels have also been reported, and high variations were quite common. Notably, catechin levels in prostate tissue were low to undetectable after the administration of Polyphenon E in one preprostatectomy study.[39] An analysis of prostate tissue obtained from the green tea drinkers revealed that both methylated and nonmethylated forms of EGCG are found in the prostate following a short-term treatment with green tea, with 48% of EGCG in the methylated form.[39] Methylated forms of EGCG are not as effective as EGCG in inhibiting cell proliferation and inducing apoptosis in prostate cancer cells, suggesting that methylation status of EGCG may affect the chemopreventive properties of green tea. Methylation status may be determined by polymorphisms of the catechol-O-methyltransferase (COMT; the enzyme that methylates EGCG) gene.[43]

Table 1. Peak Plasma EGCG Levels

Source	EGCG Dose	Condition	Duration	Median Plasma EGCG Concentration (ng/mL)
EGCG = (−)-Epigallocatechin-3-gallate; kg = kilogram(s); mg = milligram(s); mL = milliliter(s); ng = nanogram(s); SD = standard deviation; wk = week(s); y = year.
[38]	400 mg	Fed, fasted	4 wk	155.4 (fed), 161.4 (fasted)
	800 mg	Fed, fasted	4 wk	287.6 (fed), 390.36 (fasted)
[39]	800 mg (in Polyphenon E)	Fed	3–6 wk	68.8
[40]	2 mg/kg	Fasted	Single dose	77.9
[42]	200 mg (twice a day)	Fed	1 y	12.3 (SD, 24.8)

Prevention

In a single-center Italian study, 60 men diagnosed with HGPIN were randomly assigned to receive GTC capsules (GTCs, 600 mg/d) or a placebo every day for 1 year. After 6 months, 6 of the 30 men in the placebo group were diagnosed with prostate cancer, whereas none of the 30 subjects in the GTC group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the GTC group were diagnosed with prostate cancer (P < .01). These findings suggest that GTCs may help prevent prostate cancer in groups at high risk of the disease.[44] In 2008, follow-up results to this study were published, indicating that the inhibitory effects of GTCs on prostate cancer progression were long-lasting.[45] However, nearly all of the prostate cancer risk reduction in that study occurred at the 6-month biopsy, suggesting that the results may have been biased by a nonrandom distribution of occult prostate cancer at baseline.[34] No reduction in serum PSA was observed in the treatment arm of this study compared with placebo.

A larger, multicenter, randomized trial (NCT00596011) in the United States studied 97 men with either HGPIN or atypical small acinar proliferation who received a GTC mixture (Polyphenon E, 200 mg, bid).[42] Atypical small acinar proliferation is an entity that reflects a broad group of lesions of varying clinical significance with insufficient cytological or architectural atypia to establish a definitive diagnosis of prostate cancer.[9,27] Results indicated that a daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year, with detectable levels of catechins accumulated in the plasma, was well tolerated,[42][Level of evidence 1A] but it did not significantly reduce the incidence of prostate cancer in the treatment group with Polyphenon E (5/49, 10.2%) compared with the placebo group (9/48, 18.8%; P = .25). However, in a prespecified secondary analysis performed in men with HGPIN (without atypical small acinar proliferation) at baseline, Polyphenon E was associated with a significant decrease in the composite endpoint (prostate cancer plus atypical small acinar proliferation) (3/26 Polyphenon E vs. 10/25 placebo, P < .024), with these findings largely driven by the absence of atypical small acinar proliferation on end-of-study biopsy on the Polyphenon E arm (Polyphenon E [0/26] vs. placebo arm [5/25]). Because there is no clear evidence that HGPIN and atypical small acinar proliferation represent steps on a linear path to prostate cancer, these findings should be interpreted with caution. A comparison of the estimated overall treatment effect showed a significantly greater reduction of serum PSA in men treated with Polyphenon E compared with controls (-0.87 ng/mL; 95% confidence interval, -1.66 to -0.09).[42] A 2017 randomized clinical trial targeted 60 men with HGPIN who received 600 mg of green tea catechins for 1 year. Although a significant reduction in serum PSA was observed, no reduction in incidence of prostate cancer was observed in the group treated with green tea catechins compared with the placebo group.[46] Although some of the findings of the clinical trials appear to refute the large effect size suggested by the Italian study [42,44,45] that reported a 90% reduction in prostate cancer among men with HGPIN, overall, the randomized controlled trials have shown a decrease in serum PSA as well as a decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with HGPIN treated with GTCs. However, those clinical studies had relatively overall small sample sizes and not necessarily designed as pivotal phase III trials to allow confirmation of GTEs’ clinical benefits as a prostate cancer prevention drug.

Preoperative studies

Patients scheduled for radical prostatectomy were randomly assigned to drink green tea, black tea, or a soda five times a day for 5 days. Bioavailable tea polyphenols were found in prostate samples of the patients who had consumed green tea and black tea. In addition, prostate cancer cells were treated with participants’ serum, and the results showed that there was less proliferation using post-tea serum than using serum obtained before the tea intervention.[47] In an open label, phase II trial, 113 men with prostate cancer were randomly assigned to drink six cups of green tea, black tea, or water before radical prostatectomy.[48] Ninety-three patients completed the intervention. Although there were no significant differences in markers of proliferation, apoptosis, and oxidation in the prostatectomy tissue, only the men drinking green tea demonstrated small but significant decreases in PSA levels (P = .04).

In an open label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, providing 800 mg EGCG daily until surgery. The Polyphenon E treatment had a positive effect on a number of prostate cancer biomarkers, including PSA, vascular endothelial growth factor (VEGF), and IGF-1 (a protein associated with increased risk of prostate cancer).[49]

In a 2011 study, 50 prostate cancer patients were randomly assigned to receive Polyphenon E (800 mg EGCG) or a placebo daily for 3 to 6 weeks before surgery. Treatment with Polyphenon E resulted in greater decreases in serum levels of PSA and IGF-1 than did treatment with placebo, but these differences were not statistically significant. The findings of this study suggest that the chemopreventive effects of green tea polyphenols may be through indirect means and that longer intervention studies may be needed.[39]

Advanced prostate cancer

In a small, single-arm study, hormone-refractory prostate cancer patients received capsules of green tea extract twice daily (total polyphenols, 375 mg/d); not specified by polyphenol type) for up to 5 months. Although the green tea intervention was well tolerated by most study participants, no patient had a PSA response (i.e., at least 50% decrease from baseline), and all 19 patients were deemed to have progressive disease within 1 to 5 months.[50]

In a 2003 study, patients with androgen-independent metastatic prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months. Among 42 participants, 1 patient exhibited a 50% decrease in serum PSA level compared with baseline, but this response was not sustained beyond 2 months. Green tea was well tolerated by most study participants. However, six episodes of grade 3 toxicity occurred, involving insomnia, confusion, and fatigue. These results suggest that in patients with advanced prostate cancer, green tea may have limited benefits.[51]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

The safety of tea and tea compounds is supported by centuries of consumption by the human population. The bioavailability and tolerance to GTC at doses ranging from 600 to 1,000 mg EGCG at single and multiple doses, and a duration of a few days to 1 year has been well documented in phase I/II clinical trials.[36–40,43,47–51] The authors of a phase I trial of oral green tea extract in adult patients with solid tumors reported that a safe dose of green tea extract (1.0 g/m2, tid) was equivalent to seven to eight Japanese cups (120 mL) of green tea three times per day for 6 months.[52] The authors concluded that the side effects (neurological and gastrointestinal) of the green tea extract preparation were caffeine related, and not from EGCG.

In four phase I, single-dose, and multidose studies that targeted healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E, and a dose range of 200 to 1,200 mg EGCG was well tolerated.[33,34,40–42,44,45] Adverse effects with a possible relationship to the study drug reported in these studies have been grade 2 to 3 and included the following:

• Asthenia.
• Headache.
• Abdominal pain.
• Chest pain.
• Diarrhea.
• Dyspepsia.
• Eructation.
• Flatulence.
• Nausea.
• Vomiting.
• Dizziness.
• Vasodilation.
• Rash.

These studies have demonstrated that although increased oral bioavailability occurs when GTCs are consumed in a fasting state, increased gastrointestinal toxicity is also more common. Gastrointestinal adverse effects were usually mild and seen most often at the higher dose levels. Onset of gastrointestinal events typically occurred within 2 to 3 hours of dosing and resolved within 2 hours. No grade 3 or higher events were reported with a possible relationship to the study drug.[49]

Green tea has been well tolerated in clinical studies of men with prostate cancer.[43,49] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two men, who experienced severe anorexia and moderate dyspnea.[50] With the duration of intervention in these studies ranging from single, one-time administration to a maximum of 90 days, the safety data from these studies are limited to short-term safety of EGCG and GTCs.

Data from clinical trials [42,44] report long-term safety of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer. One study [44] administered approximately 300 mg EGCG per day for 1 year without any reported toxicities.

In a U.S. trial, 400 mg of EGCG containing Polyphenon E was administered for 1 year to nonfasting men with HGPIN and atypical small acinar proliferation. More possible and probable grade 2 through grade 3 events in men who received Polyphenon E were observed and compared with those in men who received placebo. Only one man who received Polyphenon E reported grade 3 nausea, which was determined to possibly be related to the study agent.[42]

In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[25,38,53–55] Most affected patients were women, and many were consuming GTEs for the purpose of weight loss. Although hepatotoxicity in most cases resolved within 4 months of stopping GTEs, there have been cases of positive rechallenge and liver failure requiring a liver transplant. One report described a case of acute liver failure that required a transplant in a woman who consumed GTE capsules.[54] The capsules contained Polyphenon 70A (a concentrated, enriched, and pasteurized hot-water extract of green tea) and 120 mg GTE. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements. In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in 2003 after reports associated hepatotoxicity (four cases in Spain and nine cases in France) with its use.[55] Time to onset of hepatotoxicity following ingestion of GTEs ranged from several days to several months. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast. Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs.[25]

The FDA’s Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, frequent liver function tests should be considered while individuals are on treatment, especially in the first few months of trial initiation.

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Overview

This section contains the following key information:

• Lycopene is a carotenoid, a natural pigment made by plants and various fruits and vegetables, including tomatoes, apricots, guavas, and watermelon.
• Lycopene’s absorption is improved with concurrent dietary fat intake.
• Lycopene inhibits androgen receptor expression in prostate cancer cells in vitro and, along with some of its metabolites, reduces prostate cancer cell proliferation and may modulate cell-cycle progression.
• Lycopene may also affect the insulin-like growth factor (IGF) intracellular pathway in prostate cancer cells.
• Results from several in vitro and animal studies have indicated that lycopene may have chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver; however, human trials have been inconsistent in their findings.
• Clinical trials utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, prostate-specific antigen [PSA] relapse, advanced disease) have yielded inconsistent results.
• The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, doses ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate gastrointestinal toxicities.

General Information and History

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red and lipophilic. As a natural pigment made by plants, lycopene helps to protect plants from light-induced stress,[1] and it also transfers light energy during photosynthesis.[2] Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.[1]

Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease. Lycopene may protect against cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins,[3] although some interventional studies have shown mixed results.[4]

A number of in vitro and in vivo studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver.[5] However, epidemiological studies have yielded inconsistent findings regarding lycopene’s potential in reducing cancer risk.

The few human intervention trials have been small and generally focused on intermediate endpoints, not response of clinically evident disease or overall survival and, thus have limited translation to practice.[2,6]

On the basis of overall evidence, the association between tomato consumption and reduced risk of prostate cancer is limited.[7]

Several companies distribute lycopene as a dietary supplement. In the United States, dietary supplements are regulated by the FDA as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of lycopene as a treatment for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

In vitro studies that have examined a link between lycopene and prostate carcinogenesis have suggested several mechanisms by which lycopene might reduce prostate cancer risk. Lycopene is broken down into a number of metabolites that are thought to have various biological effects, including antioxidant capabilities and a role in gap-junction communication.[8]

Treating normal human prostate epithelial cells with lycopene resulted in dose-dependent growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene might lower the risk of prostate cancer.[9]

In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in the S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12’-lycopenal, a lycopene metabolite, reduced prostate cancer cell proliferation and may modulate cell-cycle progression.[10]

Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), total cholesterol, and cell growth, and an increase in apoptosis. However, adding mevalonate prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anticancer activity of lycopene.[11]

Lycopene may also affect cholesterol levels in prostate cancer cells by activating the peroxisome proliferator-activated receptor gamma (PPARγ)-liver X receptor alpha (LXRα)-ATP-binding cassette, subfamily 1 (ABCA1) pathway, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and differentiation of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ antagonist, cell proliferation increased, whereas treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[12]

Adding lycopene to medium containing the LNCaP human prostate adenocarcinoma cell line resulted in decreased DNA synthesis and inhibition of androgen-receptor gene-element activity and expression.[13] In a study that examined the physiologically relevant concentration of lycopene (2 mmol/L) or placebo for 48 hours on protein expression in human primary prostatic epithelial cells, proteins that were significantly upregulated or downregulated following lycopene exposure were those proteins involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the AKT/mTOR cascade. These data are consistent with previous studies, suggesting that lycopene can prevent malignant transformation in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.[14]

A study examining the effect of lycopene on multiple points along the nuclear factor-kappa B (NF-kappa B) signaling pathways in prostate cell lines demonstrated a 30% to 40% reduction in inhibitor of kappa B (I-kappa B) phosphorylation, NF-kappa B transcriptional activity and a significant reduction in cell growth at the physiologically relevant concentration of 1.25 μM or higher.[15] These results provided evidence that the anticancer properties of lycopene may occur through inhibition of the NF-kappa B signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-kappa B–responsive gene regulation. Additionally, these effects in the cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.

Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and docetaxel, a drug used to treat patients with castration-resistant prostate cancer, or each drug alone. The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor (IGF-1R) pathway.[16]

Animal studies

In a chemoprevention study, 59 transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.[17]

Ketosamines are carbohydrate derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.[18]

Lycopene has also been studied for potential therapeutic effects in xenograft models. In one study, athymic nude mice were injected with human androgen-independent prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or beta-carotene (16 mg/kg body weight). Supplementing mice with lycopene or beta-carotene resulted in decreased tumor growth.[19] In an in vitro study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines.[20] In another study, nude mice were injected with human prostate cancer cells and treated with intraperitoneal injections of docetaxel, lycopene (15 mg/kg/d) administered via gavage, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.[16]

Human Studies

Epidemiological studies

Several epidemiological studies have assessed potential associations between lycopene intake and prostate cancer incidence.

Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risk of prostate cancer.[7,9–13] Prospective and case-control studies have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[7,16–19,21] while other studies have failed to demonstrate such a connection.[22]

An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor study in Finland. In this prospective cohort study, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio [RR], 0.55; 95% confidence interval [CI], 0.34–0.89; P = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (RR, 0.43; 95% CI, 0.23–0.79; P = .007) but not prostate cancer.[23]

A 2015 systematic review and meta-analysis of studies investigating dietary lycopene intake/circulating lycopene levels and prostate cancer risk found that when lycopene intake was higher, the incidence of prostate cancer was reduced (P = .078).[24] Similarly, a higher level of circulating lycopene was associated with lower prostate cancer risk. Likewise, a 2017 systematic review and meta-analysis evaluated lycopene dietary intake and circulating lycopene with prostate cancer risk. An inverse association between high levels of both circulating (RR, 0.88; 95% CI, 0.79–0.98; P = .019) and dietary lycopene (RR, 0.88; 95% CI, 0.78–0.98; P = .017) with prostate cancer risk was noted.[25]

The National Cancer Institute’s Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed for an average of 4.2 years. Lycopene and tomato product intakes were assessed via food frequency questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a family history of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk.[26] A follow-up study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggested no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.[27]

The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Higher lycopene intake was inversely associated with total prostate cancer risk (hazard ratio [HR], 0.91; 95% CI, 0.84–1.00) and lethal prostate cancer risk (HR, 0.72; 95% CI, 0.56–0.94). A subset analysis was restricted to men who had at least one negative PSA test at the onset, to reduce the influence of PSA screening on the association. The inverse association became markedly stronger (HR, 0.47; 95% CI, 0.29–0.75) for lethal prostate cancer. Levels of tumor markers for angiogenesis, apoptosis, and cellular proliferation and differentiation were monitored. Three of the tumor angiogenesis markers were strongly associated with lycopene intake, so that men with higher intake had tumors that demonstrated less angiogenic potential.[28]

At least two studies examined the effect of lycopene blood levels on the risk of high-grade prostate cancer. The first study examined the associations between carotenoid levels and the risk of high-grade prostate cancer, and also considered antioxidant-related genes and tumor instability. This study demonstrated that plasma carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. Higher lycopene concentrations were associated with less genomic instability among men with low-grade disease, indicating that lycopene may inhibit progression of prostate cancer early in its natural history.[29]

In another study examining whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with prostate cancer aggressiveness, results suggested that diets high in lycopene may protect against aggressive prostate cancer in White American men, and diets high in beta-cryptoxanthin may protect against aggressive prostate cancer in African American men.[30]

One study investigated the correlation between lycopene blood levels and the rate of progression of prostate cancer. This study examined plasma carotenoids and tocopherols in relation to PSA levels among men with biochemical recurrence of prostate cancer. This study indicated that the plasma cis-lutein/zeaxanthin level at 3 months was inversely related to PSA level at 3 months (P = .0008), while alpha-tocopherol (P = .01), beta-cryptoxanthin (P = .01), and all-trans-lycopene (P = .004) levels at 3 months were inversely related to PSA levels at 6 months. Percentage increase in alpha-tocopherol and trans-beta-carotene levels from baseline to month 3 was associated with lower PSA levels at 3 and 6 months. Percentage increase in beta-cryptoxanthin, cis-lutein/zeaxanthin and all-trans-lycopene was associated with lower PSA levels at 6 months only.[31]

A study examined the association of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with prostate-cancer specific mortality in a prospective cohort of men diagnosed with nonmetastatic prostate cancer. No association between serum lycopene, tomato products, and prostate-cancer specific mortality was observed. Among men with high-risk cancers (T3–T4, Gleason score 8–10, or nodal involvement), consistently reporting lycopene intake that was at or above the median was associated with lower prostate-cancer specific mortality.[32]

In a recently reported prospective study of 27,934 U.S. Adventist men who were followed for up to 7.9 years, consumption of canned and cooked tomato-based products (measured as grams for both tomato products and lycopene), was inversely related to the risk of prostate cancer compared with those with zero intake of these foods. Associations of prostate cancer risk with raw tomatoes was not statistically significant. No differences in adjusted competing risk analyses were observed between aggressive and nonaggressive prostate cancers. The study was limited to self-reported food frequency questionnaires for data collection; however, lycopene concentrations were not quantified in this population.[33]

The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; inconsistent measures of intake; differences in absorption; differences in individual lycopene metabolism; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Most studies have examined the association of lycopene intake with the risk of all prostate cancers and have not separately considered indolent versus aggressive disease. Given these caveats, results based on epidemiological evidence should be interpreted with caution.

Interventional studies

A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer.

Bioavailability

The bioavailability of lycopene has been examined and demonstrated in several studies relating lycopene to prostate cancer and other diseases. The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than in raw tomatoes.[4] Lycopene bioavailability has been observed to be highly variable, which may lead to varying biological effects after lycopene consumption. It is postulated that these variations, at least in part, can be attributed to several single nucleotide polymorphisms in genes involved in red-pigment lycopene and lipid metabolism. In a study to define the impact of typical servings of commercially available tomato products on resultant plasma and prostate lycopene concentrations,[34] men scheduled to undergo prostatectomy (n = 33) were randomly assigned to either a lycopene-restricted control group (<5 mg/d) or a tomato soup (2–2¾ cups/d prepared), tomato sauce (142–198 g/d or 5–7 oz/d), or vegetable juice (325–488 mL/d or 11–16.5 fluid oz/d) intervention providing 25 to 35 mg of lycopene per day. The end-of-study prostate lycopene concentration was 0.16 nmol/g (standard error of the mean, 0.02) in the controls, but was 3.5-, 3.6- and 2.2-fold higher in tomato soup (P = .001), sauce (P = .001), and juice (P = .165) consumers, respectively. Prostate lycopene concentration was moderately correlated with postintervention plasma lycopene concentrations (correlation coefficient, 0.60; P = .001), indicating that additional factors have an impact on tissue concentrations. While the primary geometric lycopene isomer in tomato products was all-trans (80%–90%), plasma and prostate isomers were 47% and 80% cis-lycopene, respectively, demonstrating a shift towards cis accumulation. Consumption of typical servings of processed tomato products results in differing plasma and prostate lycopene concentrations. Factors including meal composition and genetics deserve further evaluation to determine their impacts on lycopene absorption, isomerization, and biodistribution.[35]

There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.[36] Results of a randomized study published in 2005 demonstrated that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil.[37] In another study,[38] there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.

Pharmacodynamic studies

Healthy men participated in a crossover design study that attempted to differentiate the effects of a tomato matrix from those of lycopene by using lycopene-rich red tomatoes, lycopene-free yellow tomatoes, and purified lycopene. Thirty healthy men aged 50 to 70 years were randomly assigned to two groups, with each group consuming 200 g/d of yellow tomato paste (lycopene, 0 mg) and 200 g/d of red tomato paste (lycopene, 16 mg) as part of their regular diet for 1 week, separated by a 2-week washout period. Then, in a parallel design, the first group underwent supplementation with purified lycopene (16 mg/d) for 1 week, and the second group received a placebo. Sera samples collected before and after the interventions were incubated with lymph node cancer prostate cells to measure the expression of 45 target genes. In this placebo-controlled trial, circulating lycopene concentration increased only after consumption of red tomato paste and purified lycopene. Lipid profile, antioxidant status, PSA, and IGF-1 were not modified by consumption of tomato pastes and lycopene. When prostate cancer cells were treated in vitro with sera collected from men after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up-regulated, and cyclin-D1, p53, and Nrf-2 were down-regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after consumption of yellow tomato paste with low carotenoid content. Cell incubation with sera from men who consumed purified lycopene led to significant up-regulation of IGFBP-3, c-fos, and uPAR compared with sera collected after placebo consumption. These findings suggest that lycopene may not be the only factor responsible for the cancer-protective effects of tomatoes.[39]

Prevention/early treatment

In another study, the effect of tomato sauce on apoptosis in benign prostatic hyperplasia (BPH) tissue and carcinomas was examined. Patients who were scheduled for prostatectomy were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before surgery. Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as control subjects. Those who consumed the tomato sauce pasta entrees exhibited significantly decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.[40]

One study of 40 patients with high-grade prostate intraepithelial neoplasia (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in men treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements (6 of 20) than in men who had received lycopene (2 of 20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.[41] In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No statistically significant difference was observed in serum PSA levels between the two treatment groups.[42] Another randomized placebo-controlled study of consumption of a lycopene-rich tomato extract that was taken for approximately 6 months in 58 men with HGPIN reported no discernible effect on cell proliferation or cell cycle inhibition in benign prostatic epithelium or in serum PSA levels, despite a substantial increase in serum lycopene.[43]

In another study, 32 men with HGPIN received a lycopene-enriched diet (20–25 mg/day lycopene from triple-concentrated tomato paste) before undergoing a repeat biopsy after 6 months. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat biopsy showed HGPIN, prostatitis, or prostate cancer. Prostatic lycopene concentration below 1 ng/mg was associated with prostate cancer at the 6-month follow-up biopsy (P = .003).[21] For more information about trials on therapies that include lycopene, see the Multicomponent Therapies section.

Treatment

A number of clinical trials investigating lycopene as a potential treatment for prostate cancer are listed below in Table 2.

Table 2. Clinical Trials of Lycopene for Prostate Cancer Treatmenta

Reference	Trial Design	Agent/Dose/Duration	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)	Biomarkers	Results	Levels of Evidence b
Bid = twice a day; PSA = prostate-specific antigen; RCT = randomized controlled trial.
aFor more information and definition of terms, see the NCI Dictionary of Cancer Terms.
bStrongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[44]	Preprostatectomy; pilot RCT	Tomato oleoresin extract containing lycopene 30 mg/d (15 mg bid) or placebo control for 3 wk	26; 15; 11	Tumor volume	Smaller tumors (80% vs. 45%, less than 4 mL), less involvement of surgical margins and/or extraprostatic tissues with cancer (73% vs. 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs. 0%, focal involvement)	1iiDiii
[45]	Preprostatectomy; RCT	Tomato products containing 30 mg of lycopene daily, tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice and green/black tea, or a control diet for 3 wk	79; 27 (tomato), 25 (tomato plus); 27 (control)	PSA	No differences in PSA values between the intervention and control groups. Lower PSA values in men with intermediate-risk prostate cancer with highest increases in lycopene levels	1iDii
[46]	Preprostatectomy; RCT	15 mg, 30 mg, or 45 mg lycopene vs. control for 30 d	45; 10 (15 mg), 10 (30 mg), 14 (45 mg); 11 (control)	PSA, steroid hormones, Ki-67	30 mg lycopene dose level decrease in free testosterone, significant increases in mean plasma estradiol and in serum sex hormone-binding globulin, and decrease in the percentage of cells expressing Ki-67; at the 45 mg/d dose, serum total estradiol increased	1iiDii
[47]	Active surveillance; single arm	Whole-tomato supplement containing 10 mg of lycopene (Lycoplus) for 1 y	40; 40; None	PSA velocity; PSA doubling time	Statistically significant decrease in PSA velocity after lycopene treatment (P = .0007)	2Dii
[48]	Biochemical relapse after radiation therapy or surgery	15, 30, 45, 60, 90, or 120 mg/d of lycopene (Lyc-O-Mato) for 1 y	36; 36; None	PSA	Did not alter serum PSA levels	2Dii
[49]	Biochemical relapse after radiation therapy or surgery; single-arm study	Tomato juice or paste containing lycopene 30 mg/d for 4 mo	46; 46; None	PSA	Did not alter serum PSA levels except in one patient	2Dii
[50]	Metastatic, hormone-refractory prostate cancer; open label study	Lycopene 10 mg/d (Lycored softules) for 3 mo	20; 20; None	PSA	50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient exhibited a complete response after treatment	2Dii
[51]	Hormone-refractory prostate cancer; single arm study	Lycopene 15 mg/d (pills) for 6 mo	17; 17; None	PSA	PSA stabilization in 5 (29%) of 17 and PSA progression in 12 (71%) of 17	2Dii

Preprostatectomy

Other studies have examined the potential therapeutic effect of lycopene-containing products in men with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in men with localized prostate cancer in a 2002 pilot study. Men received either lycopene supplements (30 mg/d) or no intervention twice daily for 3 weeks before radical prostatectomy. Men in the intervention arm had smaller tumors (80% vs. 45%, less than 4 ml), less involvement of surgical margins and/or extraprostatic tissues with cancer (73% vs. 18%, organ-confined disease), and less diffuse involvement of the prostate by HGPIN (33% vs. 0%, focal involvement) compared with men in the control group. Mean plasma PSA levels were lower in the intervention group compared with the control group.[44] For more information on studies with lycopene, see the Multicomponent Therapies section.

In a phase II, randomized, placebo-controlled trial,[46] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene (Lyc-O-Mato) or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer.[52,53] At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and significant increases in mean plasma estradiol and in serum sex hormone-binding globulin (SHBG) (P = .022) were observed. At the 45 mg/d dose, serum total estradiol increased (P = .006) with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, in which 100% of the subjects observed an increase. These changes were not statistically significant, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.[46]

In a single-arm study of previously untreated men diagnosed with localized prostate cancer, investigators determined whether PSA velocity was altered by a 1-year intervention with lycopene supplementation (10 mg/d). A statistically significant decrease in PSA velocity after lycopene treatment was observed (P = .0007). Analysis of the PSA-doubling time (pretreatment vs. post-treatment) showed a median increase after supplementation for 174 days; however, this was not statistically significant.[47]

In one study, prostate cancer patients (N = 36) who had biochemical relapse following radiation therapy or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/d). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.[48]

In a 2004 open-label study, patients with hormone-refractory prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/d of lycopene) for 3 months. Of the study’s participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient (5% of the total sample) exhibited a complete response after treatment.[50] In a phase II study, HRPC patients took lycopene supplements daily (15 mg of lycopene/d) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a control group, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.[51]

In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/d) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level. Several episodes of gastrointestinal side effects were noted after eating the tomato paste or drinking the tomato juice.[49]

On the basis of the available evidence, early randomized clinical trials with lycopene as a single agent, in tomato products, and in combination with other agents (fish oil supplements, tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice and green/black tea) demonstrates bioavailability in serum and modulation of intermediate biomarkers implicated in prostate carcinogenesis and prostate cancer progression in most studies. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and heterogeneity of high-risk (HGPIN, atypical small acinar proliferation) and prostate cancer patient populations (indolent vs. aggressive prostate cancer or androgen-dependent vs. androgen-independent prostate cancer).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Studies evaluating lycopene in randomized clinical trials targeting men at high risk for prostate cancer and populations with prostate cancer have indicated relatively few toxicities at the dose and duration of intervention.[39,41,42,47,50] Doses of lycopene ranging between 8 mg and 45 mg administered over a period ranging from 3 weeks to 2 years have been reported to be safe in randomized clinical trials targeting the prostate. When adverse effects occurred, they tended to present as gastrointestinal symptoms [49] and, in one study, the symptoms resolved when lycopene was taken with meals.[51] Another study reported that one participant withdrew because of diarrhea.[48]

The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of GRAS.[54]

References

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3. Arab L, Steck S: Lycopene and cardiovascular disease. Am J Clin Nutr 71 (6 Suppl): 1691S-5S; discussion 1696S-7S, 2000. [PUBMED Abstract]
4. Mordente A, Guantario B, Meucci E, et al.: Lycopene and cardiovascular diseases: an update. Curr Med Chem 18 (8): 1146-63, 2011. [PUBMED Abstract]
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6. Ilic D, Forbes KM, Hassed C: Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev (11): CD008007, 2011. [PUBMED Abstract]
7. Kavanaugh CJ, Trumbo PR, Ellwood KC: The U.S. Food and Drug Administration’s evidence-based review for qualified health claims: tomatoes, lycopene, and cancer. J Natl Cancer Inst 99 (14): 1074-85, 2007. [PUBMED Abstract]
8. Mein JR, Lian F, Wang XD: Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev 66 (12): 667-83, 2008. [PUBMED Abstract]
9. Obermüller-Jevic UC, Olano-Martin E, Corbacho AM, et al.: Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr 133 (11): 3356-60, 2003. [PUBMED Abstract]
10. Ford NA, Elsen AC, Zuniga K, et al.: Lycopene and apo-12′-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer 63 (2): 256-63, 2011. [PUBMED Abstract]
11. Palozza P, Colangelo M, Simone R, et al.: Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 31 (10): 1813-21, 2010. [PUBMED Abstract]
12. Yang CM, Lu IH, Chen HY, et al.: Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (1): 8-17, 2012. [PUBMED Abstract]
13. Zhang X, Wang Q, Neil B, et al.: Effect of lycopene on androgen receptor and prostate-specific antigen velocity. Chin Med J (Engl) 123 (16): 2231-6, 2010. [PUBMED Abstract]
14. Qiu X, Yuan Y, Vaishnav A, et al.: Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev Res (Phila) 6 (5): 419-27, 2013. [PUBMED Abstract]
15. Assar EA, Vidalle MC, Chopra M, et al.: Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells. Tumour Biol 37 (7): 9375-85, 2016. [PUBMED Abstract]
16. Tang Y, Parmakhtiar B, Simoneau AR, et al.: Lycopene enhances docetaxel’s effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 13 (2): 108-19, 2011. [PUBMED Abstract]
17. Konijeti R, Henning S, Moro A, et al.: Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 70 (14): 1547-54, 2010. [PUBMED Abstract]
18. Mossine VV, Chopra P, Mawhinney TP: Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res 68 (11): 4384-91, 2008. [PUBMED Abstract]
19. Yang CM, Yen YT, Huang CS, et al.: Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res 55 (4): 606-12, 2011. [PUBMED Abstract]
20. Yang CM, Lu YL, Chen HY, et al.: Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (9): 1155-62, 2012. [PUBMED Abstract]
21. Mariani S, Lionetto L, Cavallari M, et al.: Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. Int J Mol Sci 15 (1): 1433-40, 2014. [PUBMED Abstract]
22. Kristal AR, Till C, Platz EA, et al.: Serum lycopene concentration and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 20 (4): 638-46, 2011. [PUBMED Abstract]
23. Karppi J, Kurl S, Nurmi T, et al.: Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann Epidemiol 19 (7): 512-8, 2009. [PUBMED Abstract]
24. Chen P, Zhang W, Wang X, et al.: Lycopene and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 94 (33): e1260, 2015. [PUBMED Abstract]
25. Rowles JL, Ranard KM, Smith JW, et al.: Increased dietary and circulating lycopene are associated with reduced prostate cancer risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 20 (4): 361-377, 2017. [PUBMED Abstract]
26. Kirsh VA, Mayne ST, Peters U, et al.: A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (1): 92-8, 2006. [PUBMED Abstract]
27. Peters U, Leitzmann MF, Chatterjee N, et al.: Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (5): 962-8, 2007. [PUBMED Abstract]
28. Zu K, Mucci L, Rosner BA, et al.: Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst 106 (2): djt430, 2014. [PUBMED Abstract]
29. Nordström T, Van Blarigan EL, Ngo V, et al.: Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer. Prostate 76 (4): 339-48, 2016. [PUBMED Abstract]
30. Antwi SO, Steck SE, Su LJ, et al.: Carotenoid intake and adipose tissue carotenoid levels in relation to prostate cancer aggressiveness among African-American and European-American men in the North Carolina-Louisiana prostate cancer project (PCaP). Prostate 76 (12): 1053-66, 2016. [PUBMED Abstract]
31. Antwi SO, Steck SE, Zhang H, et al.: Plasma carotenoids and tocopherols in relation to prostate-specific antigen (PSA) levels among men with biochemical recurrence of prostate cancer. Cancer Epidemiol 39 (5): 752-62, 2015. [PUBMED Abstract]
32. Wang Y, Jacobs EJ, Newton CC, et al.: Lycopene, tomato products and prostate cancer-specific mortality among men diagnosed with nonmetastatic prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Int J Cancer 138 (12): 2846-55, 2016. [PUBMED Abstract]
33. Fraser GE, Jacobsen BK, Knutsen SF, et al.: Tomato consumption and intake of lycopene as predictors of the incidence of prostate cancer: the Adventist Health Study-2. Cancer Causes Control 31 (4): 341-351, 2020. [PUBMED Abstract]
34. Borel P, Desmarchelier C, Nowicki M, et al.: Lycopene bioavailability is associated with a combination of genetic variants. Free Radic Biol Med 83: 238-44, 2015. [PUBMED Abstract]
35. Grainger EM, Hadley CW, Moran NE, et al.: A comparison of plasma and prostate lycopene in response to typical servings of tomato soup, sauce or juice in men before prostatectomy. Br J Nutr 114 (4): 596-607, 2015. [PUBMED Abstract]
36. Brown MJ, Ferruzzi MG, Nguyen ML, et al.: Carotenoid bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as measured with electrochemical detection. Am J Clin Nutr 80 (2): 396-403, 2004. [PUBMED Abstract]
37. Fielding JM, Rowley KG, Cooper P, et al.: Increases in plasma lycopene concentration after consumption of tomatoes cooked with olive oil. Asia Pac J Clin Nutr 14 (2): 131-6, 2005. [PUBMED Abstract]
38. Lee A, Thurnham DI, Chopra M: Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma. Free Radic Biol Med 29 (10): 1051-5, 2000. [PUBMED Abstract]
39. Talvas J, Caris-Veyrat C, Guy L, et al.: Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am J Clin Nutr 91 (6): 1716-24, 2010. [PUBMED Abstract]
40. Kim HS, Bowen P, Chen L, et al.: Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer 47 (1): 40-7, 2003. [PUBMED Abstract]
41. Mohanty NK, Saxena S, Singh UP, et al.: Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol 23 (6): 383-5, 2005 Nov-Dec. [PUBMED Abstract]
42. Bunker CH, McDonald AC, Evans RW, et al.: A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer 57 (2): 130-7, 2007. [PUBMED Abstract]
43. Gann PH, Deaton RJ, Rueter EE, et al.: A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia. Nutr Cancer 67 (7): 1104-12, 2015. [PUBMED Abstract]
44. Kucuk O, Sarkar FH, Djuric Z, et al.: Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 227 (10): 881-5, 2002. [PUBMED Abstract]
45. Paur I, Lilleby W, Bøhn SK, et al.: Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clin Nutr 36 (3): 672-679, 2017. [PUBMED Abstract]
46. Kumar NB, Besterman-Dahan K, Kang L, et al.: Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin Med Urol 1: 1-14, 2008. [PUBMED Abstract]
47. Barber NJ, Zhang X, Zhu G, et al.: Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 9 (4): 407-13, 2006. [PUBMED Abstract]
48. Clark PE, Hall MC, Borden LS, et al.: Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology 67 (6): 1257-61, 2006. [PUBMED Abstract]
49. Jatoi A, Burch P, Hillman D, et al.: A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group. Urology 69 (2): 289-94, 2007. [PUBMED Abstract]
50. Ansari MS, Gupta NP: Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol 22 (5): 415-20, 2004 Sep-Oct. [PUBMED Abstract]
51. Schwenke C, Ubrig B, Thürmann P, et al.: Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study. J Urol 181 (3): 1098-103, 2009. [PUBMED Abstract]
52. Gann PH, Ma J, Giovannucci E, et al.: Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59 (6): 1225-30, 1999. [PUBMED Abstract]
53. Giovannucci E, Ascherio A, Rimm EB, et al.: Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87 (23): 1767-76, 1995. [PUBMED Abstract]
54. GRAS Notice Inventory. Silver Spring, Md: Food and Drug Administration, 2018. Available online. Last accessed January 24, 2022.

Overview

This section contains the following key information:

• Citrus pectin (CP) is a complex polysaccharide found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.
• Preclinical research suggests that modified citrus pectin (MCP) may have effects on cancer growth and metastasis through multiple potential mechanisms.
• Very limited clinical research has been done with a couple of CP-containing products. For prostate cancer patients, the results suggest some potential clinical benefits with relatively minor and infrequent adverse events.

General Information and History

Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word pectin comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent also in the formulation of oral and topical medicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[1] CP is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[2] Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain CPs.[3] One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle, and apoptosis; MCP inhibits galectin-3 activity.[2]

Some research suggests that MCP may be protective against various types of cancer, including colon, lung, and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.[4]

MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.[5]

Several companies distribute MCP as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of MCP as a treatment for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; CP, Pectasol (PeS, a dietary supplement containing MCP), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.[4]

In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two MCPs previously used in human trials. The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better bioavailability than PeS. Both types of MCP were tested at a concentration of 1 mg/mL and both were effective in inhibiting cell growth and inducing apoptosis through inhibition of the MAPK/ERK signaling pathway and activation of the enzyme caspase-3.[6]

In one study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin-treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacy of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.[7]

Animal studies

Only a few studies have been reported on the effects of MCP in animals bearing implanted cancers and only one involving prostate cancer.[8,9] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in statistically significant reductions in lung metastases but did not affect primary tumor growth.[9]

Human Studies

Interventional studies

In a 2007 pilot study, patients with advanced solid tumors (various types of cancers, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life, including physical functioning, global health status, fatigue, pain, and insomnia. In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[3]

The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder/d) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.[10]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[3] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.[10]

References

1. Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008. [PUBMED Abstract]
2. Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009. [PUBMED Abstract]
3. Azemar M, Hildenbrand B, Haering B, et al.: Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1: 73-80, 2007. Available online. Last accessed January 24, 2022.
4. Jackson CL, Dreaden TM, Theobald LK, et al.: Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology 17 (8): 805-19, 2007. [PUBMED Abstract]
5. Ramachandran C, Wilk BJ, Hotchkiss A, et al.: Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complement Altern Med 11: 59, 2011. [PUBMED Abstract]
6. Yan J, Katz A: PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 9 (2): 197-203, 2010. [PUBMED Abstract]
7. Wang Y, Nangia-Makker P, Balan V, et al.: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 1: e101, 2010. [PUBMED Abstract]
8. Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev 5 (6): 546-52, 2000. [PUBMED Abstract]
9. Pienta KJ, Naik H, Akhtar A, et al.: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87 (5): 348-53, 1995. [PUBMED Abstract]
10. Guess BW, Scholz MC, Strum SB, et al.: Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 6 (4): 301-4, 2003. [PUBMED Abstract]

Overview

This section contains the following key information:

• The pomegranate tree (Punica granatum L.) is native to Asia and cultivated widely throughout world.
• Various components of the pomegranate fruit contain minerals and bioactive polyphenolic compounds, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin.
• Pomegranate juice and extract, as well as some of their bioactive components, inhibit the proliferation of various prostate cancer cell lines in vitro and induce apoptotic cell death in a dose-dependent manner.
• Cytochrome P450 enzyme inhibition and effects on insulin-like growth factor binding protein-3 (IGFBP-3) have been identified as being involved in the in vitro activity.
• Studies in rodent models of prostate cancer have shown that ingestion of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.
• The only fully reported clinical trial of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their prostate-specific antigen (PSA) doubling time (PSADT) and it was associated with improved survival (i.e., slower progression of the disease).
• No serious adverse effects have been reported in clinical trials of pomegranate juice administration (8 oz per day for up to 33 months).
• A phase II study reported that pomegranate extract was associated with an increase of at least 6 month in PSADT in both treatment arms (different doses), without adverse effects. However, a phase III placebo-controlled trial of pomegranate juice and extract did not show a significant increase in PSADT.

General Information and History

The pomegranate tree (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, the East Indies, Africa, and the United States.[1] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[2] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains minerals and a number of bioactive polyphenolic compounds, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin. The arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice.[3] The majority of antioxidant activity comes from ellagitannins.[4] It has been shown that conversion of pomegranate ellagitannins by gut microbes produces a variety of metabolites, such as the urolithins.[5]

Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[6] and may also have positive effects on oral or dental health.[7]

Several companies distribute pomegranate as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of pomegranate as a treatment or prevention for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.

Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).[8]

Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[9–12] In one study, dihydrotestosterone-stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0–100 µM).[10] Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (a major constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.[10]

Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[11,13,14] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols (punicalagin [PA] or EA), a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in statistically significant increases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen-synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments.[11] In a second study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10–100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10–100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.[14]

The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anticarcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.[15]

In addition, the insulin-like growth factor (IGF) system has been implicated in prostate cancer. A study reported in 2010 examined the effects of a POMx on the IGF system. Treating LAPC4 prostate cancer cells with POMx (10 µg/mL concentration of pomegranate extract prepared from skin and arils minus seeds) resulted in cell growth inhibition and apoptosis, but treating the cells with both reagents led to larger effects on growth inhibition and apoptosis. However, these substances may have induced apoptosis by different mechanisms. Other findings suggested that POMx treatment reduced mTOR phosphorylation at Ser2448 and Ser2481, whereas IGFBP-3 increased phosphorylation at those sites. In addition, CWR22Rv1 cells treated with POMx (1 and 10 µg/mL) exhibited a dose-dependent reduction in IGF1 mRNA levels, but treatment with IGFBP-3 or IGF-1 did not alter levels of IGF1; these results suggest that one way POMx decreases prostate cancer cell survival is by inhibiting IGF1 expression.[13]

In a study reported in 2011, human hormone-independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis. [16]

Animal studies

The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11–14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only.[14] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[8,17]

Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes before being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).[9]

In a study reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by age 20 weeks, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By age 34 weeks, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared with the water-fed mice.[18]

Human Studies

Three clinical studies have examined the effect of interventions with pomegranate products on changes in PSADT in patients with biochemically recurrent prostate cancer who had a rising PSA level after surgery or radiation therapy for presumed localized cancer.[19] The first study was a single-arm trial of 48 patients who drank 8 ounces (570 mg/d total polyphenol gallic acid equivalents) of PJ for up to 33 months. PSADT rose from a mean of 15 months (±11 months) at baseline to a mean of 54 months (±102 months, P < .001) on treatment (with a twofold increase in median PSADT from 11.8 to 24 months, P = .029).[20]

The second phase II study was published in 2013 and randomly assigned 92 patients to either 1 g (polyphenol gallic acid content equivalent to 8 ounces of pomegranate juice) (n = 47) or 3 g of pomegranate extract powder (n = 45 )for up to 18 months. Overall, median PSADT increased from 11.9 to 18.5 months (P < .001), but no dose effect was seen (P = .554). Median PSADT increased from 11.9 to 18.8 months in the low-dose arm and from 12.2 to 17.5 months in the high-dose arm.[21]

The third trial was a randomized, double-blinded, placebo controlled study published in 2015. Of the 183 patients who enrolled, 64 patients were treated with placebo, 17 patients were treated with PJ, and 102 patients were treated with pomegranate liquid extract, which contained the same compounds found in PJ, with the exception of a higher proportional content of pomegranate polyphenol and a lower anthocyanidin content. The median change in PSADT was 4.5 months for the placebo group, 1.6 months for the extract group, and 7.6 months for the juice group; however, no paired comparison of groups was statistically significant.[22]

The differences in results between the trials may be partly because of less aggressive disease in the 2006 patient population with lower starting PSA values, but they may also be because the first two trials lacked a placebo arm. All three trials found that pomegranate extract was safe to consume. Of note, in both the 2006 and 2013 studies, two patients in each trial had a 50% decline in PSA. In light of these findings, researchers wondered if there may be a sensitive subpopulation that might benefit from PJ. One potential genetic biomarker candidate is manganese superoxide dismutase (MnSOD), which is the primary antioxidant enzyme in mitochondria. A polymorphism at codon 16 of the MnSOD gene in men encodes either alanine (A) or valine (V). The AA genotype has been associated with more aggressive prostate cancer and with more sensitivity to antioxidants than the VA or VV genotype.[23] A preplanned subset analysis in the 2015 study of the 34 (22%) men with MnSOD AA genotype demonstrated a greater PSADT lengthening in the liquid extract group (median PSADT increased from 13.6 months to 25.6 months, P = .03) while no significant change was seen in the placebo group of MnSOD (median PSADT increased from 10.9–12.7 months, P = .22). In summary, the finding that men with the AA genotype who received pomegranate extract had greater lengthening of PSADT (i.e., slower progression of disease) than did men in the placebo arm, along with the safe profile of PJ and extract in three large studies, suggest that there may be benefit in further studies in the AA MnSOD subpopulation.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[20]

In a pilot study reported in 2007, the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects. In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm.[24]

References

1. Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008. [PUBMED Abstract]
2. Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000. [PUBMED Abstract]
3. Viuda-Martos M, Fernandez-Lopez J, Perez-Alvarez JA: Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9 (6): 635-54, 2010. Available online. Last accessed May 27, 2022.
4. Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009. [PUBMED Abstract]
5. Yuan T, Ma H, Liu W, et al.: Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci 7 (1): 26-33, 2016. [PUBMED Abstract]
6. Aviram M, Rosenblat M, Gaitini D, et al.: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23 (3): 423-33, 2004. [PUBMED Abstract]
7. Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006. [PUBMED Abstract]
8. Seeram NP, Aronson WJ, Zhang Y, et al.: Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55 (19): 7732-7, 2007. [PUBMED Abstract]
9. Albrecht M, Jiang W, Kumi-Diaka J, et al.: Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7 (3): 274-83, 2004. [PUBMED Abstract]
10. Gasmi J, Sanderson JT: Growth inhibitory, antiandrogenic, and pro-apoptotic effects of punicic acid in LNCaP human prostate cancer cells. J Agric Food Chem 58 (23): 12149-56, 2010. [PUBMED Abstract]
11. Hong MY, Seeram NP, Heber D: Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19 (12): 848-55, 2008. [PUBMED Abstract]
12. Lansky EP, Jiang W, Mo H, et al.: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23 (1): 11-20, 2005. [PUBMED Abstract]
13. Koyama S, Cobb LJ, Mehta HH, et al.: Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res 20 (1): 55-62, 2010. [PUBMED Abstract]
14. Malik A, Afaq F, Sarfaraz S, et al.: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 102 (41): 14813-8, 2005. [PUBMED Abstract]
15. Kasimsetty SG, Bialonska D, Reddy MK, et al.: Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57 (22): 10636-44, 2009. [PUBMED Abstract]
16. Wang L, Alcon A, Yuan H, et al.: Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 3 (7): 742-54, 2011. [PUBMED Abstract]
17. Sartippour MR, Seeram NP, Rao JY, et al.: Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32 (2): 475-80, 2008. [PUBMED Abstract]
18. Adhami VM, Siddiqui IA, Syed DN, et al.: Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33 (3): 644-51, 2012. [PUBMED Abstract]
19. Paller CJ, Pantuck A, Carducci MA: A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis 20 (3): 265-270, 2017. [PUBMED Abstract]
20. Pantuck AJ, Leppert JT, Zomorodian N, et al.: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12 (13): 4018-26, 2006. [PUBMED Abstract]
21. Paller CJ, Ye X, Wozniak PJ, et al.: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16 (1): 50-5, 2013. [PUBMED Abstract]
22. Pantuck AJ, Pettaway CA, Dreicer R, et al.: A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18 (3): 242-8, 2015. [PUBMED Abstract]
23. Iguchi T, Wang CY, Delongchamps NB, et al.: Association of MnSOD AA Genotype with the Progression of Prostate Cancer. PLoS One 10 (7): e0131325, 2015. [PUBMED Abstract]
24. Forest CP, Padma-Nathan H, Liker HR: Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res 19 (6): 564-7, 2007 Nov-Dec. [PUBMED Abstract]

Overview

This section contains the following key information:

• Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function.
• Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.
• The results of epidemiological studies suggest some complexity in the association between blood levels of selenium and the risk of developing prostate cancer.
• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large multicenter clinical trial, was initiated to examine the effects of selenium and/or vitamin E on the development of prostate cancer.
• Initial results of SELECT, published in 2009, showed no statistically significant difference in the rate of prostate cancer in men who were randomly assigned to receive the selenium supplements.
• In 2011, updated results from SELECT showed no significant effects of selenium supplementation on prostate cancer risk, but men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took a placebo.
• In 2014, an analysis of SELECT results showed that men who had high selenium status at baseline and who were randomly assigned to receive selenium supplementation had an increased risk of high-grade prostate cancer.

General Information and History

Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[1] A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium homeostasis.

Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 µg.[2] Most dietary selenium occurs as selenocysteine or selenomethionine.[1] Selenium accumulates in the thyroid gland, liver, pancreas, pituitary gland, and renal medulla.[3]

Selenium is a component of the enzyme glutathione peroxidase, an enzyme that functions as an antioxidant.[4] However, at high concentrations, selenium may function as a pro-oxidant.[2]

Selenium is implicated in a number of disease states. Selenium deficiency may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone disorder.[5] Some clinical trials have suggested that high levels of selenium may be associated with diabetes [6] and high cholesterol.[2]

Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.[7] The Nutritional Prevention of Cancer Trial (NPC) was a randomized, placebo-controlled study designed to test the hypothesis that higher selenium levels were associated with lower incidence of skin cancer. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of lung, colorectal, and prostate cancer were significantly reduced.[8]

There is evidence that selenoproteins may be associated with carcinogenesis. For example, reduced expression of glutathione peroxidase 3 and SEPP have been observed in some tumors, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[7]

Some companies distribute selenium as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of selenium as a treatment or prevention for cancer.

Preclinical/Animal Studies

In vitro studies

Different selenium-containing compounds have variable effects on prostate cancer cells as well as normal cells and tissues. Both naturally occurring and synthetic organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[9] In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic acid (MSeA) had the greatest cytotoxic effects.[10]

Studies have suggested that selenium nanoparticles may be less toxic to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the androgen receptor, which led to apoptosis and growth inhibition.[11]

Sodium selenite

In a 2010 study, prostate cancer cells treated with sodium selenite (a natural form of selenium) exhibited increased levels of p53 (a tumor suppressor). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[12]

In a second study, the hormone-sensitive prostate cancer cell line LNCaP was modified to separately overexpress each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in mitochondria may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells.[13]

One study treated prostate cancer cells and benign prostatic hyperplasia (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in hormone-insensitive PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have adverse effects in hormone-sensitive prostate cancer.[14] However, the relevance of these findings to the clinical setting is unclear. These experiments used selenium concentrations of 1 µg/mL to 10 µg/mL, whereas the average U.S. adult male serum selenium concentrations are about 0.125 µg/mL,[15] and prostate tissue concentrations are about 1.5 µg/g.[16]

Animal studies

A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect biomarkers in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in DNA damage, proliferation, or apoptosis in the prostate.[17]

At least one study has compared these three forms of selenium in athymic nude mice injected with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite.[18] Another study investigated the effect of age on selenium chemoprevention in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) diets for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more necrosis and inflammation compared with selenium-containing diets. However, in young mice, tumor development and histopathology were not affected by dietary selenium.[19]

The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of in situ murine prostate cancer development, the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse.[20] Treatment with MSeA and MSeC resulted in slower progression of prostatic intraepithelial neoplasia (PIN) lesions, decreased cell proliferation, and increased apoptosis compared with treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less aggressive prostate cancer than did mice that started treatment at 16 weeks, suggesting early intervention with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate differentiation, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in phase II detoxification or cytoprotection.[21] One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[22]

Human Studies

Epidemiological studies

The results of epidemiological studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations.[23] In a prospective pilot study, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males.[24] However, in a 2009 study of prostate cancer patients, men with higher plasma selenium levels were at greater risk of being diagnosed with aggressive prostate cancer (relative risk, 1.35; 95% confidence interval [CI], 0.99–1.84).[25]

Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, polymorphisms in the selenium-containing enzymes GPX1 and SEP15 genes were found to be associated with prostate cancer risk.[23] Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with single nucleotide polymorphisms (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status.[26] A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer–specific mortality. Among SNPs analyzed, only GPX1 rs3448 was related to overall prostate cancer risk.[27]

A retrospective analysis of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status.[28] In the Physicians’ Health Study, links between SNPs in the SEPP gene (SEPP1) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: rs11959466 was associated with increased risk, and rs13168440 was associated with decreased risk. Tumor SEPP1 mRNA expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer.[29] In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (AA) genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine (V) allele.[25]

An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% CI, 0.73–1.91), 1.33-fold (95% CI, 0.77–2.30), and 2.60-fold (95% CI, 1.44–4.70) increased prostate cancer mortality risk compared with nonusers, respectively (P_trend = .001). The authors reported no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality.[30]

In summary, these epidemiological studies present a conflicting picture. Some studies showed that higher selenium levels were associated with a decreased risk of prostate cancer; others showed a correlation between higher selenium levels and more aggressive prostate cancer. Genetic differences in the SEPP gene may explain the different responses to selenium.

Interventional studies

Interventional studies have examined the efficacy of selenium in preventing and treating prostate cancer.

Prevention

In one study, 60 healthy adult males were randomly assigned to receive either a daily placebo or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements had significantly increased activities of two blood selenium enzymes and significantly decreased levels of prostate-specific antigen (PSA) at the end of the study.[31]

A meta-analysis published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).[32]

However, in 2013, results of a phase III randomized, placebo-controlled trial were reported. The trial investigated the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease. Participants (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high–Se-yeast (200 µg/d or 400 µg/d). The participants were monitored every 6 months for up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[33] Another study examined men with high-grade prostatic intraepithelial neoplasia (HGPIN) who were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results also suggested that selenium supplementation had no effect on prostate cancer risk.[34]

A 2018 Cochrane review that examined the role of selenium in cancer prevention consolidated these studies in a meta-analysis and noted a risk ratio of 1.01 (95% CI, 0.90–1.14) when four prostate cancer studies were reviewed that involved 18,942 patients.[35]

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

On the basis of findings from earlier studies,[8,36] the SELECT, a large multicenter clinical trial, was initiated by the National Institutes of Health in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a phase III, randomized, double-blind, placebo-controlled, population-based trial.[37] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico, were randomly assigned to receive vitamin E (alpha-tocopherol acetate, 400 IU/d) and a placebo, selenium (L-selenomethionine, 200 µg/d) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The primary endpoint of the clinical trial was incidence of prostate cancer.[37]

Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (P = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of diabetes mellitus (P = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[38]

Updated results of SELECT were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly higher in the vitamin E–alone group (P = .008) and represented a 17% increase in prostate cancer risk. The incidence of prostate cancer was also higher in men who took selenium than in men who took placebo, but the differences were not statistically significant.[39]

A number of explanations have been suggested, including the dose and form of vitamin E used in the trial and the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and Se-yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores.[40] In addition, there were concerns about product consistency with high–Se-yeast.[41] However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have antitumor properties.[42,43]

Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Although selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline, it increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (P = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes.[44]

Complicating this picture, an international collaboration compiled and reanalyzed data from 15 studies, including the SELECT trial, that investigated the association between blood and toenail selenium concentrations and prostate cancer risk.[45] In the analysis of 6,497 men with prostate cancer and 8,107 controls, blood selenium level was not associated with the risk of total prostate cancer, but high blood selenium level was associated with a lower risk of aggressive disease. Toenail selenium concentration was inversely associated with risk of total prostate cancer (odds ratio, 0.29; 95% CI, 0.22–0.40; P_trend < .001), including both aggressive and nonaggressive disease.

In a case-cohort analysis of the SELECT trial, 1,434 men underwent analysis of SNPs in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer; selenium or vitamin E supplementation may modify an individual’s response to those risks.[46]

In summary, data from the SELECT trial did not provide evidence that selenium, when given to unselected populations, decreased the risk of prostate cancer. Subsequent analyses have shown that baseline selenium levels may influence the outcomes of selenium supplementation, though the evidence remains conflicting. Emerging evidence suggests that SNPs in genes related to both selenium and prostate cancer likely modify the effect of selenium supplementation. Further research is needed to better understand which patients may benefit from or be harmed by selenium supplementation.

To date, the most recent literature demonstrates that when administered to a non-selected population, selenium has no significant effect on either prostate cancer prevention or PSA levels.

Treatment

A study explored the potential role of selenium in prostate cancer patients on active surveillance. It examined 140 men who were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of Se-yeast. The results showed no significant difference in PSA velocity across treatment groups. Concerningly, men who received high-dose selenium and had the highest baseline plasma selenium levels, had a higher PSA velocity than did men in the placebo group. There was no significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[47]

Another study examined the potential role selenium played in the adjuvant setting. Prostate cancer patients were randomly assigned to receive either combination silymarin (570 mg) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants who received supplements reported improved quality of life and showed decreases in low-density lipoprotein cholesterol and total cholesterol.[48]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[33,47] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (P = .08).[38]

References

1. Brown KM, Arthur JR: Selenium, selenoproteins and human health: a review. Public Health Nutr 4 (2B): 593-9, 2001. [PUBMED Abstract]
2. Tanguy S, Grauzam S, de Leiris J, et al.: Impact of dietary selenium intake on cardiac health: experimental approaches and human studies. Mol Nutr Food Res 56 (7): 1106-21, 2012. [PUBMED Abstract]
3. Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [PUBMED Abstract]
4. Bodnar M, Konieczka P, Namiesnik J: The properties, functions, and use of selenium compounds in living organisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30 (3): 225-52, 2012. [PUBMED Abstract]
5. Sunde RA: Selenium. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. Informa Healthcare, 2010, pp 711-8.
6. Boosalis MG: The role of selenium in chronic disease. Nutr Clin Pract 23 (2): 152-60, 2008 Apr-May. [PUBMED Abstract]
7. Davis CD, Tsuji PA, Milner JA: Selenoproteins and cancer prevention. Annu Rev Nutr 32: 73-95, 2012. [PUBMED Abstract]
8. Clark LC, Combs GF, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [PUBMED Abstract]
9. Pinto JT, Sinha R, Papp K, et al.: Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells. Int J Cancer 120 (7): 1410-7, 2007. [PUBMED Abstract]
10. Lunøe K, Gabel-Jensen C, Stürup S, et al.: Investigation of the selenium metabolism in cancer cell lines. Metallomics 3 (2): 162-8, 2011. [PUBMED Abstract]
11. Kong L, Yuan Q, Zhu H, et al.: The suppression of prostate LNCaP cancer cells growth by Selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis. Biomaterials 32 (27): 6515-22, 2011. [PUBMED Abstract]
12. Sarveswaran S, Liroff J, Zhou Z, et al.: Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer. Int J Oncol 36 (6): 1419-28, 2010. [PUBMED Abstract]
13. Xiang N, Zhao R, Zhong W: Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells. Cancer Chemother Pharmacol 63 (2): 351-62, 2009. [PUBMED Abstract]
14. Kandaş NO, Randolph C, Bosland MC: Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutr Cancer 61 (2): 251-64, 2009. [PUBMED Abstract]
15. Niskar AS, Paschal DC, Kieszak SM, et al.: Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994. Biol Trace Elem Res 91 (1): 1-10, 2003. [PUBMED Abstract]
16. Takata Y, Morris JS, King IB, et al.: Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 69 (15): 1635-42, 2009. [PUBMED Abstract]
17. Waters DJ, Shen S, Kengeri SS, et al.: Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis. Nutrients 4 (11): 1650-63, 2012. [PUBMED Abstract]
18. Li GX, Lee HJ, Wang Z, et al.: Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29 (5): 1005-12, 2008. [PUBMED Abstract]
19. Holmstrom A, Wu RT, Zeng H, et al.: Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice. J Nutr Biochem 23 (9): 1086-91, 2012. [PUBMED Abstract]
20. Wang L, Bonorden MJ, Li GX, et al.: Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila) 2 (5): 484-95, 2009. [PUBMED Abstract]
21. Zhang J, Wang L, Anderson LB, et al.: Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3 (8): 994-1006, 2010. [PUBMED Abstract]
22. Gundimeda U, Schiffman JE, Chhabra D, et al.: Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells. J Biol Chem 283 (50): 34519-31, 2008. [PUBMED Abstract]
23. Steinbrecher A, Méplan C, Hesketh J, et al.: Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 19 (11): 2958-68, 2010. [PUBMED Abstract]
24. Muecke R, Klotz T, Giedl J, et al.: Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 48 (3): 452-6, 2009. [PUBMED Abstract]
25. Chan JM, Oh WK, Xie W, et al.: Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer. J Clin Oncol 27 (22): 3577-83, 2009. [PUBMED Abstract]
26. Méplan C, Rohrmann S, Steinbrecher A, et al.: Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer. PLoS One 7 (11): e48709, 2012. [PUBMED Abstract]
27. Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013. [PUBMED Abstract]
28. Meyer HA, Hollenbach B, Stephan C, et al.: Reduced serum selenoprotein P concentrations in German prostate cancer patients. Cancer Epidemiol Biomarkers Prev 18 (9): 2386-90, 2009. [PUBMED Abstract]
29. Penney KL, Li H, Mucci LA, et al.: Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival. Prostate 73 (7): 700-5, 2013. [PUBMED Abstract]
30. Kenfield SA, Van Blarigan EL, DuPre N, et al.: Selenium supplementation and prostate cancer mortality. J Natl Cancer Inst 107 (1): 360, 2015. [PUBMED Abstract]
31. Zhang W, Joseph E, Hitchcock C, et al.: Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr Res 31 (2): 165-8, 2011. [PUBMED Abstract]
32. Hurst R, Hooper L, Norat T, et al.: Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 96 (1): 111-22, 2012. [PUBMED Abstract]
33. Algotar AM, Stratton MS, Ahmann FR, et al.: Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer. Prostate 73 (3): 328-35, 2013. [PUBMED Abstract]
34. Marshall JR, Tangen CM, Sakr WA, et al.: Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila) 4 (11): 1761-9, 2011. [PUBMED Abstract]
35. Vinceti M, Filippini T, Del Giovane C, et al.: Selenium for preventing cancer. Cochrane Database Syst Rev 1: CD005195, 2018. [PUBMED Abstract]
36. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
37. Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [PUBMED Abstract]
38. Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [PUBMED Abstract]
39. Klein EA, Thompson IM, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [PUBMED Abstract]
40. Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [PUBMED Abstract]
41. Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [PUBMED Abstract]
42. Hatfield DL, Gladyshev VN: The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9 (1): 18-21, 2009. [PUBMED Abstract]
43. Ohta Y, Kobayashi Y, Konishi S, et al.: Speciation analysis of selenium metabolites in urine and breath by HPLC- and GC-inductively coupled plasma-MS after administration of selenomethionine and methylselenocysteine to rats. Chem Res Toxicol 22 (11): 1795-801, 2009. [PUBMED Abstract]
44. Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [PUBMED Abstract]
45. Allen NE, Travis RC, Appleby PN, et al.: Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies. J Natl Cancer Inst 108 (11): , 2016. [PUBMED Abstract]
46. Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-1058, 2016. [PUBMED Abstract]
47. Stratton MS, Algotar AM, Ranger-Moore J, et al.: Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer. Cancer Prev Res (Phila) 3 (8): 1035-43, 2010. [PUBMED Abstract]
48. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy – a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010. [PUBMED Abstract]

Overview

This section contains the following key information:

• Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
• Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein (the most abundant), daidzein, and glycitein.
• Genistein affects components of multiple growth and proliferation-related pathways in prostate cancer cells, including the COX-2/prostaglandin, epidermal growth factor (EGF), and insulin-like growth factor (IGF) pathways.
• Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
• Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.
• Epidemiological studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
• Early-phase clinical trials with isoflavones, soy, and soy products for the prevention and treatment of prostate cancer have been limited to relatively short durations of intervention and sample sizes with low statistical power. These studies targeted heterogeneous prostate cancer patient populations (in high-risk, early- and later-stage disease) and varying doses of isoflavones, soy, and soy products, and have not demonstrated evidence of reducing prostate cancer progression.
• Other trials evaluating the role of isoflavones, soy, or soy products in the management of androgen deprivation therapy (ADT) side effects have found no improvement with isoflavone treatment compared with placebo.
• Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.

General Information and History

Soybean, a major food source and a medicinal substance, has been used in China for centuries. Soybean was used as one of the early food sources in China.[1,2] Soybean was mentioned in the book titled, The Classic of Poetry (Shijing, 11th–7th centuries BCE), with its collection and cultivation. During the Warring States period (475–221 BCE), soybean became one of five major foods (“five grains”) of the Chinese. The medical use of soybean was also discussed in one of the major Chinese medicine books titled, Inner Canon of the Yellow Emperor (Huangdi Neijing, 400 BCE and 260 BCE), which stated that “five grains are used to nourish and replenish the body.” In traditional Chinese medicine, soybean has been used to treat kidney conditions, promote water retention and reduce swelling, and for weakness, dizziness, poor sleep, and night sweats.

Although records of soy use in China date back to the 11th century BCE, it was not until the 18th century that the soy plant reached Europe and the United States. The soybean is an incredibly versatile plant. It can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[3]

Soy foods contain a number of phytochemicals that may have health benefits, but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[4] Other isoflavones found in soy include daidzein and glycitein.[5] Many of these isoflavones are also found in other legumes and plants, such as red clover.

Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours after soy product consumption.[6] Isoflavones are phytoestrogens that bind to estrogen receptors. Prostate tissue is known to express estrogen receptor beta and it has been shown that the isoflavone genistein has greater affinity for estrogen receptor beta than for estrogen receptor alpha.[7]

A link between isoflavones and prostate cancer was first observed in epidemiological studies that demonstrated a lower risk of prostate cancer in populations consuming considerable amounts of dietary soy.[8,9] Subsequent studies evaluating the role of soy in experimental models further showed anticancer properties of soy, specifically relevant to prostate carcinogenesis. These early studies have led to a few clinical trials in humans using soy food products or supplements that targeted men with varying stages of prostate cancer. Although these studies showed modulation of intermediate endpoints or surrogate biomarkers of prostate cancer progression, the results indicating beneficial effects from soy or soy products have been mixed.

Several companies distribute soy as a dietary supplement. In the United States, dietary supplements are regulated by the U.S. Food and Drug Administration (FDA) as a separate category from foods, cosmetics, and drugs. Unlike drugs, dietary supplements do not require premarket evaluation and approval by the FDA unless specific disease prevention or treatment claims are made. The quality and amount of ingredients in dietary supplements are also regulated by the FDA through Good Manufacturing Practices (GMPs). The FDA GMPs requires that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition, and limits on contamination that may adulterate dietary supplements. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency every year, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of soy as a treatment for cancer or any other medical condition.

Preclinical/Animal Studies

In vitro studies

Individual isoflavones

A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[10] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin-8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[11] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro. However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[12]

Combinations of isoflavones

Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzein, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggested that products containing a combination of active compounds (e.g., whole foods) may be more effective in preventing cancer than individual compounds.[13] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[14]

At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[15]

Animal studies

Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors epidermal growth factor receptor (EGFR) and insulin like growth factor-1 receptor (IGF-1R) in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[16] In one study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[17]

In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis but no change in primary tumor volume, compared with mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[18]

In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/d or 400 mg genistein/kg body weight/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[19]

Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/d), mixed isoflavones (50 mg/kg body weight/d; contained 43% genistein, 21% daidzein, and 2% glycitein), and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[20]

In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[21,22]

Human Studies

Human studies evaluating isoflavones and soy for the prevention and treatment of prostate cancer have included epidemiological studies and early-phase trials. Several phase I-II randomized clinical studies have examined isoflavones and soy product for bioavailability, safety, and effectiveness in prostate cancer prevention or treatment.[23–25] These studies have included a wide range of subject populations, including high-risk men; prostate cancer patient populations (localized and later-stage disease); varying doses of isoflavones, soy, and soy products; and were limited to relatively short durations of observation or intervention and sample sizes with low statistical power.

Epidemiological studies

In 2018, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[26] However, these data from population studies must be interpreted with caution as the studies relied on self-reported data obtained using varying forms of dietary data collection instruments with recall bias, in addition to numerous forms of individual or multiple isoflavones, soy supplements, and soy foods. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.

Prevention studies

Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (see Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5–10 mcg/mL at baseline). The duration of intervention was between 6 months [15] and 1 year [27,28], with varying formulations of isoflavones derived from soy [15,27] and red clover.[28] In a single trial that showed no significant changes in serum PSA after intervention with isoflavones, a reduction in prostate cancer progression at 1 year in a subgroup of men older than 65 years was demonstrated. Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials.

Table 3. Randomized Placebo-controlled Trials of Isoflavones or Soy for Prostate Cancer Preventiona

Reference	Isoflavone Dose	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)	Duration of Intervention		Toxicities	Results	Levels of Evidence b
ALT = alanine transaminase; AST = aspartate transaminase; PCa = prostate cancer; PSA = prostate-specific antigen.
aMen with a negative biopsy and elevated PSA max 10 mcg/mL.
bStrongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[15]	Soy isoflavones (40 mg/d; comprising 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg/d) versus placebo	85; 43; 42	6 mo		No significant adverse effects either in the placebo or supplement groups; one subject on placebo experienced severe diarrhea during the trial and dropped out subsequently	Decrease in serum PSA (P < .05)	1iDii
[28]	60 mg/d isoflavone extract from red clover	20; 20; None	12 mo		Significant increase in ALT and AST after 3 mo (P < .001)	Decrease in serum PSA (P < .05)	2Dii
[27]	60 mg/d isoflavones	158; 78; 80	12 mo		Two patients had grade 3 adverse events, one in the isoflavone group suffered iliac artery stenosis and the other in the placebo group suffered ileus; other adverse events were mild in severity	Decrease in PCa incidence in men older than 65 years with isoflavones (P < .05)	1iDi

Treatment of prostate cancer

Clinical trials evaluating isoflavones, soy supplements, and soy products (see Table 4 and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.

Isoflavones

Table 4. Randomized Placebo-controlled Trials of Isoflavones Before Prostatectomy in Men With Localized Prostate Cancer

Reference	Isoflavone Dose	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)	Duration of Intervention	Toxicities		Results	Levels of Evidencea
AR = androgen receptor; PSA = prostate-specific antigen.
aStrongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[29]	30 mg/d genistein	54; 23; 24	3–6 wk	Clinical adverse events were Grade 1 (mild); two biochemical adverse events recorded, both in the genistein group (one increase in serum lipase, one increase in serum bilirubin) potentially related to study agent		Decrease in serum PSA (P < .05), decrease in total cholesterol (P < .01), increase in plasma genistein (P < .001)	1iDiii
[30]	Soy isoflavone capsules (total isoflavones, 80 mg/d)	86; 42; 44	6 wk	All adverse events were Grade 1 (mild)		Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared with men receiving placebo were not statistically significant	1iDii
[31]	Supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones/d versus placebo followed by open-label	53; 28; 25	6 mo intervention followed by 6 mo open label (active surveillance)	Not evaluated		Significant increase in serum genistein and daidzein; no significant findings regarding serum PSA changes	1iDii
[32,33]	Isoflavone tablets (60 mg/d)	60; 25; 28	4–12 wk	Adverse events were Grade I and II in both groups, with two events that were identified as Grade III in the treatment arm and determined to be unrelated to agent (constitutional symptoms of fever related to a viral infection)		Increase in plasma isoflavones (P < .001) in the isoflavone-treated group versus placebo; greater concentrations of plasma isoflavones daidzein (P = .02) and genistein (P = .01) were inversely correlated with changes in serum PSA	1iDii
[32,34]	Isoflavone capsules 40, 60, or 80 mg	45;12 (40 mg), 11 (60 mg) ,10 (80 mg); 11	27–33 d	Adverse events were Grade I-II		Increased plasma isoflavones at all doses; increased serum total estradiol in the 40 mg (P = .02) isoflavone-treated arm versus placebo; increased serum-free testosterone in the 60 mg isoflavone-treated arm (P = .003)	1iiDii
[35]	Cholecalciferol (vitamin D3) 200,000 IU + genistein (G-2535) 600 mg/d	15; 7; 8	21–28 d	Adverse events occurred in four patients in the placebo group and five patients in the vitamin D + genistein group		Increased AR expression (P < .05); no other significant findings	1iiDii

Soy protein or whole soy products

Table 5. Randomized Placebo-controlled Trials of Soy Protein or Soy Products Before Prostatectomy in Men With Localized Prostate Cancer

Reference	Intervention Dose	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)	Duration of Intervention		Toxicities	Results	Levels of Evidencea
COX = cyclooxygenase; GI = gastrointestinal; PSA = prostate-specific antigen.
aStrongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[36]	Soy supplement with 60 mg isoflavone versus placebo supplement	60; 29; 30	12 wk		Nine grade I-II GI toxicities in the placebo group and eight from the isoflavone group	No significant findings	1iDii
[37]	Soy supplements (three 27.2 mg tablets/d; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo	19; 11; 8	2 wk before surgery		Not evaluated	Higher isoflavone concentration (x6) in tissue than in serum following treatment with the soy supplements	1iDiii
[38]	Soy isoflavone supplements (total isoflavones, 160 mg/d and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein)	33; 17; 16	12 wk		Not evaluated	No significant difference between groups	1iDii
[39]	Soy (high phytoestrogen), soy and linseed (high phytoestrogen), or wheat (low phytoestrogen)	29; 8 (soy), 10 (soy and linseed); 8 (wheat)	8–12 wk		Not evaluated	Reduction in total PSA (P = .02); percentage of change in free/total PSA ratio (P = .01); percentage of change in free androgen index (P = .04)	1iDii
[10]	Soy isoflavone supplement (providing isoflavones, 81.6 mg/d) or placebo	25; 13; 12	2 wk before surgery (pilot)		Not evaluated	Decrease in COX-2 mRNA levels (P < .01); increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with placebo group	1iDii

Isoflavones and soy products for biochemical recurrence after treatment

Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [40–43] with one study suggesting modulation of systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of myeloid-derived suppressor cells [43] (see Table 6).

Table 6. Clinical Trials of Soy and Soy Products in Men on Active Surveillance or With Biochemical Recurrence After Treatment for Prostate Cancer

Reference	Trial Design	Dose	Duration of Intervention	Treatment Group (Enrolled; Treated; Placebo or No Treatment Control)	Toxicities	Results	Levels of Evidencea
GCP = genistein combined polysaccharide; GI = gastrointestinal; PCa = prostate cancer; RCT = randomized controlled trial.
aStrongest evidence reported that the treatment under study has activity or improves the well-being of cancer patients. For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[40]	Nonrandomized	Soy beverage daily (providing approximately 65–90 mg isoflavones)	6 mo	34; 29; None	Adverse events included minor GI side effects	No statistically significant findings regarding PSA, PSA-doubling time	2C
[41]	Open-label	Soy milk 3x/d (isoflavones, 141 mg/d)	12 mo	20; 20; None	Toxicity data lacks details; GI (loose stools) toxicities were the most common complaint from a small number of men in the GCP group	No statistically significant findings regarding serum PSA changes	2Dii
[42]	RCT	Beverage powder containing soy-protein isolate (20 g protein) or calcium caseinate	2 y	177; 87; 90	All adverse events were grades I-II; there were no differences in adverse events between the two groups	No significant findings regarding serum PSA changes	1iDii
[43]	RCT	Two slices of soy bread containing 68 mg/d soy isoflavones or soy bread containing almond powder	56 d	32; 25; None	Soy and soy-almond breads were without grade 2 or higher toxicity	Significant modulation of multiple plasma cytokines and chemokines	1iiDii

Management of androgen deprivation therapy side-effects

ADT is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neithe

Complementary and alternative medicine (CAM) is a form of treatment used in addition to (complementary) or instead of (alternative) standard treatments.

In the United States, about 1 out of every 8 men will be diagnosed with prostate cancer. It is the second most common cancer in men in the United States. CAM use among men with prostate cancer is common. Studies of why men with prostate cancer decide to use CAM show that their choice is based on medical history, beliefs about the safety and side effects of CAM compared to standard treatments, and a need to feel in control of their treatment.

CAM treatments used by men with prostate cancer include certain foods, dietary supplements, herbs, vitamins, and minerals.

Different types of studies have been done to study the use of CAM in prostate cancer. These study types include:

CAM treatments have been studied to see if their use lowers the risk of prostate cancer, kills prostate cancer cells, or lowers the risk that cancer will come back after treatment. Most of these studies used prostate-specific antigen (PSA) levels to find out whether the treatment worked. This is a weaker measure of how well the treatment works than direct measures, such as fewer new cases of prostate cancer, or smaller tumor size or lower rate of recurrence after treatment for prostate cancer.

This PDQ summary has sections about the use of specific foods and dietary supplements to prevent or treat prostate cancer:

Each section includes the following information for each food or dietary supplement:

Studies of CAM use to treat prostate cancer have shown the following:

Studies of CAM use to lower prostate cancer risk or to prevent it from coming back have shown the following:

For more information, see Prostate Cancer Prevention.

1. What is calcium?

   Calcium is a common mineral in the body that helps blood vessels, muscles, and nerves send signals from cell to cell and release hormones. The body stores most calcium in bones and teeth.

2. How is calcium given or taken?

   The main sources of calcium are in foods and dietary supplements. About one-third of dietary calcium comes from milk and milk products like cheese and yogurt. Vegetable sources include bok choy, kale, and broccoli. Calcium is sometimes added to foods and drinks, such as fruit juices, tofu, and cereals.

   Most research about calcium and prostate cancer risk has studied calcium in the diet, not calcium in supplements.

3. Have any laboratory or animal studies been done using calcium?

   For information on laboratory and animal studies done using calcium, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of calcium been done in people?

   Studies of people in many parts of the world have been done to find out if there is a link between dairy products, calcium supplements, and prostate cancer risk. The results of these studies have been mixed. Some studies have shown that calcium has an effect on the overall risk of developing prostate cancer or on stopping cancer from coming back after treatment, and others have not.

   For information on studies in people taking calcium supplements, dairy products, or non-dairy calcium products, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

5. Is calcium approved by the FDA for use as a cancer treatment in the United States?

   The FDA has not approved the use of calcium as a treatment for cancer.

   The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of calcium supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is green tea?

   Tea comes from the Camellia sinensis plant. The way tea leaves are processed determines whether green tea, black tea, or oolong tea is made. Green tea is made by steaming and drying the leaves.

   The health benefits studied in green tea are thought to be from compounds called polyphenols. Polyphenols are a group of plant chemicals that include catechins (antioxidants that help protect cells from damage). Catechins make up most of the polyphenols in green tea and vary based on the source of the tea leaves and how they are processed. This makes it hard to identify most of the chemical factors linked to the health benefits of green tea.

   Some studies suggest that green tea may protect against heart and blood vessel disease.

2. How is green tea given or taken?

   People usually drink green tea or take it as a dietary supplement.

3. Have any laboratory or animal studies been done using green tea?

   For information on laboratory and animal studies done using green tea, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of green tea been done in people?

   Population studies and clinical trials have been done to find out if green tea can prevent or treat prostate cancer. Results have been mixed. Some studies have shown a short-term decrease in prostate-specific antigen (PSA) level or a lower risk of having prostate cancer, and others have not. There is not enough evidence to know whether green tea can prevent or treat prostate cancer.

   Overall, population studies suggest that green tea may help protect against prostate cancer in Asian populations. Prostate cancer deaths in Asia are among the lowest in the world. Other populations have not been studied.

   For information on studies in people drinking green tea or taking green tea supplements, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

5. Have any side effects or risks been reported from green tea?

   A trial of oral green tea extract in patients with solid tumors reported that drinking 7 to 8 Japanese-style cups (equal to 3 ½ to 4 US cups) of tea 3 times a day for 6 months was a safe dose.

   Clinical trials have reported on the safety of long-term use of green tea to prevent prostate cancer. In a United States trial, men at risk of prostate cancer were given green tea extract or a placebo for 1 year. There were more side effects in the group who received the green tea extract than in the group who received the placebo.

   In safety studies of green tea for men with prostate cancer, short-term green tea use for up to 90 days was well tolerated. One study found that the most reported side effects of green tea were headache, chest pain, or gastrointestinal symptoms, such as nausea and diarrhea. These were mild except for two reports of trouble breathing and severe anorexia. In men with advanced prostate cancer, side effects of green tea included insomnia, confusion, and fatigue. In rare cases, liver problems have occurred.

6. Is green tea approved by the FDA for use as a cancer treatment in the United States?

   The FDA has not approved the use of green tea as a treatment for cancer or any other medical condition.

   The FDA Division of Drug Oncology Products recommends that green tea extract be taken with food by participants in clinical trials and that frequent liver function tests be considered during treatment, especially in the first few months of starting a clinical trial.

   Green tea is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of green tea supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is lycopene?

   Lycopene is a carotenoid (a natural red color made by plants). It mixes with or dissolves in fats. Lycopene protects plants from light-related stress and helps them use the energy of the sun to make nutrients. Lycopene is found in fruits and vegetables like tomatoes, apricots, guavas, and watermelons.

   The main source of lycopene in the United States is tomato-based products. Lycopene is easier for the body to use when it is eaten in processed tomato products like tomato paste and tomato puree than in raw tomatoes.

   Lycopene has been studied for its role in the prevention of heart and blood vessel disease.

2. How is lycopene given or taken?

   Lycopene may be eaten in food or taken in dietary supplements.

3. Have any laboratory or animal studies been done using lycopene?

   For information on laboratory and animal studies done using lycopene, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of lycopene been done in people?

   Population studies and clinical trials have been done to find out if lycopene can prevent or treat prostate cancer. Some studies have shown a lower risk of prostate cancer or a decrease in prostate-specific antigen (PSA) level, and others have not. These mixed results may be explained by differences within the studies, such as the sources and types of lycopene studied, the diets of the participants, and differences in participants’ prostate cancer risk factors (e.g., genetics, obesity, and tobacco and alcohol use). Also, most research has studied the effects of lycopene on the risk of all prostate cancers, and has not studied effects of lycopene on low-grade prostate cancer compared with high-grade prostate cancer. There is not enough evidence to know whether lycopene can prevent or treat prostate cancer.

   For information on studies in people taking lycopene supplements or foods containing lycopene, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

   For information on trials of combination therapies that include lycopene, see the Combination Therapies section of this summary.

5. Have any side effects or risks been reported from lycopene?

   Lycopene has been given in many clinical trials with very few side effects. Side effects, such as diarrhea, nausea and vomiting, bloating, increased gas, and stomach irritation have been reported. In one study, symptoms went away when lycopene was taken with meals.

6. Is lycopene approved by the FDA for use to prevent or treat cancer in the United States?

   The FDA has not approved the use of lycopene as a treatment for cancer or any other medical condition.

   Lycopene is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of lycopene supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is modified citrus pectin?

   Pectin is a substance made of small sugar molecules that are linked together. Pectin is found in the cell wall of most plants and has gel-like qualities that are useful in making many types of food and medicine.

   Citrus pectin is found in the peel and pulp of citrus fruits such as oranges, grapefruit, lemons, and limes. Citrus pectin can be modified (changed) during manufacturing so that it can be dissolved in water and absorbed by the body. This changed citrus pectin is called modified citrus pectin (MCP).

2. How is MCP given or taken?

   MCP may be taken by mouth in powder or capsule form.

3. Have any laboratory or animal studies been done using MCP?

   For information on laboratory and animal studies done using MCP, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of MCP been done in people?

   Few studies have been done in men with prostate cancer. There is not enough evidence to know whether MCP has any effect on prostate cancer.

5. Have any side effects or risks been reported from MCP?

   Side effects that have been reported include itching, upset stomach, abdominal cramps, increased gas, and diarrhea.

6. Is MCP approved by the FDA for use to prevent or treat cancer in the United States?

   The FDA has not approved the use of MCP as a treatment for cancer or any other medical condition.

   MCP is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of MCP supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is pomegranate?

   The pomegranate is a fruit grown in Asia and in the Mediterranean, East Indies, Africa, and the United States. Pomegranate has been used as medicine for hundreds of years.

   The pomegranate is made up of the following:

   • The peel, which makes up half the fruit and contains polyphenols and minerals.
   • The seeds.
   • The aril (the layer between the peel and the seeds), which contains phenolics and flavonoids including anthocyanins, which give the pomegranate fruit and juice a red color.
2. How is pomegranate given or taken?

   Pomegranate fruit and juice may be taken as food, drink, or a dietary supplement.

3. Have any laboratory or animal studies been done using pomegranate?

   For information on laboratory and animal studies done using pomegranate, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of pomegranate been done in people?

   In a 2015 study, 183 men with recurrent prostate cancer were randomly assigned to receive either pomegranate juice, pomegranate extract, or a placebo. The study found no difference in how fast the prostate-specific antigen (PSA) level rose between the 3 groups. There is not enough evidence to know whether pomegranate can prevent or treat prostate cancer.

5. Have any side effects or risks been reported from pomegranate?

   No serious side effects have been reported from the use of pomegranate.

6. Is pomegranate approved by the FDA for use to prevent or treat cancer in the United States?

   The FDA has not approved the use of pomegranate as a treatment for cancer or any other medical condition.

   Pomegranate is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of pomegranate supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is selenium?

   Selenium is a mineral that is essential to people in tiny amounts. Selenium is needed for many body functions, including reproduction and immunity. Food sources of selenium include meat, vegetables, and nuts. The amount of selenium found in the food depends on the amount of selenium in the soil where the food grows. Selenium is stored in the thyroid gland, liver, pancreas, pituitary gland, and kidneys.

   Selenium may play a role in many diseases, including cancer. Results of the large National Cancer Institute-sponsored Selenium and Vitamin E Cancer Prevention Trial (SELECT) suggest that men with prostate cancer should not take selenium supplements.

2. How is selenium given or taken?

   Selenium may be eaten in food or taken in dietary supplements.

3. Have any laboratory or animal studies been done using selenium?

   For information on laboratory and animal studies done using selenium, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of selenium been done in people?

   Population studies and clinical trials have been done to find out if selenium can prevent or treat prostate cancer. The results of these studies have been mixed, but the results of a large, randomized clinical trial showed selenium had no effect on preventing prostate cancer.

   For information on studies in people taking selenium, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

5. Have any side effects or risks of selenium supplements been reported?

   Selenium supplements have been well tolerated in many clinical trials. But, in the Selenium and Vitamin E Cancer Prevention Trial, the use of selenium supplements was linked with a slight increase in the rate of diabetes mellitus.

   In several large studies, men with high selenium levels were at greater risk of being diagnosed with aggressive prostate cancer or dying from prostate cancer.

6. Is selenium approved by the FDA for use as a cancer treatment in the United States?

   The FDA has not approved the use of selenium supplements for the treatment or prevention of cancer.

   Selenium is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of selenium supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is soy?

   The soybean plant has been grown in Asia for food for hundreds of years. Soybeans are used to make soy milk, miso, tofu, soy flour, oil, and other food products.

   Soy foods contain phytochemicals that may have health benefits. Isoflavones are the most widely studied compounds in soy. Major isoflavones in the soybean include genistein, daidzein, and glycitein.

   Isoflavones are phytoestrogens (estrogen-like substances found in plants) that attach to estrogen receptors found in prostate cancer cells. Genistein may affect some processes inside prostate cancer cells that are involved in the growth and spread of cancer.

2. How is soy given or taken?

   Soy may be eaten in food or taken in dietary supplements.

3. Have any laboratory or animal studies been done using soy?

   For information on laboratory and animal studies done using soy, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of soy been done in people?

   Population studies and clinical trials have been done to find out if soy can prevent or treat prostate cancer. The results of these studies have been mixed. Some studies have shown a lower risk of prostate cancer or a change in prostate-specific antigen (PSA) level, and others have not. The results may be mixed because of the small number of men who participated in the studies and the different types and doses of soy products given.

   Small randomized clinical trials have been done to study the effects of isoflavones or soy on prostate cancer. The results of these studies have been mixed. See Table 3, Table 4, and Table 5 of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements for information on randomized, placebo-controlled clinical trials of isoflavones and soy.

   For more information on studies in people taking soy supplements, soy products, or soy found in foods, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

5. Have any side effects or risks been reported from soy?

   Soy products and isoflavones have caused very few side effects in people with prostate cancer who participated in clinical trials. The most commonly reported side effects were gastrointestinal symptoms, such as diarrhea.

6. Is soy approved by the FDA for use to prevent or treat cancer in the United States?

   The FDA has not approved the use of soy as a treatment for cancer or any other medical condition.

   Soy is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of soy supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is vitamin D?

   Vitamin D is a fat-soluble vitamin found in fatty fish, fish liver oil, and eggs. Vitamin D may also be added to dairy products. Vitamin D:

   • Helps absorb calcium from food in the small intestine.
   • Improves muscle strength and immune system function.
   • Lowers inflammation.
   • Maintains levels of calcium and phosphate in the blood.
   • Helps with bone growth and protects against osteoporosis in adults.

   A person’s vitamin D level is checked by measuring the amount of 25-hydroxyvitamin D in the blood.

2. How is vitamin D given or taken?

   Vitamin D is made by the body when exposed to sunlight. Vitamin D may also be eaten in food or taken in dietary supplements.

3. Have any laboratory or animal studies been done using vitamin D?

   For information on laboratory and animal studies done using vitamin D, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any studies of vitamin D been done in people?

   Population studies and clinical trials have been done to study the effects of vitamin D on prostate cancer. The results of these studies have been mixed. Some studies have shown a link between Vitamin D levels and prostate cancer, and others have not. There is not enough evidence to know whether vitamin D can prevent prostate cancer.

   Studies often look at specific factors that affect a person’s vitamin D levels to see how those factors influence prostate cancer risk. Factors that have been studied include:

   • Low sun exposure.
   • Levels of vitamin D in the diet and blood.
   • Genetic changes.

   Some genetic changes in tumor features that interact with vitamin D might affect the growth and spread of prostate cancer. One of those features is a molecule called a vitamin D receptor. Studies suggest that changes in this receptor could influence a person’s risk of prostate cancer or increase the chance that the cancer will spread. More research is needed to confirm that vitamin D receptors play a role in prostate cancer.

   For information on studies in people taking vitamin D supplements, vitamin D products, or vitamin D in food, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

5. Have any side effects or risks been reported from vitamin D?

   Vitamin D can cause serious health problems when taken at high doses over many years. Taking high levels of Vitamin D can cause too much calcium to be absorbed in the intestines, leading to rapid increases in blood calcium levels. This condition is called hypercalcemia.

   In a group of 26 studies, Vitamin D was reviewed for safety, how well it works, and whether it interacts with drugs used to treat prostate cancer and other tumors. The reviewers found the risk of side effects and interactions with other drugs to be low.

   Several studies looked at the safety of high-dose vitamin D and how well it works with chemotherapy (docetaxel) to treat men with prostate cancer that did not respond to hormone therapy. The side effects that occurred after treatment with high-dose vitamin D and docetaxel were the same as the side effects noted after treatment with docetaxel alone.

6. Is vitamin D approved by the FDA for use as a cancer treatment in the United States?

   The FDA has not approved the use of vitamin D as a treatment for cancer.

   Vitamin D is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of vitamin D supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

1. What is vitamin E?

   Vitamin E is an antioxidant that may help protect cells from damage. Vitamin E also affects how signals are sent within cells and how the cell makes RNA and proteins.

   There are eight forms of vitamin E: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-). Alpha-tocopherol, the form of vitamin E used in dietary supplements, is found in greater amounts in the body and is the most active form of vitamin E. Most vitamin E in the diet comes from gamma-tocopherol. Food sources of vitamin E include vegetable oils, nuts, and egg yolks.

   Vitamin E may protect against chronic diseases, such as heart and blood vessel disease.

2. How is vitamin E given or taken?

   Vitamin E may be eaten in food or taken in dietary supplements.

3. Have any studies of vitamin E been done in people?

   Population studies and clinical trials have been done to find out if vitamin E may prevent prostate cancer. The results of these studies have been mixed. Some studies have shown no change in the overall risk of prostate cancer, and others have shown an increased risk of prostate cancer. There is not enough evidence to know whether vitamin E affects the risk of prostate cancer.

   For information on studies in people taking vitamin E supplements, vitamin E products, or vitamin E in food, see the Human Studies section of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

4. Have any side effects or risks been reported from vitamin E?

   In the Physicians’ Health Study II and the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, there was a higher number of strokes caused by a broken blood vessel in the brain in men who took vitamin E than in men who took a placebo.

5. Is vitamin E approved by the FDA for use as a cancer treatment in the United States?

   The FDA has not approved the use of vitamin E as a treatment for cancer.

   Vitamin E is available in the United States in food products and dietary supplements. The FDA regulates dietary supplements separately from foods, cosmetics, and drugs. The FDA’s Good Manufacturing Practices require that every finished batch of supplements is safe and that the claims on the label are true and do not mislead the consumer. However, the FDA does not regularly review the way that supplements are made, so all batches and brands of vitamin E supplements may not be the same.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)

Polyphenols are found in many plants and give some flowers, fruits, and vegetables their color. Polyphenols have antioxidant activity that may help protect cells from damage.

A food supplement that is high in polyphenols was studied in a group of men who had prostate cancer that had not spread. This supplement contained the following:

• Pomegranate whole fruit powder.
• Green tea extract.
• Broccoli powder.
• Turmeric powder.

One hundred and ninety-nine men were randomly assigned to receive either the food supplement or a placebo for 6 months. The food supplement was well tolerated. However, men in the supplement group were more likely to have gastrointestinal symptoms, such as increased gas and loose bowels.

Lycopene, Selenium, and Green Tea

A dietary supplement was studied in 60 men at high risk of prostate cancer (high-grade prostatic intraepithelial neoplasia). The supplement contained the following:

• Lycopene.
• Selenium.
• Green tea catechins.

The men were randomly assigned to receive the supplement or a placebo. Men who took the supplement for 6 months had higher rates of prostate cancer when they had a repeat biopsy than men who did not take the supplement. This result may be due to cancers missed at the start of the study.

Lycopene and Other Therapies

A study enrolled 79 men who were scheduled to have a prostatectomy. For 3 weeks before surgery, the men were assigned to eat or drink either:

• Tomato products containing lycopene.
• Tomato products plus selenium, omega 3-fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea.
• A diet without added nutrients.

The prostate-specific antigen (PSA) levels were the same for men who received added nutrients and those who did not. However, among men with intermediate-risk prostate cancer, lower PSA levels were found in those who ate the tomato products or had the highest increases in lycopene levels.

Zyflamend

Zyflamend is a dietary supplement that contains extracts of 10 different herbs in olive oil:

• Rosemary.
• Turmeric.
• Ginger.
• Holy basil.
• Green tea.
• Hu zhang (Polygonum cuspidatum).
• Chinese goldthread.
• Barberry.
• Oregano.
• Baikal skullcap.

The herb extracts used in Zyflamend may have anti-inflammatory activity. There is not enough evidence to know whether Zyflamend can prevent or treat prostate cancer.

Zyflamend is taken as a dietary supplement in capsule form.

No serious side effects have been reported for Zyflamend. In one study, some men had mild heartburn that went away when Zyflamend was taken with food.

Overview

African cherry (pygeum africanum) and beta-sitosterol are two supplements that have been studied for general prostate health and the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. For more information, see the African cherry (pygeum africanum) and beta-sitosterol sections of the health professional version of Prostate Cancer, Nutrition, and Dietary Supplements.

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the use of nutrition and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

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Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.

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A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/prostate-supplements-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389501]

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The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

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The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

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This cancer information summary provides an overview of the use of mistletoe as a treatment for people with cancer. The summary includes a brief history of mistletoe research, the results of clinical trials, and possible side effects of mistletoe use.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

Mistletoe, a semiparasitic plant, holds interest as a potential anticancer agent because extracts derived from it have been shown to kill cancer cells in vitro [1–10] to down-regulate central genes involved in tumor progression, malignancy, and cell migration and invasion, such as TGF-beta and matrix-metalloproteinases.[11,12] Mistletoe extracts have been shown to do the following:[10–31]

Three components of mistletoe, namely viscotoxins, polysaccharides, and lectins, may be responsible for these effects.[10,13–15,19–21,23–25,32–39] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune system–stimulating activity.[1,6,20,21,40,41] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (e.g., immune system cells) and inducing biochemical changes in them.[10,42–45]

In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier.[42] Biological response modifiers constitute a diverse group of biological molecules that have been used individually, or in combination with other agents, to treat cancer or to lessen the side effects of anticancer drugs. Mistletoe extracts have been demonstrated in preclinical settings to have other mechanisms of action, such as antiangiogenesis.[29]

Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[46] Commercially available extracts are marketed under a variety of brand names, including Iscador (see explanation of suffixes below), Eurixor, Helixor, Isorel, Iscucin, Plenosol, and abnobaVISCUM. Some extracts are marketed under more than one name. Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album (Loranthaceae) (Viscum album L. or European mistletoe). They are not sold as a drug in the United States. Eurixor, Isorel, and Vysorel are no longer commercially available.

In addition to European mistletoe, extracts from a type of Korean mistletoe (Viscum album var. coloratum [Kom.] Ohwi) have demonstrated in vitro and in vivo cytotoxicity in laboratory studies.[47–51]

Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the following:[8,43,52–55]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,6,22,52,53,56–59] Some extracts are prepared according to homeopathic principles, and others are not. Accordingly, as homeopathic preparations, they are typically not chemically standardized extracts.[10,60] In addition, the commercial products can be subdivided according to the species of host tree, which is typically indicated in the product name by a suffix letter. Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as one of the following:[57]

Helixor, an unfermented aqueous extract of Viscum album L. that is standardized by its biological effect on human leukemia cells in vitro, is marketed as one of the following:[57]

Eurixor (which is no longer commercially available), an unfermented aqueous extract of Viscum album L. harvested from poplar trees, is reportedly standardized to contain a specific amount of one of mistletoe’s lectins (i.e., the lectin ML-1).[57] For more information, see the History section. Some proponents contend the choice of extract should depend on the type of tumor and the sex of the patient.[55,57,61,62]

A recombinant ML-1 from Escherichia coli bacteria known as rViscumin or aviscumine has been studied in the laboratory and in phase I clinical trials. Because this is not an extract of mistletoe, it is out of the purview of this summary.[63]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[19,22–26,39,43,55,57,60,64–70] In most reported studies, subcutaneous injections were given 2 to 3 times a week, but the overall duration of treatment varied considerably.

Viscum album is listed in the Homeopathic Pharmacopoeia of the United States, which is the officially recognized compendium for homeopathic drugs in this country.[71] Although the U.S. Food and Drug Administration (FDA) has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection, such as the mistletoe product described in this summary.

In this summary, the mistletoe extract or product used in each study will be specified wherever possible.

References

1. Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
2. Kuttan G, Vasudevan DM, Kuttan R: Effect of a preparation from Viscum album on tumor development in vitro and in mice. J Ethnopharmacol 29 (1): 35-41, 1990. [PUBMED Abstract]
3. Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
4. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
5. Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]
6. Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
7. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
8. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
9. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
10. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
11. Podlech O, Harter PN, Mittelbronn M, et al.: Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med 2012: 501796, 2012. [PUBMED Abstract]
12. Schötterl S, Hübner M, Armento A, et al.: Viscumins functionally modulate cell motility-associated gene expression. Int J Oncol 50 (2): 684-696, 2017. [PUBMED Abstract]
13. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
14. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
15. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
16. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
17. Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4 (4): 224-8, 1997.
18. Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complement Ther Med 5 (3): 141-6, 1997.
19. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb. [PUBMED Abstract]
20. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
21. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
22. Mistletoe. In: Murray MT: The Healing Power of Herbs. Prima Publishing, 1995, pp 253-9.
23. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
24. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al.: The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37 (1): 23-31, 2001. [PUBMED Abstract]
25. Goebell PJ, Otto T, Suhr J, et al.: Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol 168 (1): 72-5, 2002. [PUBMED Abstract]
26. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
27. Saha C, Das M, Stephen-Victor E, et al.: Differential Effects of Viscum album Preparations on the Maturation and Activation of Human Dendritic Cells and CD4⁺ T Cell Responses. Molecules 21 (7): , 2016. [PUBMED Abstract]
28. Hegde P, Maddur MS, Friboulet A, et al.: Viscum album exerts anti-inflammatory effect by selectively inhibiting cytokine-induced expression of cyclooxygenase-2. PLoS One 6 (10): e26312, 2011. [PUBMED Abstract]
29. Elluru SR, VAN Huyen JP, Delignat S, et al.: Antiangiogenic properties of viscum album extracts are associated with endothelial cytotoxicity. Anticancer Res 29 (8): 2945-50, 2009. [PUBMED Abstract]
30. Elluru SR, Duong van Huyen JP, Delignat S, et al.: Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer 8: 161, 2008. [PUBMED Abstract]
31. Elluru S, Duong Van Huyen JP, Delignat S, et al.: Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador. Arzneimittelforschung 56 (6A): 461-6, 2006. [PUBMED Abstract]
32. Frohne D, Pfander HJ: Viscum album. In: Frohne D, Pfander HJ: Giftpflanzen: ein Handbuch für Apotheker, Ärzte, Toxikologen und Biologen. 3rd rev. ed. Wissenschaftliche Verlagsgesellschaft, 1987, pp 179-80.
33. Pusztai A, Grant G, Pfuller U, et al.: Nutritional and metabolic effects of mistletoe lectin ML-1 (type 2 RIP) in the rat. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 164-7.
34. Pusztai A, Grant G, Gelencsér E, et al.: Effects of an orally administered mistletoe (type-2 RIP) lectin on growth, body composition, small intestinal structure, and insulin levels in young rats. J Nutr Biochem 9 (1): 31-6, 1998.
35. Ewen SWB, Bardocz S, Grant G, et al.: The effects of PHA and mistletoe lectin binding to epithelium of rat and mouse gut. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 221-5.
36. Pryme IF, Bardocz S, Grant G, et al.: The plant lectins PHA and ML-1 suppress the growth of a lymphosarcoma tumour in mice. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 215-20.
37. Tubeuf KFv, Neckel G, Marzell H: Monographie der Mistel. R. Oldenbourg, 1923.
38. Teuscher E: Viscum album. In: Hansel R, Keller K, Rimpler H, et al.: Hagers Handbuch der Pharmazeutischen Praxis, Vol. 6. 5th ed. Springer-Verlag, 1994, pp 1160-83.
39. Grossarth-Maticek R, Kiene H, Baumgartner SM, et al.: Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun. [PUBMED Abstract]
40. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
41. Schrader G, Apel K: Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur J Biochem 198 (3): 549-53, 1991. [PUBMED Abstract]
42. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
43. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Birkhauser Verlag, 1999, pp 223-41.
44. Abdullaev FI, de Mejia EG: Antitumor effect of plant lectins. Nat Toxins 5 (4): 157-63, 1997. [PUBMED Abstract]
45. Kilpatrick DC: Mechanisms and assessment of lectin-mediated mitogenesis. Mol Biotechnol 11 (1): 55-65, 1999. [PUBMED Abstract]
46. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008. [PUBMED Abstract]
47. Khil LY, Kim W, Lyu S, et al.: Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells. World J Gastroenterol 13 (20): 2811-8, 2007. [PUBMED Abstract]
48. Kim MS, Lee J, Lee KM, et al.: Involvement of hydrogen peroxide in mistletoe lectin-II-induced apoptosis of myeloleukemic U937 cells. Life Sci 73 (10): 1231-43, 2003. [PUBMED Abstract]
49. Choi SH, Lyu SY, Park WB: Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res 27 (1): 68-76, 2004. [PUBMED Abstract]
50. Romagnoli S, Fogolari F, Catalano M, et al.: NMR solution structure of viscotoxin C1 from Viscum album species Coloratum ohwi: toward a structure-function analysis of viscotoxins. Biochemistry 42 (43): 12503-10, 2003. [PUBMED Abstract]
51. Yoon TJ, Yoo YC, Kang TB, et al.: Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cells. Arch Pharm Res 26 (10): 861-7, 2003. [PUBMED Abstract]
52. Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 (Suppl 1): 35-41, 1986. [PUBMED Abstract]
53. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
54. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
55. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
56. Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994. [PUBMED Abstract]
57. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
58. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986. [PUBMED Abstract]
59. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
60. Mellor D: Mistletoe in homoeopathic cancer treatment. Prof Nurse 4 (12): 605-7, 1989. [PUBMED Abstract]
61. Fellmer KE: A clinical trial of Iscador: follow-up treatment of irradiated genital carcinomata for the prevention of recurrences. Br Homeopath J 57: 43-7, 1968.
62. Kjaer M: Mistletoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989. [PUBMED Abstract]
63. Schöffski P, Riggert S, Fumoleau P, et al.: Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol 15 (12): 1816-24, 2004. [PUBMED Abstract]
64. Matthes HF, Schad F, Buchwald D, et al.: Endoscopic ultrasound-guided fine-needle Injection of Viscum album L. (mistletoe; Helixor M) in the therapy of primary inoperable pancreas cancer: a pilot study. [Abstract] Gastroenterology 128 (Suppl 2): A-T988, A433-A434, 2005.
65. Matthes HF, Schad F, Schenk G: Viscum album in the therapy of primary inoperable hepatocellular carcinoma (HCC). [Abstract] Gastroenterology 126 (Suppl 2): A-755, A101-A102, 2004.
66. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complement Ther Med 6 (4): 172-7, 1998.
67. Kleeberg UR, Brocker EB, Lejeune F, et al.: Adjuvant trial in melanoma patients comparing rlFN-alpha to rlFN-gamma to Iscador to a control group after curative resection of high risk primary (>=3mm) or regional lymphnode metastasis (EORTC 18871). [Abstract] Eur J Cancer 35 (Suppl 4): A-264, s82, 1999.
68. Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998.
69. Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000.
70. Cho JS, Na KJ, Lee Y, et al.: Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum(®) Injection) for Malignant Pleural Effusion. Ann Thorac Cardiovasc Surg 22 (1): 20-6, 2016. [PUBMED Abstract]
71. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States: Homoeopathic Pharmacopoeia of the United States. 2002, Monograph 9444 Visc.

Mistletoe has been used for centuries for its medicinal properties.[1–6] It was reportedly used by the Druids and the ancient Greeks, and it appears in legend and folklore as a panacea. It has been used in various forms to treat cancer, epilepsy, infertility, menopausal symptoms, nervous tension, asthma, hypertension, headache, and dermatitis. The use of mistletoe in the treatment of cancer is about 100 years old, and its use in the treatment of other indications is much older. Modern interest in mistletoe as an anticancer treatment began in the 1920s. Most of the results of clinical studies have been published exclusively in German. For more information, see the Human/Clinical Studies section.

Another reported activity of mistletoe that may be relevant to optimum functioning of the immune system in individuals with cancer is stabilization of the DNA in white blood cells, including white blood cells that have been exposed to DNA-damaging chemotherapy drugs.[7–11]

Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[2,3,9,11–53] Immune system–enhancing cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, are released by white blood cells after exposure to mistletoe extracts.[1,3,7,9–11,14,19,29,33,37,42–46,48–50,52–54] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [3,4,8,11,33,42–46,52,55–63] and by inducing apoptosis.[3,11,36,42,46,52,64–66] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[18,67]

References

1. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
2. Mistletoe. In: Murray MT: The Healing Power of Herbs. Prima Publishing, 1995, pp 253-9.
3. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Birkhauser Verlag, 1999, pp 223-41.
4. Olsnes S, Stirpe F, Sandvig K, et al.: Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 257 (22): 13263-70, 1982. [PUBMED Abstract]
5. Becker H: Botany of European mistletoe (Viscum album L.). Oncology 43 (Suppl 1): 2-7, 1986. [PUBMED Abstract]
6. Watkins D: A berry Christmas. Nurs Times 93 (51): 28-9, 1997 Dec 17-23. [PUBMED Abstract]
7. Büssing A, Azhari T, Ostendorp H, et al.: Viscum album L. extracts reduce sister chromatid exchanges in cultured peripheral blood mononuclear cells. Eur J Cancer 30A (12): 1836-41, 1994. [PUBMED Abstract]
8. Büssing A, Lehnert A, Schink M, et al.: Effect of Viscum album L. on rapidly proliferating amniotic fluid cells. Sister chromatid exchange frequency and proliferation index. Arzneimittelforschung 45 (1): 81-3, 1995. [PUBMED Abstract]
9. Büssing A, Regnery A, Schweizer K: Effects of Viscum album L. on cyclophosphamide-treated peripheral blood mononuclear cells in vitro: sister chromatid exchanges and activation/proliferation marker expression. Cancer Lett 94 (2): 199-205, 1995. [PUBMED Abstract]
10. Bussing A, Jungmann H, Suzart K, et al.: Suppression of sister chromatid exchange-inducing DNA lesions in cultured peripheral blood mononuclear cells by Viscum album L. J Exp Clin Cancer Res 15 (2): 107-14, 1996.
11. Büssing A, Suzart K, Bergmann J, et al.: Induction of apoptosis in human lymphocytes treated with Viscum album L. is mediated by the mistletoe lectins. Cancer Lett 99 (1): 59-72, 1996. [PUBMED Abstract]
12. Rentea R, Lyon E, Hunter R: Biologic properties of iscador: a Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab Invest 44 (1): 43-8, 1981. [PUBMED Abstract]
13. Bloksma N, Schmiermann P, de Reuver M, et al.: Stimulation of humoral and cellular immunity by Viscum preparations. Planta Med 46 (4): 221-7, 1982. [PUBMED Abstract]
14. Hajto T: Immunomodulatory effects of iscador: a Viscum album preparation. Oncology 43 (Suppl 1): 51-65, 1986. [PUBMED Abstract]
15. Hajto T, Lanzrein C: Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 43 (2): 93-7, 1986. [PUBMED Abstract]
16. Hamprecht K, Handgretinger R, Voetsch W, et al.: Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharmacol 9 (2): 199-209, 1987. [PUBMED Abstract]
17. Hajto T, Hostanska K, Gabius HJ: Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49 (17): 4803-8, 1989. [PUBMED Abstract]
18. Mueller EA, Hamprecht K, Anderer FA: Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity. Immunopharmacology 17 (1): 11-8, 1989 Jan-Feb. [PUBMED Abstract]
19. Hajto T, Hostanska K, Frei K, et al.: Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50 (11): 3322-6, 1990. [PUBMED Abstract]
20. Beuth J, Ko HL, Gabius HJ, et al.: Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 70 (8): 658-61, 1992. [PUBMED Abstract]
21. Kuttan G, Kuttan R: Immunological mechanism of action of the tumor reducing peptide from mistletoe extract (NSC 635089) cellular proliferation. Cancer Lett 66 (2): 123-30, 1992. [PUBMED Abstract]
22. Kuttan G, Kuttan R: Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089). Immunol Invest 21 (4): 285-96, 1992. [PUBMED Abstract]
23. Gabius HJ, Walzel H, Joshi SS, et al.: The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res 12 (3): 669-75, 1992 May-Jun. [PUBMED Abstract]
24. Beuth J, Ko HL, Tunggal L, et al.: Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo 7 (5): 407-10, 1993 Sep-Oct. [PUBMED Abstract]
25. Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993. [PUBMED Abstract]
26. Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
27. Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct. [PUBMED Abstract]
28. Beuth J, Ko HL, Tunggal L, et al.: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 8 (6): 989-92, 1994 Nov-Dec. [PUBMED Abstract]
29. Heiny BM, Beuth J: Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 14 (3B): 1339-42, 1994 May-Jun. [PUBMED Abstract]
30. Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994. [PUBMED Abstract]
31. Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
32. Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
33. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
34. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
35. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
36. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
37. Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4 (4): 224-8, 1997.
38. Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complement Ther Med 5 (3): 141-6, 1997.
39. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb. [PUBMED Abstract]
40. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
41. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
42. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
43. Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar. [PUBMED Abstract]
44. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
45. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
46. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
47. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
48. Goebell PJ, Otto T, Suhr J, et al.: Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol 168 (1): 72-5, 2002. [PUBMED Abstract]
49. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complement Ther Med 6 (4): 172-7, 1998.
50. Kunze E, Schulz H, Gabius HJ: Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration. J Cancer Res Clin Oncol 124 (2): 73-87, 1998. [PUBMED Abstract]
51. Kunze E, Schulz H, Adamek M, et al.: Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response. J Cancer Res Clin Oncol 126 (3): 125-38, 2000. [PUBMED Abstract]
52. Mengs U, Schwarz T, Bulitta M, et al.: Antitumoral effects of an intravesically applied aqueous mistletoe extract on urinary bladder carcinoma MB49 in mice. Anticancer Res 20 (5B): 3565-8, 2000 Sep- Oct. [PUBMED Abstract]
53. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
54. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
55. Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982. [PUBMED Abstract]
56. Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
57. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
58. Sweeney EC, Palmer RA, Pfüller U: Crystallization of the ribosome inactivating protein ML1 from Viscum album (mistletoe) complexed with beta-D-galactose. J Mol Biol 234 (4): 1279-81, 1993. [PUBMED Abstract]
59. Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
60. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
61. Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
62. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
63. Burger AM, Mengs U, Schüler JB, et al.: Anticancer activity of an aqueous mistletoe extract (AME) in syngeneic murine tumor models. Anticancer Res 21 (3B): 1965-8, 2001 May-Jun. [PUBMED Abstract]
64. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
65. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
66. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
67. Mueller EA, Anderer FA: Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalacturonan enhancing cytotoxicity of human NK cells. Immunopharmacology 19 (1): 69-77, 1990 Jan-Feb. [PUBMED Abstract]

The immune system–stimulating and cytotoxic properties of mistletoe have been investigated in laboratory and animal studies.

Viscotoxins and lectins have been investigated as active components in mistletoe; most research has focused on the lectins.[1–9] Purified mistletoe lectins have demonstrated cytotoxic and immune system–stimulating activities. Four different lectins have been identified in mistletoe extracts as follows:

ML-1 (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-1 from Viscum album extracts, their cytotoxic and immune system–stimulating properties were markedly reduced.[10,11] It should be noted that fermentation eliminates most of the ML-1 in mistletoe extracts. Iscador, and other fermented mistletoe extracts, contain only the mistletoe lectins ML-2 and ML-3, whereas the proteins of the ML-1 complex are missing.[12–14] Polysaccharide and oligosaccharide components of mistletoe extracts with substantial immune-stimulating properties have been reviewed.[15,16]

The molecular structure of ML-1 consists of an alpha chain and a beta chain, which can be separated from one another.[1,6–9,13,17,18] Each chain type appears to mediate a subset of the activities described for the intact lectin. Cytotoxicity is associated mainly with the alpha chain. In laboratory studies, the ML-1 alpha chain has been coupled to monoclonal antibodies to produce immunotoxins that target and kill specific cell types.[19–21]

Recombinant ML-1, rML (also known as rViscumin or aviscumine) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Because this is not an extract of mistletoe, it is out of the purview of this summary.

The beta chain of ML-1 is responsible for binding to the surface of a target cell.[23] Studies of mistletoe lectin binding to cancer cells have examined whether the extent of cell binding can predict disease outcome or survival. Studies show that the prognostic value of ML-1 binding depends on the type of cancer.[24] For human breast cancer cells, the amount of lectin-bound cells correlates positively with disease outcome. However, for human adenocarcinoma of the lung, there is no correlation between the amount of lectin-bound cells and disease survival.[25] Though much research has looked at this particular aspect, there have not been studies that directly link the concentration of that component to any clinical activity of mistletoe.

Laboratory studies have shown that mistletoe extracts can stimulate the activity of white blood cells in vitro and cause them to release molecules thought to be important for anticancer immune responses.[4,6,8,9,17,26–33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,8,23,34–37]

There are conflicting reports concerning the stimulation of cancer cell growth in vitro. In one study, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-1.[1] However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]

Preclinical studies demonstrating biological effects on cancer cell lines and animal models are summarized in Table 1 and Table 2.

Table 1. In Vitro Studiesa

IscadorQu = IscadorQ; ML-1 = mistletoe extracts with mistletoe lectins I.
aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
Iscador
Cell Line	Outcome	Reference
Various human cancer cell lines	Iscador preparations containing a high lectin concentration (15 μg/mL) showed >70% growth inhibition in the mammary cancer cell line (MAXF 401NL) compared with untreated control cells; 30%–70% growth inhibition in three tumor cell lines (leukemia RPMI 8226, non-small cell lung LXFE 66NL, and uterine UXF 1138L) for IscadorM and in seven tumor cell lines (central nervous system SF268, gastric GXF 251L, non-small cell lung LXFE 66NL and LXFL 529L, prostate PC3M, renal RXF 944L, and uterine UXF 1138L) for IscadorQu	[35]
Human medulloblastoma cells Daoy, D341, D425, and UW 228-2	Viscum album preparations (0.1–100 µg/mL) induced cell death through apoptosis. Growth-inhibition correlated with the lectin content of the used preparation	[37]
Various human cancer cell lines: SF268 (central nervous system); GXF 251 (gastric); H460, LXFA 629L, LXFE 66NL, LXFL 529L (lung); CCRFCEM, MOLT-4, HL-60, K562, U937, RPMI 8226 (leukemia and lymphoma); MCF7, MAXF 401NL (mammary); HT144, MALME-3M, SK-MEL28, MEXF 462NL, MEXF 514L (melanoma); PC3M (prostate); RXF 393NL, RXF 944L (renal); Hs729, SK-LMS-1, SK-UT-1B (sarcoma); and UXF 1138L (uterus)	IscadorM and IscadorQu with a high lectin content demonstrated antitumor activity in vitro at high test concentrations (15–150 µg/mL)	[38]
Human cell lines: HCC1937, HCC1143 (breast), PA-TU-8902 (pancreas), DU145 (prostate), NCI-H460 (lung)	Cell proliferation inhibition was detected with a mistletoe dose at 100 μg/mL in cell lines PA-TU-8902 and NCI-H460, and a dose at ≥10 μg/mL in cell lines HCC1937, HCC1143, and DU145	[40]
Glioblastoma cells: LNT-229, LN-308	Cell growth was reduced with IscadorQ and IscadorM at lectin concentrations of 100 µg/mL	[41]
Helixor
Cell Line	Outcome	Reference
Various human cancer cell lines	Helixor mistletoe preparations (15–150 µg/mL) and ML-1 (10–100 ng/mL) did not induce cell proliferation	[39]
abnobaVISCUM
Cell Line	Outcome	Reference
Human tumor cell lines: B-cell hybridomas, P815, EL-4, Ke37, MOLT-4, and U937	Growth arrest was caused by the induction of apoptosis (50% of U937 cells at 100 ng/mL of ML-1 and 40% of B-cell hybridomas and EL-4 cells at concentrations as low as 1 ng/mL of ML-1)	[10]

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5–9,36,42–50] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection; some of the differences in results may have resulted from the difference in route of administration. For example, IscadorM administration was associated with a prolonged survival of female Swiss mice when the route of administration was intraperitoneal [51] but not when the route was subcutaneous.[52] Other differences between these two studies were the number of cells used in the Ehrlich ascites inoculum and the doses of IscadorM administered.

Table 2. In Vivo Studiesa

ALL = acute lymphoblastic leukemia; ME-A = mistletoe extracts (fir tree Abies); ME-M = mistletoe extracts (apple tree Malus); ML-1 = mistletoe extracts with mistletoe lectins I; ML-3 = mistletoe extracts with mistletoe lectins III; MT-A = mistletoe extracts obtained from fir trees; MT-P = mistletoe extracts obtained from pine trees; NK = natural killer.
aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
Iscador
Animal Model	Outcome	Reference
Mice	Antiproliferative and antimetastatic effects in melanoma cell line MV3 were only achieved with low-dose ML-1 (30 ng/kg body weight) and not with higher doses (150 ng/kg and 500 ng/kg); increased number of infiltrating dendritic cells suggests stimulation of the immune system	[44]
Mice	Viscum album extract (20 µg/mouse/d) mediated inhibition of B16F1 melanoma cells tumor growth was associated with immunomodulation via induction of IL-12 secretion leading to enhanced T-cell and NK-cell functions	[45]
Mice	Organ colonization was investigated on day 14 after RAW 117 H 10 lymphosarcoma cell and L-1 sarcoma cell inoculation and demonstrated statistically significant (P < .05) reductions of experimental liver and lung metastases for standardized aqueous mistletoe extract–treated mice (2 µg, 20 µg, 100 µg, and 500 µg per mouse)	[47]
Mice (Nude and VMDk mice)	Glioblastoma tumor growth was reduced (cell lines LNT-229 and LN-308), the expression of genes associated with tumor progression was reduced, and NK cell mediated glioblastoma cell lysis was enhanced when IscadorQ and IscadorM 100 µg/mL was administered by an intratumoral injection	[41]
BDF and Swiss albino mice	Treatment with IscadorM (50 mg/kg/d and 100 mg/kg/d) increased the survival time of mice that had been implanted with Ehrlich ascites mouse cancer cells, but not L1210 leukemia or B16 melanoma cancer cells	[51]
Swiss albino mice	No antitumor effect or improvement in survival was observed when IscadorM (15.75 mg, 750 mg, 10.5 mg, 500 mg) was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells; IscadorM (5 mg, 200 mg, 150 mg, 3.75 mg) was also not effective in treating mice that had been injected with Ehrlich ascites cells; in addition, IscadorP (135 mg) was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells	[52]
Helixor
Animal Model	Outcome	Reference
SCID mice	Despite a considerably lower ML-3 content, MT-A (50 mg/kg and 100 mg/kg) was more effective and less toxic than MT-P (50 mg/kg) in a human acute lymphoblastic leukemia cell line (NALM-6); both were given intraperitoneally in mice inoculated with human ALL	[43]
Human ductal breast carcinoma cell line BT474	As compared with tumors of control mice, tumors of the ME-A– and ME-M–treated groups (5 mg intratumoral injection) showed a decreased cell proliferation rate, as well as an increased cell necrosis and apoptosis rate	[46]
abnobaVISCUM
Animal Model	Outcome	Reference
Nude mice	Intratumoral injections of mistletoe extract (abnobaVISCUM Fraxini-2, 8 mg/kg body weight and lectin at 5.3 µg/kg body weight) demonstrated more antitumor activity than did intravenous gemcitabine when injected into mice bearing xenografts of human pancreatic adenocarcinoma cancer (PAXF 736)	[53]
Isorel
Animal Model	Outcome	Reference
Mice	In mice transplanted with fibrosarcoma (CMC-2), when IsorelM (140 mg/kg) was used alone, no effect on either tumor growth or animal survival was observed. When IsorelM (140 mg/kg) was combined with x-ray therapy of tumors, there was substantial improvements in survival of mice compared with survival of mice treated with x-ray therapy (43 Gy) alone	[54]
Eurixor
Animal Model	Outcome	Reference
Mice	Aqueous mistletoe extract (30 ng/mL or 300 ng/mL) showed antitumoral activity on urinary bladder carcinoma (MB49) in mice, which was considered to be mainly caused by the cytotoxic properties of mistletoe lectins	[6]
Lektinol
Animal Model	Outcome	Reference
Mice	Treatment with Lektinol (0.3, 3, 30, or 300 ng/mL/kg/d) slowed the growth of tumors formed in mice from implants of three types of mouse cancers (colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not from two other mouse cancers (B16 melanoma and Lewis lung carcinoma)	[7]

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26. Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
27. Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
28. Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
29. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
30. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
31. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
32. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
33. Hallek M: Interleukin-6-mediated cell growth in multiple myeloma–a role for Viscum album extracts? Onkologie 28 (8-9): 387, 2005. [PUBMED Abstract]
34. Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
35. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
36. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
37. Zuzak TJ, Rist L, Eggenschwiler J, et al.: Paediatric medulloblastoma cells are susceptible to Viscum album (Mistletoe) preparations. Anticancer Res 26 (5A): 3485-92, 2006 Sep-Oct. [PUBMED Abstract]
38. Kelter G, Fiebig HH: Absence of tumor growth stimulation in a panel of 26 human tumor cell lines by mistletoe (Viscum album L.) extracts Iscador in vitro. Arzneimittelforschung 56 (6A): 435-40, 2006. [PUBMED Abstract]
39. Kelter G, Schierholz JM, Fischer IU, et al.: Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro. Anticancer Res 27 (1A): 223-33, 2007 Jan-Feb. [PUBMED Abstract]
40. Weissenstein U, Kunz M, Urech K, et al.: Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro. BMC Complement Altern Med 14: 6, 2014. [PUBMED Abstract]
41. Podlech O, Harter PN, Mittelbronn M, et al.: Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med 2012: 501796, 2012. [PUBMED Abstract]
42. Cebović T, Spasić S, Popović M: Cytotoxic effects of the Viscum album L. extract on Ehrlich tumour cells in vivo. Phytother Res 22 (8): 1097-103, 2008. [PUBMED Abstract]
43. Seifert G, Jesse P, Laengler A, et al.: Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. Cancer Lett 264 (2): 218-28, 2008. [PUBMED Abstract]
44. Thies A, Dautel P, Meyer A, et al.: Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model. Br J Cancer 98 (1): 106-12, 2008. [PUBMED Abstract]
45. Van Huyen JP, Delignat S, Bayry J, et al.: Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma. Cancer Lett 243 (1): 32-7, 2006. [PUBMED Abstract]
46. Beuth J, Ko HL, Schneider H, et al.: Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model. Anticancer Res 26 (6B): 4451-6, 2006 Nov-Dec. [PUBMED Abstract]
47. Braun JM, Ko HL, Schierholz JM, et al.: Standardized mistletoe extract augments immune response and down-regulates local and metastatic tumor growth in murine models. Anticancer Res 22 (6C): 4187-90, 2002 Nov-Dec. [PUBMED Abstract]
48. Pryme IF, Bardocz S, Pusztai A, et al.: Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma. Histol Histopathol 17 (1): 261-71, 2002. [PUBMED Abstract]
49. Elsässer-Beile U, Ruhnau T, Freudenberg N, et al.: Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model. Cancer 91 (5): 998-1004, 2001. [PUBMED Abstract]
50. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
51. Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 (Suppl 1): 42-50, 1986. [PUBMED Abstract]
52. Berger M, Schmähl D: Studies on the tumor-inhibiting efficacy of Iscador in experimental animal tumors. J Cancer Res Clin Oncol 105 (3): 262-5, 1983. [PUBMED Abstract]
53. Rostock M, Huber R, Greiner T, et al.: Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res 25 (3B): 1969-75, 2005 May-Jun. [PUBMED Abstract]
54. Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]

Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1–20]

The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, abnobaVISCUM,[21] and recombinant lectin ML-1. For more information, see the appropriate subsections and tables in this section.

The findings from more than 50 clinical trials of mistletoe extracts in patients with cancer have been published, and several systematic reviews and meta-analyses of the results of these studies have been performed. Three of the most recent systematic reviews addressed quality of life (QOL), survival, and symptom relief in patients with various cancer types.[18,20,22] Most studies reported an improvement in QOL, as did a noncontrolled, nonrandomized, real-world study that analyzed patient registry data.[23]

In one systematic review that examined 26 randomized controlled trials (RCTs), 22 trials reported an improvement in QOL. All 10 of the nonRCTs also reported the same benefit. Improvement in fatigue, nausea and vomiting, depression, emotional well-being, and concentration were reported. Some of the studies were well designed, while others reported weaknesses.[22]

Tumor response, QOL, and psychological distress were measured in a review of 21 RCTs of various cancers in which different mistletoe preparations were used either alone, with chemotherapy, or with radiation therapy.[18] Survival times were included in 13 of the studies. Most of the studies reported benefits for patients, although this review was limited by small sample size and methodological weaknesses. Thus, the authors were unable to suggest practice guidelines for the use of mistletoe.

The oldest of these three reviews investigated the results of 10 RCTs that used a variety of mistletoe extracts in patients with various malignancies. There was no difference in survival or other benefits for cancer patients who received mistletoe. Therefore, mistletoe was not recommended as a curative or supportive care therapy.[20]

A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other QOL measures.[22]

Although mistletoe was found to be therapeutically effective in most of the reported studies, many of the studies had one or more major design weaknesses as mentioned above that raised doubts about the reliability of the findings. These weaknesses include the following:

In addition, evaluation of the studies is often hindered by incomplete descriptions of the study design and by incomplete reporting of clinical data, including data about previous and concurrent therapies received by the patients. Note: In studies with small numbers of patients, the mean survival time can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a less biased measure.

A selection of studies is discussed below, organized by the type of mistletoe extract used. Studies on Iscador are summarized in Table 3. Studies on Helixor, abnobaVISCUM, Eurixor, Isorel, and Lektinol are summarized in Table 4. Eurixor, Isorel, and Vysorel are no longer available on the market for sale.

Iscador

Quality of life

Miscellaneous cancers

Although the quality of literature is limited by methodological flaws, prospective and controlled studies that explored the efficacy of Iscador use on QOL in patients with cancer generally report positive effects in favor of complementary treatment. A meta-analysis of several studies (RCTs: n = 9; non-RCTs: n = 4; patients n = 734) reported a statistically significant overall treatment effect in favor of Iscador application (standard mean deviation [SMD], 0.56; 95% confidence interval [CI], 0.41–0.71; P < .0001).[24] Tumor localization and study design were not significantly associated with a better or worse study outcome following multivariable regression.

Breast cancer

A randomized study of postoperative early-stage breast cancer patients (T1, 3N0, 2M0) who received adjuvant chemotherapy with cyclophosphamide, Adriamycin, and fluorouracil found that patients who also received IscadorM treatment, a Viscum album extract harvested from apple (Mali) trees (n = 30), had significantly superior QOL ratings compared with patients who received chemotherapy alone (n = 31) (95% CI, P ≤ .017).[7] Significant improvements were noted in physical functioning, role functioning, emotional functioning, and social functioning. Improvements were also noted in appetite, nausea and vomiting, diarrhea, fatigue, pain, dyspnea, insomnia, and financial difficulties.[7]

Non-small cell lung cancer (NSCLC)

At least two RCTs have assessed the QOL of patients with advanced NSCLC. Patients who received carboplatin/gemcitabine or carboplatin/pemetrexed and were randomly assigned to receive open-label IscadorQu treatment, a Viscum album extract harvested from oak (Quercus) trees, did not report statistically significant improvements in QOL when compared with NSCLC patients who received carboplatin-based combinations alone.[25] An assessment of QOL was performed in a study of patients with NSCLC who received adjuvant chemotherapy with IscadorQu and IscadorU (harvested from elm [Ulmi] trees) or a vitamin B mixture (control) over 2 years.[26] A subjective improvement in general well-being was more often seen in patients treated with Iscador.

Osteosarcoma

QOL was assessed as a secondary endpoint in a small (n = 20) study of patients with osteosarcoma. Patients were free from disease after their second metastatic relapse and were randomly assigned to receive either open-label IscadorP therapy, a Viscum album extract harvested from pine (Pini) trees, or oral etoposide. Patients who received Iscador therapy experienced significant improvements in overall (global) and individual QOL domains when compared with baseline functioning (global health/QOL; 95% CI, 2.62–19.72; P = .013).[27] Improvements over baseline values were also reported in the following areas:

• Physical functioning (95% CI, 0.15–14.44; P = .046).
• Social functioning (95% CI, 4.64–18.88; P = .003).
• Fatigue (95% CI, −16.31 to −3.38; P = .005).
• Pain (95% CI, −18.83 to −2.60; P = .012).
• Dyspnea (95% CI, −16.94 to −8.32; P < .0001).
• Financial difficulties (95% CI, −16.21 to −6.70; P < .0001).

Ovarian cancer

Ovarian cancer patients without metastases (n = 21 pairs) were randomly assigned to receive adjuvant Iscador (host tree unspecified) or no further treatment. Significant improvements in QOL were noted, as assessed by the degree of psychosomatic self-regulation, described as the capacity for autonomous regulation of emotional, social, and psychological factors, within 12 months of treatment (estimated median difference: 0.58; 95% CI, 0.30–0.90; P = .0002).[11]

Uterine cancer

Secondary endpoint analysis of uterine cancer patients without metastases (randomized: n = 30 pairs; nonrandomized: n = 103 pairs) who received adjuvant Iscador displayed significant improvements in psychosomatic self-regulation within 12 months of treatment when compared with women who received conventional oncological therapy alone (estimated median difference and 95% CI, 0.40 [0.15–0.70]; P = .0012; and 0.70 [0.25–1.15], P = .0037, respectively).[10]

Symptom management

Breast cancer

In a study of postoperative early-stage breast cancer patients (T1, 3N0, 2M0) who were randomly assigned to receive open-label IscadorM therapy after chemotherapy (n = 30), a secondary endpoint analysis did not demonstrate statistically significant improvements in neutropenia (neutrophil count <1,000/µL) when compared with patients who received chemotherapy alone (n = 31).[7]

Another study (retrolective design) of postoperative early-stage breast cancer patients (T2, 4N0, 2M0) who received adjuvant conventional treatment (chemotherapy, radiation therapy, or hormonal therapy) (n = 710) compared the outcomes of patients who received Iscador with patients who did not receive any added therapy. Patients who received Iscador developed significantly less adverse drug reactions associated with conventional treatment compared with women treated with conventional therapy alone (n = 732) (16% vs. 54.0%, respectively; adjusted odds ratio [OR], 0.47; 95% CI, 0.32–0.67; P < .001).[28,29] Relief or significant reductions in nausea, vomiting, loss of appetite, headache, fatigue, depression, skin and mucosal reactions (including mucositis), disturbed concentration and memory, and irritability were observed.[29,30]

Head and neck cancers

After surgery of squamous cell lesions of the larynx and pharynx, male patients who were randomly assigned to receive complementary IscadorQu treatment (n = 10) displayed significantly fewer adverse effects from chemotherapy and radiation therapy (radiation therapy with 50–60 Gy, chemotherapy with cisplatin and fluorouracil) on the microcirculation and immunological capacities of white blood cells compared with men who received conventional treatment alone (n = 10) (P = .05).[31] Patients who received adjuvant IscadorQu treatment also displayed significant accelerations in the restitution process when compared with the control group (P = .05).

Non-small cell lung cancer (NSCLC)

Patients with advanced NSCLC who received carboplatin/gemcitabine or carboplatin/pemetrexed and were randomly assigned to receive open-label IscadorQu treatment (n = 33) displayed the following reactions when compared with patients who received chemotherapy alone (n = 39):[25]

• Significantly fewer hospitalizations (24% of Iscador-treated patients vs. 54% of control patients; P = .016).
• Chemotherapy dose reductions (13% of Iscador-treated patients vs. 44% of control patients; P = .005).
• Grades 3 and 4 nonhematological toxicities (16% of Iscador-treated patients vs. 41% of control patients; P = .043).

The grades 3 and 4 hematological toxicity was not significantly different between the groups.

Survival

Miscellaneous cancers

A systematic review and meta-analysis of several studies published from 1963 to 2014, including RCTs, found that adjuvant treatment with Iscador is associated with improved cancer survival outcomes when compared with conventional treatment alone.[32] Pooled analysis of controlled clinical studies (32 studies; total n = 13,745) that investigated overall survival (OS) and event-free survival (EFS) (i.e., disease-free survival [DFS], progression-free survival [PFS] or relapse-free survival, or the time until these events occurred in cancer patients), demonstrates a statistically significant hazard ratio (HR) of 0.59 (95% CI, 0.53–0.65; P < .0001) in favor of Iscador treatment. A significant difference in survival between cancer types was noted (P < .01), with the strongest association of Iscador use and general survival found in in patients with cervical cancer (HR, 0.43) and more modest outcomes in patients with lung cancer (HR, 0.84). In the meta-analysis, randomization was performed in only 14 studies. While subgroup analysis displayed a greater association between EFS and OS in patients who received Iscador in nonrandomized clinical trials (HR, 0.56; CI, 0.50–0.62) compared with patients who were randomized (HR, 0.68; CI, 0.55–0.83); this difference is not statistically significant (P = .13).[32] Many of the studies used study designs, analytical methods, and/or cancer treatment regimens that were outdated. While moderate heterogeneity between study results was noted (I2, 50.9%; P < .0001), neither differences in design, sample size, nor publication year demonstrated significant effects on these survival outcomes. The reviewed studies were blinded; therefore, they ran the risk of performance bias, given the knowledge of allocated interventions. It is unlikely that performance bias affected study outcomes associated with general survival (which is the reason why the U.S. Food and Drug Administration does not mandate blinding in survival studies); however, performance bias may exist for those reporting on EFS.

Breast cancer

Primary breast cancer patients (without recurrences, lymphatic metastases, or distant metastases at the initiation of study observation; n = 84 pairs) who received Iscador therapy adjuvant to conventional treatment (surgery, chemotherapy, radiation therapy, or hormone therapy) displayed prolonged cancer-specific survival rates when matched to paired individuals with similar prognostic criteria who received conventional treatment alone (HR, 0.43; 95% CI, 0.27–0.68).[8] In the same report, patients with breast cancer who were randomly assigned to receive Iscador did not demonstrate a significant extension of OS when compared with their matched pairs.[8]

In another study, OS was evaluated as a secondary endpoint in patients with nonmetastatic breast cancer (T2, 4N0, 2M0) who underwent adjuvant treatment concomitant with regimented Iscador injections.[28,29] Women treated with subcutaneous Iscador therapy complementary to their conventional treatment regimen (n = 710) displayed significant extensions of overall mortality when compared with patients treated with conventional therapy alone (n = 732) (adjusted HR, 0.46; 95% CI, 0.22–0.96; P = .038).[28,29]

Cervical cancer

Patients with metastatic (n = 66) or local (n = 102) cervical cancer who elected to receive Iscador in addition to conventional oncological treatment demonstrated significant extensions of OS when compared with women with similar prognostic criteria who received conventional treatment alone (HR and 95% CI, 0.37 [0.17–0.80] and 0.23 [0.14–0.39], respectively).[9] However, this finding was not seen when women with metastatic cervical cancer were randomly assigned to receive open-label adjuvant Iscador.

Colorectal cancer

Patients with surgically-treated, nonmetastatic colorectal cancer (CRC) (stages I–III) (n = 429) who received Iscador treatment with conventional aftercare displayed a statistically significant extension of DFS (HR, 0.60; P = .013) when compared with CRC patients who received conventional therapy alone (n = 375) after a median observation period of 58 months for patients who received Iscador and 51 months for patients who received conventional therapy alone.[33] A secondary analysis of this data was preformed specific to CRC patients who received IscadorQu extract, a Viscum album extract harvested from oak (Quercus) trees. Patients who had specifically received IscadorQu extract (n = 106) displayed an estimated 69% risk reduction in metastasis formation (HR, 0.31; 95% CI, 0.13–0.711; P = .006) relative to conventionally-treated controls (n = 212).[34]

Melanoma

A phase III study of melanoma patients (n = 102) with high-risk primary disease (stage II, Breslow thickness >3mm) or regional lymph node metastasis (stage III, after curative dissection) treated with IscadorM found no clinical benefit of low-dose adjuvant therapy in the disease-free interval when compared with the control group (n = 102) after one year of treatment (or until tumor progression).[5]

Non-small cell lung cancer (NSCLC)

Lymph node–positive NSCLC patients (n = 87) who were randomly assigned to receive Iscador therapy (without concurrent treatment) displayed significant extensions in median survival rates when compared with untreated controls.[35] Clinical benefit in median survival was not observed in patients with nonmetastatic NSCLC.[35] Similarly, a three-arm comparison with a sheep spleen glycopeptide, reported to be an immunostimulant and an inhibitor of tumor cell glycolysis, and a vitamin B preparation (placebo) (n = 107), found no clinical benefit in median survival above placebo in patients with advanced NSCLC who were randomly assigned to receive IscadorQu and IscadorU (n = 105) after two years of open-label treatment.[26]

Osteosarcoma

Osteosarcoma patients who underwent a complete surgical resection after a second relapse were randomly assigned to receive IscadorP maintenance therapy (subcutaneous injections three times a week) (n = 9) for 1 year. After a follow-up period of 12 years, patients displayed a 71% reduced risk of relapse (measured as postrelapse DFS; HR, 0.287; 95% CI, 0.076–0.884; P = .03) when compared with patients who received 6 months of oral etoposide treatment (50 mg/m2 a day for 21 days, every 28 days) (n = 10).[36]

Ovarian cancer

Primary ovarian cancer patients without distant metastases (n = 21 pairs) who received Iscador therapy after conventional treatment (surgery and chemotherapy) displayed prolonged OS rates when compared with patients with similar prognostic criteria who received conventional treatment alone (HR, 0.47; 95% CI, 0.31–0.69; P = .0002).[11] Patients who were randomized to receive Iscador treatment did not display a significant difference in OS when compared with matched controls. Patients with metastatic ovarian cancer, randomly assigned to receive complementary Iscador therapy (n = 20 pairs), also demonstrated a significant extension of OS when compared with matched pairs (HR, 0.33; 95% CI, 0.12–0.92; P = .033), although a significant extension in OS was not observed in the nonrandomized arm.[11]

Pancreatic cancer

Patients with locally advanced or metastatic pancreatic cancer (UICC stage III or stage IV) who were randomly assigned to receive open-label Iscador therapy as an adjuvant to best supportive care methods (n = 110) demonstrated prolonged survival when compared with patients under similar prognostic criteria who received supportive care alone (n = 110). The median OS was 4.8 months for patients who received Iscador and 2.2 months for patients who received supportive care alone (prognosis-adjusted HR, 0.49; 95% CI, 0.36–0.65; P < .0001).[37]

A retrospective analysis investigated the effects of mistletoe and chemotherapy with hyperthermia versus mistletoe and chemotherapy in the palliative treatment of patients with pancreatic cancer. The results of the analysis found a significant improvement in survival rates for patients who received all three treatments. Weaknesses of the analysis include the retrospective nature of the study, multiple types of chemotherapy (gemcitabine/nab-paclitaxel, 34%; FOLFIRINOX, 36%; gemcitabine, 30%) and mistletoe (e.g., Iscador, Abnoba viscum, or Helixor) regimens used, and the lack of a study arm for hyperthermia and chemotherapy.[38] Furthermore, the study was not stratified despite enrolling patients who were previously treated with 1 to 3 lines of therapy, making the group median survival rates clinically insignificant.

In a retrospective analysis of patients with stages I to IV pancreatic cancer (n = 292) who received Iscador (host tree unspecified) therapy alone or adjuvant to conventional treatment (surgery, chemotherapy, radiation therapy, hormone therapy, or a combination) (n = 61), a median survival of 6.58 months was reported.[39]

Uterine cancer

Patients with corpus uteri cancer without distant metastases (n = 30 pairs) were randomly assigned to receive Iscador therapy adjuvant to conventional treatment (surgery or radiation therapy). Patients had longer OS (time from initial diagnosis to tumor-related death) than matched pairs of patients with similar prognostic criteria who received conventional treatment alone (HR, 0.36; 95% CI, 0.16–0.82; P = .014).[10] However, corpus uteri cancer patients with distant metastases randomly assigned to receive adjuvant Iscador did not display a significant difference in OS when compared with matched controls who were randomly assigned to conventional oncologic care only. In the nonrandomized portion of the study, corpus uteri cancer patients, with (n = 95 pairs) or without (n = 103 pairs) distant metastases, who previously received the complementary therapy, demonstrated a significant extension of OS when compared with matched pairs of similar prognostic criteria who received conventional treatment alone (prognosis-adjusted HR and 95% CI, 0.61 [0.39–0.93], P = .023 and 0.41 [0.26–0.63], P < .0001, respectively).[10]

Table 3. Use of Iscador in Cancer Treatment: Clinical Reports Describing Therapeutic End Pointsa

Reference	Trial Design	Condition or Cancer Type	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)b	Results	Concurrent Therapy Usedc	Level of Evidence Scored
DFS = disease-free survival; LN+ = lymph node–positive disease; No. = number; OS = overall survival; QOL = quality of life.
aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
bNumber of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studied and for whom results were reported; historical control subjects are not included in number of patients enrolled.
cChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
dFor information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
eControl patients were treated with a vitamin B mixture as a placebo; 100 additional evaluable patients were treated with Polyerga Neu, a sheep spleen glycopeptide reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; treatment with Polyerga Neu was not found to be beneficial.
fRadiation therapy for metastases distant from the site of the primary tumor was permitted; radiation therapy to the primary tumor site or use of other anticancer treatment was not permitted.
gAmong 10,226 cancer patients enrolled in a retrospective matched-pair, case-control study, 1,751 had been treated with Iscador or another mistletoe product and 8,475 had not been treated with mistletoe; from the 8,475 untreated patients, two sets of matched pairs were formed for prospective studies; in the prospective studies, one member of each pair was randomly assigned to be treated with Iscador and the other member served as a control subject.
hPatients were strictly matched according to sex, year of birth ± 3 years, year of diagnosis ± 3 years, type of tumor, stage of disease, and conventional therapy received.
[26]	Randomized trial	Lung, non-small cell, inoperable	408; 105; 107e	Subjective improvement in QOL	Yesf	1iiA
[35]	Randomized trial	Lung, non-small cell, stages I–IV	218; 87; 96	Improved median survival, LN+ patients only	No	1iiA
[5]	Randomized trial	Melanoma, stages II–III	204; 102; 102	No improvement in DFS or OS rates	No	1iiA
[37,40]	Randomized trial	Pancreatic, advanced or metastatic	220; 110; 110	Improved OS	No	1iiA
[27]	Randomized trial	Osteosarcoma, second metastatic relapse	20; 9 (viscum); 11 (etoposide)	Improved DFS compared with etoposide group	No	1iiDii
[41]	Randomized trial	Breast	95; 30 (IscadorM) and 34 (HelixorA); 31	No differences in the primary outcome between groups	Yes	1iiC
[29]	Comparative, retrolective, cohort study	Breast, stages I–IV	1,442; 710; 732	Fewer adverse drug reactions with mistletoe	Yes	2B
[28]	Comparative, retrolective, cohort study	Melanoma, stages II–III	686; 329; 357	Improved overall disease-specific survival	Unknown	2A
[4]	Cohort study	Breast, stage III	8,475g; 17h; 17h	Improved mean survival	Yes	None
[4]	Cohort study	Various types, stages I–IV	8,475g; 39h; 39h	Improved mean survival	Yes	None
[4]	Cohort study	Various types, stages I–IV	10,226g; 396h; 396h	Improved mean survival	Yes	None
[33]	Retrospective, observational, cohort study	Nonmetastatic colorectal	804; 429; 375	Lower incidence of diarrhea, nausea, loss of appetite, dermatitis, fatigue, and mucositis	Yes	2C
[38]	Retrospective analysis study	Pancreatic	206 (subgroup of 142 using survival data on 124); 25 (chemotherapy alone); 48 (chemotherapy and mistletoe), 50 (chemotherapy, mistletoe, and hyperthermia); 1 (chemotherapy and hyperthermia)	Improved survival was reported in the triplet arm	Yes	2A
[39]	Nonconsecutive case series	Pancreatic	292; 292; various historical controls	Improved median survival	Yes	3iiiA

Helixor

Safety

The first intravenous (IV) trial of mistletoe (HelixorM) is completed.[42] A standard 3 + 3 phase I design was used. The study included 21 patients with heavily pretreated metastatic solid tumors. A dose of 600 mg IV 3 times a week was determined to be the maximum tolerated dose recommended for future phase II trials. Three patients had tumor shrinkage, though none met RECIST criteria for a partial response. The disease control rate was 23.8% and the median stable disease was 15 weeks. Two patients had stable disease for almost 6 months. The most common treatment-related adverse events were fatigue (28.6%), nausea (9.5%), and chills (9.5%). A secondary endpoint analysis found that QOL was significantly improved during treatment as measured by the Functional Assessment of Cancer Therapy-General assessment, with a change in score from 79.7 to 93 between week 1 and week 4.[42] Future research should be conducted to examine the effect of mistletoe on chemotherapy tolerability and to gather more information about its effect on QOL, PFS, and OS.

Quality of life

Miscellaneous cancers

Patients with cancer (breast, n = 67; ovarian, n = 66; NSCLC, n = 91) were randomly assigned to receive open-label treatment with HelixorA (viscum album abietis) concurrent with standard chemotherapy (n = 115). These patients demonstrated significant improvements in QOL (as assessed by Functional Living Index-Cancer, Karnofsky Performance Index, and Traditional Chinese Medicine Index questionnaires) when compared with patients in the control group, who received conventional oncologic treatment and Lentinan, an immunomodulating agent derived from the shiitake mushroom (n = 109) (P < .05).[43] Patients who received HelixorA also experienced fewer adverse events (AEs) from chemotherapy when compared with the control group (52 AEs reported in the HelixorA and chemotherapy group vs. 90 AEs in the control group).

Symptom management

Malignant pleural effusion

Pleurodesis with HelixorM (Viscum album mali) may be an effective procedure to control malignant pleural effusions (MPE) in patients with advanced lung cancer.[44] Over half (52%) of lung cancer patients treated with HelixorM pleurodesis (n = 42) were free from recurrence of MPE one month after the procedure. Neither patient characteristics (including age, gender, histopathology, or systemic treatment), nor MPE characteristics (including location and chemistry) was deemed significantly associated with the outcome of HelixorM pleurodesis in this study.[44]

Survival

Breast cancer

Patients with breast cancer (T1–3, N0–3, M0; local recurrence) were randomly assigned to receive Helixor adjuvant to conventional therapy (i.e., surgery and radiation therapy) (n = 192). These patients demonstrated a significant extension in 5-year survival when compared with patients who received conventional treatment alone (n = 274) (5-year survival rates, 69.1% vs. 59.7%, respectively) (P = .048).[45]

Colorectal cancer

Patients with metastatic CRC were randomly assigned to receive Helixor adjuvant to chemotherapy (n = 20). These patients demonstrated significant extensions in mean survival (26.7 ± 11.9 months in complete/partial responders) when compared with patients randomly assigned to receive chemotherapy alone (n = 20) (13.6 ± 4.4 months in complete/partial responders).[46]

abnobaVISCUM

Quality of life

Breast cancer

As per QLQ-C30 function scales, health-related QOL in patients with breast cancer (stages I–III) who received abnobaVISCUMM concurrent with chemotherapy (n = 270) remained stable throughout the course of chemotherapy and significantly improved 4 weeks after treatment (P < .0001) when compared with the initial visit.[47] Patients also showed significant improvements above baseline in all parameters of the QLQ-BR23 function scale (a QOL module specific to breast cancer) at final examination (P < .0001).

Stomach cancer

Postoperative patients with gastric cancer (stage IB or stage II) were randomly assigned to receive abnobaVISCUMQ adjuvant to oral chemotherapy (n = 15). These patients demonstrated a significant improvement in global health status (a parameter constructed by totaling scores on two questions from the QLQ-C30 questionnaire) at week 16 and at completion of treatment (week 24), when compared with patients who received oral chemotherapy alone (n = 14) (P = .0098).[48] All other function and symptom scales of the QLQ-C30 and the QLQ-STO22 (a QOL module specific to stomach cancer) did not show statistical significance when abnobaVISCUMQ treatment was added.[48]

Symptom management

Miscellaneous cancers

Patients with advanced cancer were treated with abnobaVISCUM pleurodesis for MPE (n = 62). These patients demonstrated a significant improvement in mean response rate (P < .0001) when compared with reference values (97% and 64%, respectively).[49] Forty-nine patients (79%) demonstrated a complete response (no recurrence of MPE at least 4 weeks after treatment) and 11 patients (18%) demonstrated partial response (reaccumulation of pleural effusion under 50% of the pretreatment volume), while 2 patients (3.23%) did not respond (recurrence of pleural effusion within 4 weeks after treatment) to mistletoe-mediated pleurodesis with abnobaVISCUM.[49]

Colorectal cancer

Symptomatic relief was reported by 40% of patients with metastatic CRC who were resistant to fluorouracil and leucovorin (5-FU/LV)-based chemotherapy and received abnobaVISCUMQ therapy (n = 25). Symptomatic relief was assessed as a secondary endpoint measure for a median duration of 14 weeks.[50] Relief of the following symptoms was reported:

• Nausea and vomiting (24% of patients).
• Diarrhea (12% of patients).
• Constipation (8% of patients).
• Fatigue (24% of patients).
• Dyspnea (8% of patients).

Stomach cancer

In one study, postoperative patients with gastric cancer (stage IB or stage II) were randomly assigned to receive abnobaVISCUMQ adjuvant to oral chemotherapy (n = 15). The secondary endpoint analyses demonstrated a significant improvement in leukocyte (P = .01) and eosinophil (P = .0036) counts when compared with patients who received oral chemotherapy alone (n = 14) after a 24-week treatment cycle.[48]

Survival

Bladder cancer

A marker tumor remission rate of 55.6% (95% CI, 38.1–72.1) was achieved in 20 of 36 patients with nonmuscle-invasive bladder cancer (Ta G1/G2 or T1 G1/G2) 12 weeks after beginning bladder instillation therapy with abnobaVISCUMF (once a week for 6 weeks).[51] Of the 19 evaluable patients, 14 (73.7%) did not have recurrent tumor at 1 year after initiation of treatment (95% CI, 48.8%–90.9%), corresponding to a 1-year recurrence rate of 26.3% (95% CI, 9.1%–51.2%).

Colorectal cancer

Objective tumor response was not observed in a phase II study of patients with metastatic CRC who were resistant to 5-FU/LV-based chemotherapy and received abnobaVISCUMQ therapy for a median time period of 14 weeks. Stable disease was noted in 21 of 25 patients (84%), lasting for a median of 2.5 months (range; 1.5–7 months).[50]

Eurixor

Eurixor is no longer available on the market for sale.

Quality of life

Colorectal cancer

Patients with metastatic CRC were randomly assigned to receive Eurixor adjuvant to standard cancer treatment (n = 38). These patients demonstrated improved QOL (P = .0001) when compared with patients randomly assigned to receive standard treatment alone (n = 41).[52,53]

Symptom management

Breast cancer

Patients with breast cancer (UICC stages I–IIIB) underwent postoperative chemotherapy, radiation therapy, or hormone therapy, and received complementary treatment with Eurixor (n = 219) for a median time period of 270 days. These patients demonstrated significant improvements in disease- or therapy-induced adverse reactions (P < .0001) when compared with patients who received standard cancer therapy alone (n = 470) at up to 285 days of follow-up.[54] Significant improvements in nausea, appetite reduction, stomach pain, fatigue, depression, memory, and irritability/restlessness were reported (P < .0001, in each subgroup).

Survival

Bladder cancer

Patients with bladder cancer (pTa G1/G2) (n = 45) received subcutaneous Eurixor injections after transurethral resection. These patients did not demonstrate differences in time-to-first recurrence, total number of recurrences, or recurrence-free outcomes at up to 18 months after primary treatment compared with patients who were randomly assigned to receive no adjuvant treatment.[3]

Head and neck cancers

Patients treated with Eurixor before and after resection of squamous cell carcinomas of the head and neck, with or without follow-up radiation therapy, demonstrated no difference in DFS when compared with patients who received surgery alone or surgery followed by radiation therapy, without adjuvant Eurixor treatment.[2]

Isorel

Isorel is no longer available on the market for sale.

Biomarker study

Gastrointestinal cancers

Perioperative use of Isorel in patients with cancer of the digestive tract (esophageal, stomach, pancreatic, ileac, colorectal) has been shown to increase the lymphocyte count in patients within 14 days of administration.[55]

Survival

Colorectal cancer

Patients with advanced CRC (Dukes C and D) were randomly assigned to receive Isorel along with adjuvant postoperative chemotherapy with 5-FU (6 cycles) (n = 29). These patients demonstrated prolonged survival (P < .05) when compared with patients who received postoperative chemotherapy only (n = 21) and patients who received surgery only (n = 14) without postoperative chemotherapy or Isorel treatment (n = 14).[56]

Lektin/Lektinol

Quality of life

Breast cancer

Patients with breast cancer were randomly assigned to receive open-label PS76A (an aqueous mistletoe extract standardized to the galactoside-specific mistletoe lectin [ML]) adjuvant to chemotherapy (n = 176). These patients demonstrated improved QOL when compared with patients who received chemotherapy alone.[13]

In a double-blind study, patients with breast cancer (stages II–III) were randomly assigned to receive PS76A2 (Lektinol; 30 ng ML/mL) adjuvant to cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (4 cycles) for a period of 15 consecutive weeks (n = 65). These patients demonstrated statistically significant improvements in self-assessments of QOL (P = .0121 and P = .0021 for GLQ-8 and Spitzer’s uniscale, respectively) when compared with patients who were randomly assigned to receive chemotherapy treatment alone (n = 66).[57] Only the medium dose (30 ng ML/mL) indicated a significant preventative effect against placebo; no treatment effect of low- or high-dose Lektinol (10 ng ML/mL or 70 ng ML/mL) was established against the placebo. In a second confirmatory study, superiority of complementary Lektinol (30 ng ML/mL) (n = 176) over the placebo (n = 176) was observed according to three FACT-G subscales (physical, emotional, and functional well-being) assessed during the fourth CMF cycle (P < .0001).[58]

Systematic Reviews/Meta-analyses of Various Viscum Album Extract (VAE) Types

Quality of life

Miscellaneous cancers

Some systematic reviews have found that studies of better methodological quality typically show that Viscum album extracts (VAEs) have few beneficial effects on QOL in cancer,[18,20,59] while others studies suggest that mistletoe extracts produce a significant, though medium-sized, effect on QOL in cancer patients (mean difference = 0.61; 95% CI, 0.41–0.81, P < .00001).[60]

However, another systematic review reached different conclusions. In a review consisting of 26 RCTs, 22 reported a benefit of mistletoe therapy (supplied with or without concomitant surgery, chemotherapy, or radiation therapy), whereas 3 reported no difference, and 1 did not indicate a result.[22] All 10 nonRCTs reported a benefit of VAE treatment, whether it was supplied with or without concomitant therapy.[22] Among the studies designated as higher in methodological quality, most reported a benefit of VAE treatment, whereas one reported no difference from standard oncological treatment. Most consistently, studies reported improvements regarding the following:[22]

• Coping.
• Fatigue.
• Sleep.
• Exhaustion.
• Energy.
• Nausea.
• Vomiting.
• Appetite.
• Depression.
• Anxiety.
• Ability to work.
• Emotional and functional well-being.

Survival

Miscellaneous cancers

Systematic reviews reported inconsistent results regarding the efficacy of mistletoe treatment on survival outcomes on the basis of methodological quality of the study.[61] In a review that consisted of 28 publications (n = 2,639) investigating a wide range of cancers (bladder, breast, cervix, lungs, uterus, ovaries, colon, stomach, pancreas, gliomas, head and neck cancers, melanomas, and osteosarcomas), most studies did not show that adjuvant mistletoe had an effect on survival, especially those of high methodological quality.[62] This finding is consistent with other review articles. In an investigation of 13 RCTs, 6 showed evidence of a survival benefit, but none of these studies were of high methodological quality.[18]

In another review of 23 controlled clinical studies (16 randomized, 2 quasi-randomized, and 5 nonrandomized) that investigated the use of VAE in patients with cancers of the breast, lung, stomach, colon, rectum, head and neck, kidney, genitals, bladder, melanomas, and gliomas, positive effects on survival were indicated in 8 studies and tumor remission was supported by 1 study.[16] Four studies reported no effect on survival, one indicated no effect on DFS, two reported no benefit of treatment on tumor recurrence, and three indicated no effect on cancer remission.

Table 4. Use of Other Mistletoe Products in Cancer Treatment: Clinical Reports Describing Therapeutic End Pointsa

Reference	Trial Design	Product Tested	Condition or Cancer Type	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)b	Results	Concurrent Therapy Usedc	Level of Evidence Scored
DFS = disease-free survival; No. = number; QOL = quality of life.
aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms for additional information and definition of terms.
bNumber of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studied and for whom results were reported; historical control subjects are not included in number of patients enrolled.
cChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
dFor information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
eThis was a four-arm trial; patients were randomly assigned to surgery only or to surgery plus radiation therapy, followed by a second randomization to no mistletoe treatment or to treatment with Eurixor; the resulting treatment groups contained the following numbers of evaluable patients: surgery only = 105, surgery plus Eurixor = 97, surgery plus radiation therapy = 137, and surgery plus radiation therapy plus Eurixor = 138; radiation therapy and Eurixor treatment overlapped; no treatment approach was superior in terms of disease-free survival, disease-specific survival, improvement in QOL, or stimulation of the immune system; in the table, mistletoe-treated and nontreated (control) patients were grouped (i.e., number treated = 97 + 138 = 235, and number control = 105 + 137 = 242).
[3]	Randomized trial	Eurixor	Bladder, noninvasive	45; 23; 22	DFS did not vary between groups	No	1iiDi
[1,63]	Randomized trial	Eurixor	Brain, glioma; 74% of patients, stages III–IV; 26% of patients, no stage information	47; 20; 18	Improved survival, stages III–IV patients only	Yes	1iiA
[52,53]	Randomized trial	Eurixor	Colorectal, metastatic	107; 38; 41	Improved QOL	Yes	1iiC
[2]	Randomized trial	Eurixor	Head and neck, squamous cell, stages I–IV	495; 235e; 242e	No differences in DFS between groups	Yese	1iiDi
[45]	Randomized trial	Helixor	Breast, stages I–III	692; 192 (Helixor) and 177 (chemotherapy); 274	Improved survival	Yes	1iiA
[46]	Randomized trial	Helixor	Colorectal, metastatic	60; 20; 20	Improved mean survival	Yes	1iiA
[43]	Randomized trial	Helixor	Breast, ovarian, and non-small cell lung	224; 115; 109	Improved QOL	Yes	1iiC
[41]	Randomized trial	HelixorA, IscadorM	Breast	95; 34 (HelixorA) and 30 (IscadorM); 31	No differences in the primary outcome between groups	Yes	1iiC
[13]	Randomized controlled trial	PS76A (Lektin)	Breast	352; 176; 176	Improved QOL	Yes	1iC
[57]	Randomized trial	Lektinol	Breast	261; 195; 66	Improved QOL	Yes	1iC
[58]	Randomized trial	Lektinol	Breast	352; 176; 176	Improved QOL	Yes	1iC
[56]	Randomized trial	Isorel	Colorectal	64; 50; 14	Improved survival and tolerance to either adjuvant or palliative treatment	Yes	1iiA
[55]	Nonrandomized controlled trial	Isorel	Digestive tract	70; 40; 30	Enhanced cellular immunity and improved QOL	No	2C
[50]	Nonrandomized controlled trial	abnobaVISCUM Quercus	Metastatic colorectal	25; 25; none	No objective tumor response	Yes	2Diii
[21]	Nonrandomized controlled trial	Viscum fraxini-2	Hepatocellular carcinoma	23; 23; none	Improved survival	No	2Dii

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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