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 Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.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 hydrazine sulfate as a treatment for people with cancer. The summary includes a brief history of hydrazine sulfate research, results of clinical trials, and possible side effects of hydrazine sulfate 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.

Hydrazine sulfate has been investigated as an anticancer treatment for more than 30 years. It has been studied in combination with established treatments as a chemotherapy agent. It has also been studied as a treatment for cancer-related anorexia (loss of appetite) and cachexia (loss of muscle mass and body weight). Similar to other hydrazine compounds, it has a core chemical structure that consists of two nitrogen atoms and four hydrogen atoms.

Hydrazine sulfate is marketed in the United States as a dietary supplement/nutraceutical by some companies. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can, however, remove from the market dietary supplements that it deems unsafe. The use of hydrazine sulfate as an anticancer treatment outside of clinical trials has not been approved by the FDA. The FDA has not approved the use of hydrazine sulfate for any medical condition.

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. The FDA has granted IND status to at least three groups of researchers to study hydrazine sulfate as a treatment for cancer.[1–3]

In animal studies, hydrazine sulfate has been added to the drinking water or the food supply, or it has been given by injection. In clinical trials involving cancer patients, hydrazine sulfate has been administered in pills or capsules.[4] In the clinical studies conducted thus far, the dose and the duration of hydrazine sulfate administration have varied.

References

1. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 8 (1): 9-15, 1990. [PUBMED Abstract]
2. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979. [PUBMED Abstract]
3. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975. [PUBMED Abstract]
4. Toth B: A review of the antineoplastic action of certain hydrazines and hydrazine-containing natural products. In Vivo 10 (1): 65-96, 1996 Jan-Feb. [PUBMED Abstract]

During the past 90 years, hydrazine compounds have been studied in animal cells grown in the laboratory, in live animals, and in humans.[1] More than 400 hydrazine analogs (related compounds) have been screened for their ability to kill tumors. In 1996, a retrospective review of scientific studies in which the anticancer activity of hydrazine analogs was investigated found that 65 of 82 evaluated compounds showed some anticancer activity in xenograft models (tumor cells of one species transplanted to another species).[1] Of the 82 tested compounds, seven showed activity against human tumor cells and were, therefore, selected for further testing in pilot studies and phase I clinical trials. Among these seven compounds, only procarbazine (a methylhydrazine derivative, also called ibenzmethyzin or natulan) completed preliminary testing in humans. Procarbazine exhibited anticancer activity in patients with Hodgkin disease, melanoma, and lung carcinoma, and it was ultimately used in several first-line treatment regimens in the 1960s.[1–3] In view of the initial success with procarbazine, hydrazine sulfate, which is similar in chemical composition, was investigated for anticancer activity beginning in the 1970s. During this period, investigation of hydrazine sulfate as a treatment for cancer-related cachexia was also initiated. Research on hydrazine sulfate both as a single agent and in combination with standard chemotherapy regimens continued through the mid-1990s.[4–9]

Although it was proposed in the early 1900s that hydrazine compounds are toxic to animals and to humans, they have been administered as antidepressant (e.g., iproniazid), chemotherapy (e.g., procarbazine), and antituberculosis (e.g., isoniazid) drugs. In addition to medicinal uses, hydrazine compounds have been used in industry and agriculture as components of rocket fuel, as herbicides, and as antioxidants in boiler and cooling-tower water.[10–12] Many scientists consider hydrazine sulfate and other hydrazine analogs to be cancer-causing agents, and they have expressed concern about the safety of these compounds.[1,10,12–21] In the 10th Report on Carcinogens, hydrazine and hydrazine sulfate are listed by the U.S. Department of Health and Human Services’ National Toxicology Program as “reasonably anticipated to be human carcinogens.”[22] When the antituberculosis drug isoniazid and hydrazine antidepressants are combined with purified DNA in the laboratory, they produce hydrogen peroxide and free radicals that can damage the DNA.[14,17,23] Hydrazine compounds have been reported to cause mutations and chromosome damage in bacteria and in plant and animal cells.[10]

Two mechanisms of action have been proposed for hydrazine sulfate to explain its potential antitumor and anticachexia properties. Both mechanisms involve the utilization of glucose (sugar), which tumors require as a main source of energy for growth. In one proposed mechanism, hydrazine sulfate blocks gluconeogenesis through inhibition of the enzyme phosphoenolpyruvate carboxykinase.[24–29] Gluconeogenesis is a process by which extra glucose (in addition to that obtained from the diet) can be formed in the liver and the kidneys from the breakdown products of sugars, lipids (fats), and proteins. It has been suggested that cachexia occurs because the body must use increasing amounts of energy and other resources, including its own protein, to meet the demand for glucose by tumors.[24–30] Blocking gluconeogenesis and interfering with the supply of nutrients to tumors has been proposed as one way to inhibit tumor growth and to prevent cachexia.

In the second proposed mechanism, hydrazine sulfate inhibits tumor necrosis factor (TNF)-alpha activity.[31–34] TNF-alpha, which is also known as cachectin, is one of a number of substances normally produced by white blood cells in the body in response to infection by microorganisms and in response to other stimuli such as tissue damage.[31,32,34–36] Higher-than-normal TNF-alpha production has been observed in white blood cells obtained from cancer patients. It has been suggested that higher-than-normal levels of TNF-alpha can cause the anorexia, increased energy expenditure, and increased muscle protein breakdown seen in cancer patients.[31,35–37] Some of the muscle protein breakdown products would become available for gluconeogenesis. Inhibition of TNF-alpha activity might, therefore, inhibit tumor growth and prevent cachexia.

References

1. Toth B: A review of the antineoplastic action of certain hydrazines and hydrazine-containing natural products. In Vivo 10 (1): 65-96, 1996 Jan-Feb. [PUBMED Abstract]
2. DeVita VT, Serpick A, Carbone PP: Preliminary clinical studies with ibenzmethyzin. Clin Pharmacol Ther 7 (4): 542-6, 1966 Jul-Aug. [PUBMED Abstract]
3. Samuels ML, Leary WV, Alexanian R, et al.: Clinical trials with N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride in malignant lymphoma and other disseminated neoplasia. Cancer 20 (8): 1187-94, 1967. [PUBMED Abstract]
4. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 8 (1): 9-15, 1990. [PUBMED Abstract]
5. Kosty MP, Fleishman SB, Herndon JE, et al.: Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 12 (6): 1113-20, 1994. [PUBMED Abstract]
6. Loprinzi CL, Kuross SA, O’Fallon JR, et al.: Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. J Clin Oncol 12 (6): 1121-5, 1994. [PUBMED Abstract]
7. Loprinzi CL, Goldberg RM, Su JQ, et al.: Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12 (6): 1126-9, 1994. [PUBMED Abstract]
8. Filov VA, Gershanovich ML, Danova LA, et al.: Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS) in the advanced cancer patients. Invest New Drugs 13 (1): 89-97, 1995. [PUBMED Abstract]
9. Tayek JA, Sutter L, Manglik S, et al.: Altered metabolism and mortality in patients with colon cancer receiving chemotherapy. Am J Med Sci 310 (2): 48-55, 1995. [PUBMED Abstract]
10. Kimball RF: The mutagenicity of hydrazine and some of its derivatives. Mutat Res 39 (2): 111-26, 1977. [PUBMED Abstract]
11. Nelson SD, Gordon WP: Metabolic activation of hydrazines. Adv Exp Med Biol 136 Pt B: 971-81, 1981. [PUBMED Abstract]
12. Vasudeva M, Vashishat RK: Mutagenic and recombinogenic activity of hydrazine sulphate in Saccharomyces cerevisiae. Mutat Res 155 (3): 113-5, 1985. [PUBMED Abstract]
13. Toth B: Synthetic and naturally occurring hydrazines as possible cancer causative agents. Cancer Res 35 (12): 3693-7, 1975. [PUBMED Abstract]
14. Rosenkranz HS, Carr HS: Hydrazine antidepressants and isoniazid: potential carcinogens. Lancet 1 (7713): 1354-5, 1971. [PUBMED Abstract]
15. Douglas GR, Gingerich JD, Soper LM: Evidence for in vivo non-mutagenicity of the carcinogen hydrazine sulfate in target tissues of lacZ transgenic mice. Carcinogenesis 16 (4): 801-4, 1995. [PUBMED Abstract]
16. Quintero-Ruiz A, Paz-Neri LL, Villa-Treviño S: Indirect alkylation of CBA mouse liver DNA and RNA by hydrazine in vivo. A possible mechanism of action as a carcinogen. J Natl Cancer Inst 67 (3): 613-8, 1981. [PUBMED Abstract]
17. Freese E, Sklarow S, Freese EB: DNA damage caused by antidepressant hydrazines and related drugs. Mutat Res 5 (3): 343-8, 1968 May-Jun. [PUBMED Abstract]
18. Bhide SV, D’Souza RA, Sawai MM, et al.: Lung tumour incidence in mice treated with hydrazine sulphate. Int J Cancer 18 (4): 530-5, 1976. [PUBMED Abstract]
19. Severi L, Biancifiori C: Hepatic carcinogenesis in CBA-Cb-Se mice and Cb-Se rats by isonicotinic acid hydrazide and hydrazine sulfate. J Natl Cancer Inst 41 (2): 331-49, 1968. [PUBMED Abstract]
20. Toth B: Lung tumor induction and inhibition of breast adenocarcinomas by hydrazine sulfate in mice. J Natl Cancer Inst 42 (3): 469-75, 1969. [PUBMED Abstract]
21. Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983. [PUBMED Abstract]
22. National Institute of Environmental Health Sciences: 11th Report on Carcinogens. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, 2005. Available online. Last accessed April 11, 2016.
23. National Toxicology Program: Hydrazine and hydrazine sulfate. Rep Carcinog 10: 138-9, 2002. [PUBMED Abstract]
24. Ray PD, Hanson RL, Lardy HA: Inhibition by hydrazine of gluconeogenesis in the rat. J Biol Chem 245 (4): 690-6, 1970. [PUBMED Abstract]
25. Gold J: Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 25 (1): 66-71, 1971. [PUBMED Abstract]
26. Gold J: Inhibition by hydrazine sulfate and various hydrazides, of in vivo growth of Walker 256 intramuscular carcinoma, B-16 melanoma, Murphy-Sturm lymphosarcoma and L-1210 solid leukemia. Oncology 27 (1): 69-80, 1973. [PUBMED Abstract]
27. Gold J: Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer 3 (1): 13-9, 1981. [PUBMED Abstract]
28. Gold J: Hydrazine sulfate: a current perspective. Nutr Cancer 9 (2-3): 59-66, 1987. [PUBMED Abstract]
29. Dills WL: Nutritional and physiological consequences of tumour glycolysis. Parasitology 107 (Suppl): S177-86, 1993. [PUBMED Abstract]
30. Gold J: Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology 22 (2): 185-207, 1968. [PUBMED Abstract]
31. Hughes TK, Cadet P, Larned CS: Modulation of tumor necrosis factor activities by a potential anticachexia compound, hydrazine sulfate. Int J Immunopharmacol 11 (5): 501-7, 1989. [PUBMED Abstract]
32. De SK, Silverstein R, Andrews GK: Hydrazine sulfate protection against endotoxin lethality: analysis of effects on expression of hepatic cytokine genes and an acute-phase gene. Microb Pathog 13 (1): 37-47, 1992. [PUBMED Abstract]
33. Johnson DC, Freudenberg MA, Jia F, et al.: Contribution of tumor necrosis factor-alpha and glucocorticoid in hydrazine sulfate-mediated protection against endotoxin lethality. Circ Shock 43 (1): 1-8, 1994. [PUBMED Abstract]
34. Jia F, Morrison DC, Silverstein R: Hydrazine sulfate selectively modulates the TNF response to endotoxin in mouse macrophages. Circ Shock 42 (2): 111-4, 1994. [PUBMED Abstract]
35. Parnes HL, Aisner J: Protein calorie malnutrition and cancer therapy. Drug Saf 7 (6): 404-16, 1992 Nov-Dec. [PUBMED Abstract]
36. Lowry SF, Moldawer LL: Tumor necrosis factor and other cytokines in the pathogenesis of cancer cachexia. Princ Pract Oncol Updates 4 (8): 1-12, 1990.
37. Bruera E: Current pharmacological management of anorexia in cancer patients. Oncology (Huntingt) 6 (1): 125-30; discussion 132, 137, 1992. [PUBMED Abstract]

Hydrazine compounds have been studied both as potential anticancer drugs and as cancer-causing agents. Early studies of hydrazines, including hydrazine sulfate, were conducted to determine whether these compounds could cause cancer in healthy laboratory animals.[1–11] Substantial increases in tumor incidence were observed in most studies that used rats, mice, or hamsters.[1–5,7–9] Hydrazine administration was associated with increases in lung, liver, and breast tumors in rats,[2,5] increases in lung and liver tumors in mice,[1–4,8] and increases in liver tumors in hamsters.[7,9] In one study, hydrazine sulfate increased the incidence of lung tumors in both males and females of the mouse strain C3H, but reduced the incidence of breast adenocarcinomas in C3H females.[3]

Animal studies of hydrazine sulfate as a treatment for cancer have investigated this compound as a single agent and in combination with established chemotherapy drugs.[12–18] In studies conducted in one laboratory, hydrazine sulfate alone was found to cause dose-dependent inhibition of tumor growth in rats bearing Walker 256 carcinosarcoma or Murphy-Sturm lymphosarcoma tumors and in mice bearing B-16 melanoma tumors.[12–14] Hydrazine sulfate alone had no effect on solid tumors formed from L-1210 leukemia cells in mice.[13] In work performed in another laboratory, hydrazine sulfate alone inhibited the growth of FBCa bladder cancer tumors in one of two experiments in rats, but it had no effect on the growth of 13762NF mammary adenocarcinomas in rats.[17] Findings from a third laboratory demonstrated that hydrazine sulfate alone had no effect on the growth of Dunning prostate cancer tumors in rats.[18]

It is important to note that the best tumor responses to hydrazine sulfate as a single agent (i.e., tumor reductions of approximately 50% or more) were accompanied by substantial losses in animal body weight.[12–14] This finding appears to be inconsistent with the proposed use of hydrazine sulfate as an anticachexia agent.

In other experiments, hydrazine sulfate was combined with individual chemotherapy drugs (cyclophosphamide, mitomycin C, methotrexate, bleomycin, fluorouracil [5-FU], carmustine [BCNU], or neocarzinostatin) to treat Walker 256 carcinosarcoma tumors in rats and solid L-1210 leukemia tumors in mice.[13–15] For both tumor types, enhanced anticancer effects were observed. In the experiments with L-1210 tumors, cyclophosphamide and mitomycin C were more effective when combined with hydrazine sulfate than they were when used alone.[13] As indicated previously, hydrazine sulfate alone had no effect against solid L-1210 tumors.[13]

Addition of the drug clofibrate to the hydrazine sulfate plus chemotherapy drug combinations was reported to produce even greater antitumor effects.[15] Clofibrate lowers blood lipid levels and has the potential to inhibit gluconeogenesis by limiting the availability of lipid breakdown products for the synthesis of glucose. This three drug treatment regimen, however, was tested against only one type of tumor (Walker 256 carcinosarcomas in rats).[15]

Hydrazine sulfate has also been tested in combination with drugs that affect the uptake of glucose by cells. The combination of hydrazine sulfate and phloretin, a drug that blocks glucose uptake, showed greater activity against FBCa bladder cancer tumors in rats than was found with hydrazine sulfate alone; however, this combination did not exhibit enhanced antitumor activity against 13762NF mammary adenocarcinomas in rats.[17] When hydrazine sulfate was combined with the drug phloridzin, which is similar to phloretin, using the same two tumor models, no increase in anticancer activity was observed.[17] When hydrazine sulfate was combined with the drug phenformin, which increases glucose uptake by cells (and lowers blood glucose levels), enhanced antitumor activity against Walker 256 carcinosarcomas in rats was observed.[16]

In the 1980s, the National Cancer Institute (NCI) conducted preclinical studies of hydrazine sulfate as a single agent, using many of the animal tumor models described above. With the exception of borderline activity against Walker 256 carcinosarcomas in rats, no evidence of antitumor activity was found.[19] In view of these results, NCI recommended against further evaluation of hydrazine sulfate as an anticancer agent.[19] However, clinical investigation of this compound continued, largely because of its potential as a treatment for cancer-related anorexia and cachexia.

References

1. Bhide SV, D’Souza RA, Sawai MM, et al.: Lung tumour incidence in mice treated with hydrazine sulphate. Int J Cancer 18 (4): 530-5, 1976. [PUBMED Abstract]
2. Severi L, Biancifiori C: Hepatic carcinogenesis in CBA-Cb-Se mice and Cb-Se rats by isonicotinic acid hydrazide and hydrazine sulfate. J Natl Cancer Inst 41 (2): 331-49, 1968. [PUBMED Abstract]
3. Toth B: Lung tumor induction and inhibition of breast adenocarcinomas by hydrazine sulfate in mice. J Natl Cancer Inst 42 (3): 469-75, 1969. [PUBMED Abstract]
4. Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983. [PUBMED Abstract]
5. Biancifiori C, Giornelli-Santilli FE, Milia U, et al.: Pulmonary tumours in rats induced by oral hydrazine sulphate. Nature 212 (60): 414-5, 1966. [PUBMED Abstract]
6. Toth B: Tumorigenesis studies with 1,2-dimethylhydrazine dihydrochloride, hydrazine sulfate, and isonicotinic acid in golden hamsters. Cancer Res 32 (4): 804-7, 1972. [PUBMED Abstract]
7. Shimizu H, Toth B: Effect of lifetime administration of 2-hydroxyethylhydrazine on tumorigenesis in hamsters and mice. J Natl Cancer Inst 52 (3): 903-6, 1974. [PUBMED Abstract]
8. Maru GB, Bhide SV: Effect of antioxidants and antitoxicants of isoniazid on the formation of lung tumours in mice by isoniazid and hydrazine sulphate. Cancer Lett 17 (1): 75-80, 1982. [PUBMED Abstract]
9. Bosan WS, Shank RC, MacEwen JD, et al.: Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. Carcinogenesis 8 (3): 439-44, 1987. [PUBMED Abstract]
10. Toth B: Synthetic and naturally occurring hydrazines as possible cancer causative agents. Cancer Res 35 (12): 3693-7, 1975. [PUBMED Abstract]
11. National Toxicology Program: Hydrazine and hydrazine sulfate. Rep Carcinog 10: 138-9, 2002. [PUBMED Abstract]
12. Gold J: Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 25 (1): 66-71, 1971. [PUBMED Abstract]
13. Gold J: Inhibition by hydrazine sulfate and various hydrazides, of in vivo growth of Walker 256 intramuscular carcinoma, B-16 melanoma, Murphy-Sturm lymphosarcoma and L-1210 solid leukemia. Oncology 27 (1): 69-80, 1973. [PUBMED Abstract]
14. Gold J: Enhancement by hydrazine sulfate of antitumor effectiveness of cytoxan, mitomycin C, methotrexate and bleomycin, in walker 256 carcinosarcoma in rats. Oncology 31 (1): 44-53, 1975. [PUBMED Abstract]
15. Gold J: Potentiation by clofibrate of in-vivo tumor inhibition by hydrazine sulfate and cytotoxic agents, in Walker 256 carcinosarcoma. Cancer Biochem Biophys 3 (1): 41-5, 1978. [PUBMED Abstract]
16. Dilman VM, Anisimov VN: Potentiation of antitumor effect of cyclophosphamide and hydrazine sulfate by treatment with the antidiabetic agent, 1-phenylethylbiguanide (phenformin). Cancer Lett 7 (6): 357-61, 1979. [PUBMED Abstract]
17. Nelson JA, Falk RE: The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 13 (6A): 2287-92, 1993 Nov-Dec. [PUBMED Abstract]
18. Kamradt JM, Pienta KJ: The effect of hydrazine sulfate on prostate cancer growth. Oncol Rep 5 (4): 919-21, 1998 Jul-Aug. [PUBMED Abstract]
19. Henney JE: Unproven methods of cancer treatment. In: DeVita VT, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. JB Lippincott Company, 1985, pp 2333-44.

Most of the information presented here is summarized in a table located at the end of this section.

Hydrazine sulfate has been studied extensively in patients with advanced cancer. These studies have evaluated the following: a) tumor response and/or survival among patients with various types of cancer,[1–13] b) changes in body weight,[1–6,8,10–12,14] c) carefully measured quality of life,[4–6,15] and d) changes in nutritional or metabolic status.[1,4,12,13,16,17] Clinical studies of hydrazine sulfate have been funded by a pharmaceutical company,[3] the Russian government,[7,9,10,18] and by grants from the National Cancer Institute (NCI).[1,2,4–6,8,11,12,15,16] They have also been sponsored by the North Central Cancer Treatment Group (NCCTG) [5,6] and the Cancer and Leukemia Group B (CALGB).[4,15]

The first clinical tests of hydrazine sulfate as a treatment for cancer were conducted in the mid-1970s by a pharmaceutical company.[3] In an uncontrolled study of 158 patients with advanced disease, it was found that 45 of 84 evaluable patients had subjective improvements (i.e., the patients reported an increase in appetite, a decrease in weight loss, an increase in strength, or a decrease in pain) and that 14 had objective improvements (i.e., there was measurable tumor regression, stable disease, or improvement in a cancer-related disorder) in response to treatment with hydrazine sulfate. Among the patients with objective responses, two had long-term (17 and 18 months) stabilization of their disease and seven had measurable tumor regression, although the extent and duration of these regressions were not specified. Major weaknesses of this study included the absence of a control (i.e., comparison) group and the fact that 74 of the 158 initially recruited patients could not be evaluated because of poor prognosis, missing documentation, insufficient duration of treatment, and/or concurrent therapy (i.e., therapy given at the same time) with other anticancer drugs.[3]

In 1976, Russian investigators reported findings from 95 patients with advanced cancer who had been treated with hydrazine sulfate after all previous therapy (surgery, chemotherapy, and/or radiation therapy) had failed.[9] Three partial responses (i.e., reductions in tumor size of greater than 50% observed for a period of 4 weeks or more) and no complete responses were noted after 1 to 5 months of treatment. Tumor regressions of 50% or less and stable disease (i.e., cessation of tumor growth for a period of 1.5 to 2.0 months or more) were reported for 16 and 20 patients, respectively.

In 1981, the same investigators published findings from 225 patients with advanced disease who had been treated with hydrazine sulfate after all previous therapy had failed.[10] It appears that the 225 patients described in this second report [10] included the 95 patients described in the first report.[9] Partial responses and stable disease were reported for 4 and 95 patients, respectively, after 1 to 6 months of treatment. No patient experienced a complete response. Subjective improvements in appetite, weight stabilization or gain, pain, fever, breathing, and/or mental outlook were reported by 147 patients.

In 1995, the same Russian investigators published findings from 740 patients with advanced cancer.[7] Once again, it appears that 225 of these 740 patients were described in the earlier reports.[9,10] Partial responses and stable disease were reported for 25 and 263 patients, respectively. Complete responses were noted for six patients. Subjective improvements in cancer-related symptoms were reported by 344 patients.

In 1994, the same investigators reported findings from a clinical series involving 46 patients with malignant brain tumors (38 with glioblastomas, four with astrocytomas, and four with meningiomas) and six patients with benign brain tumors.[18] These patients were not described in the other reports.[7,9,10] All patients in this series appear to have been treated with surgery in addition to hydrazine sulfate therapy, and at least some of the patients were also treated with radiation therapy. Complete or partial regression of neurologic symptoms (e.g., seizures, headaches, sensory and motor disorders, and hallucinations) was reported for 73% of the patients. In addition, longer-than-average survival was reported for most patients. Among the patients with glioblastomas, the increase in average survival time was from 6 months to more than 13 months.[18]

Evaluation of the findings from these Russian clinical series [7,9,10,18] is made difficult by the limited information provided about the patients and their treatment histories. In addition, insufficient information was given about study design and methodology. The absence of control groups; the receipt of prior or concurrent surgery, chemotherapy, and/or radiation therapy by all patients; and the reliance on subjective measures of quality of life are major study weaknesses. Therefore, it is difficult to ascribe any of the positive findings to treatment with hydrazine sulfate. In contrast with the previously described clinical series, three NCI-funded clinical series found no complete responses or partial responses among a total of 79 patients treated with hydrazine sulfate.[2,8,11] In addition, only temporary, minor improvements in appetite, pain, and weight stabilization or gain were reported by the patients in these series. A weakness in these three clinical series was the absence of control groups.

Findings from four placebo-controlled, randomized clinical trials, however, also fail to support the effectiveness of hydrazine sulfate as a cancer treatment in humans.[1,4–6,15] In these trials, survival,[1,4–6,15] objective tumor response,[1,4,15] and carefully measured quality of life [4–6,15] were major endpoints.

One of the trials involved 65 patients with advanced non-small cell lung cancer and examined the effects of hydrazine sulfate on survival and nutritional status.[1] In this trial, patients received either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. When all patients were evaluated, no improvement in survival was found with hydrazine sulfate therapy. In addition, no differences were noted in objective tumor response between the hydrazine sulfate group and the placebo group. However, on the basis of caloric intake and the maintenance of serum albumin levels, the nutritional status of the patients in the hydrazine sulfate group was judged better than that of the patients in the placebo group. However, the moderate increases in body weight associated with hydrazine sulfate use did not achieve statistical significance.

A CALGB-sponsored trial also evaluated the use of hydrazine sulfate as a treatment for patients with advanced non-small cell lung cancer.[4,15] In this trial, 266 patients received either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. No differences in survival, objective tumor response, anorexia, weight gain or loss, or nutritional status were observed between the hydrazine sulfate group and the placebo group. However, the quality of life of the patients who received hydrazine sulfate was found to be statistically significantly worse than that of the patients who received placebo.

The use of hydrazine sulfate as a treatment for patients with non-small cell lung cancer was also evaluated in an NCCTG-sponsored trial.[6] In this trial, 243 patients were randomly assigned to receive either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. No statistically significant differences were found between the hydrazine sulfate group and the placebo group with respect to either survival or quality of life.

Another NCCTG-sponsored trial tested hydrazine sulfate alone versus placebo in the treatment of 127 patients with metastatic colorectal cancer.[5] In this trial, the patients who received hydrazine sulfate had, on average, shorter survival than the patients who received placebo, a finding that was statistically significant. There were no statistically significant differences between the hydrazine sulfate group and the placebo group with respect to weight gain or loss, anorexia, or quality of life.

Four other clinical trials did find some objective evidence of benefit with hydrazine sulfate therapy.[12,13,16,17] These trials had either nutritional status or metabolic status as the primary endpoint. In a placebo-controlled, randomized trial involving 38 patients with advanced disease, hydrazine sulfate was found to improve the abnormal glucose metabolism seen in cancer patients.[13] In another placebo-controlled, randomized trial that involved 101 patients with advanced cancer and weight loss, the use of hydrazine sulfate was associated with statistically significant improvements in appetite and either weight increase or weight maintenance.[12] However, the higher average caloric intake observed in this study for patients treated with hydrazine sulfate compared with patients treated with placebo was not statistically significant.[12] Two other clinical studies involving a total of 34 patients with either lung cancer or colon cancer found that hydrazine sulfate was able to reduce the body protein breakdown associated with cancer cachexia.[16,17] In view of the totality of evidence, the overall importance of the findings from these four clinical trials is not clear.

A search of the PDQ clinical trials database indicates that no clinical trials of hydrazine sulfate as a therapy for cancer are being conducted at this time.

Studies of Hydrazine Sulfate in Which Therapeutic Benefit Was Assesseda

Reference Citation(s)	Type of Study	Type of Cancer	No. of Patients: Enrolled; Treated; Controlb	Strongest Benefit Reportedc	Concurrent Therapyd	Level of Evidence Scoree
No. = number.
aSee text for more details.
bNumber of patients treated plus number of control patients 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 given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
cThe strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients. See text and glossary for definition of terms.
dSurgery, chemotherapy, or radiation therapy given/allowed at the same time as hydrazine sulfate treatment.
eFor information about levels of evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
fThis study included six additional patients with benign brain tumors.
gInsufficient information given to permit a level of evidence analysis.
[1]	Randomized clinical trial	Advanced non-small cell lung	65; 32; 33, placebo	None	Yes	1iA
[4,15]	Randomized clinical trial	Advanced non-small cell lung	291; 135; 131, placebo	None	Yes	1iA
[5]	Randomized clinical trial	Advanced colorectal	128; 63; 64, placebo	None	No	1iA
[6]	Randomized clinical trial	Advanced non-small cell lung	243; 119; 118, placebo	None	Yes	1iA
[2]	Nonconsecutive case series	Various advanced	25; 25; None	Slight regression of some metastatic lesions, 1 patient with melanoma	No	3iiiDiii
[3]	Nonconsecutive case series	Various advanced	158; 84; None	Measurable tumor regression, 7 patients	Yes	3iiiDiii
[7,9,10]	Nonconsecutive case series	Various advanced	763; 740; None	Complete tumor regression, 6 patients	No	3iiiDiii
[8]	Nonconsecutive case series	Various advanced	25; 25; None	None	No	3iiiDiii
[11]	Nonconsecutive case series	Various advanced	32; 29; None	None	Unknown	3iiiDiii
[12]	Nonconsecutive case series	Various advanced	101; 71; 30, placebo	Improved weight maintenance or gain, 41 hydrazine sulfate treated vs. 17 placebo-treated patients	Yes	3iiiDiii
[18]	Nonconsecutive case series	Glioblastoma, astrocytoma, or meningiomaf	465; 46; None	Improved survival, patients with glioblastoma	Yes	Noneg

References

1. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 8 (1): 9-15, 1990. [PUBMED Abstract]
2. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979. [PUBMED Abstract]
3. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975. [PUBMED Abstract]
4. Kosty MP, Fleishman SB, Herndon JE, et al.: Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 12 (6): 1113-20, 1994. [PUBMED Abstract]
5. Loprinzi CL, Kuross SA, O’Fallon JR, et al.: Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. J Clin Oncol 12 (6): 1121-5, 1994. [PUBMED Abstract]
6. Loprinzi CL, Goldberg RM, Su JQ, et al.: Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12 (6): 1126-9, 1994. [PUBMED Abstract]
7. Filov VA, Gershanovich ML, Danova LA, et al.: Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS) in the advanced cancer patients. Invest New Drugs 13 (1): 89-97, 1995. [PUBMED Abstract]
8. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60 (7): 959-60, 1976. [PUBMED Abstract]
9. Gershanovich ML, Danova LA, Kondratyev VB, et al.: Clinical data on the antitumor activity of hydrazine sulfate. Cancer Treat Rep 60 (7): 933-5, 1976. [PUBMED Abstract]
10. Gershanovich ML, Danova LA, Ivin BA, et al.: Results of clinical study antitumor action of hydrazine sulfate. Nutr Cancer 3 (1): 7-12, 1981. [PUBMED Abstract]
11. Ochoa M, Wittes RE, Krakoff IH: Trial of hydrazine sulfate (NSC-150014) in patients with cancer. Cancer Chemother Rep 59 (6): 1151-4, 1975 Nov-Dec. [PUBMED Abstract]
12. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 59 (3): 406-10, 1987. [PUBMED Abstract]
13. Chlebowski RT, Heber D, Richardson B, et al.: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44 (2): 857-61, 1984. [PUBMED Abstract]
14. Gold J: Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer 3 (1): 13-9, 1981. [PUBMED Abstract]
15. Herndon JE, Fleishman S, Kosty MP, et al.: A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials 18 (4): 286-300, 1997. [PUBMED Abstract]
16. Tayek JA, Sutter L, Manglik S, et al.: Altered metabolism and mortality in patients with colon cancer receiving chemotherapy. Am J Med Sci 310 (2): 48-55, 1995. [PUBMED Abstract]
17. Tayek JA, Heber D, Chlebowski RT: Effect of hydrazine sulphate on whole-body protein breakdown measured by 14C-lysine metabolism in lung cancer patients. Lancet 2 (8553): 241-4, 1987. [PUBMED Abstract]
18. Filov VA, Gershanovich ML, Ivin BA, et al.: [Therapy of primary brain tumors with segidrin] Vopr Onkol 40 (7-12): 332-6, 1994. [PUBMED Abstract]

The side effects associated with hydrazine sulfate use have been mainly gastrointestinal and neurologic.[1–12] Nausea and/or vomiting, dizziness, and sensory and motor neuropathies have been reported.[1–12] The sensory and motor neuropathies have included paresthesias (abnormal touch sensations, such as burning or prickling, in the absence of external stimuli) of the upper and lower extremities (i.e., the arms and the legs, including the hands and the feet), polyneuritis (simultaneous inflammation of several peripheral nerves), and impaired fine motor function (e.g., an impaired ability to write).[2,5,7–9] Other side effects have included dry skin and/or itching, insomnia, and hypoglycemia.[1,2,7,9] One case of fatal liver and kidney failure and one case of severe encephalopathy (an injury to the brain) have been associated with the use of hydrazine sulfate.[13,14] The former case involved a man aged 55 years with squamous cell carcinoma of the maxillary sinus who purchased hydrazine sulfate from a source found on the Internet and proceeded to take it without medical advice or supervision. After 4 months he presented with evidence of renal and liver toxicity, which eventually resulted in death. This case highlights the danger of accessing materials and medical information on the Internet and proceeding with self-medication without seeking proper medical advice and supervision.[15]

The side effects of hydrazine sulfate have been described as mild to moderate in severity, and their incidence appears to have been low. Most side effects are reported to resolve when treatment is stopped. However, limited evidence from animal studies suggests that hydrazine sulfate is highly toxic when combined with either alcohol or barbiturates.[16–19]

References

1. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979. [PUBMED Abstract]
2. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975. [PUBMED Abstract]
3. Kosty MP, Fleishman SB, Herndon JE, et al.: Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 12 (6): 1113-20, 1994. [PUBMED Abstract]
4. Loprinzi CL, Goldberg RM, Su JQ, et al.: Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12 (6): 1126-9, 1994. [PUBMED Abstract]
5. Filov VA, Gershanovich ML, Danova LA, et al.: Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS) in the advanced cancer patients. Invest New Drugs 13 (1): 89-97, 1995. [PUBMED Abstract]
6. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60 (7): 959-60, 1976. [PUBMED Abstract]
7. Gershanovich ML, Danova LA, Kondratyev VB, et al.: Clinical data on the antitumor activity of hydrazine sulfate. Cancer Treat Rep 60 (7): 933-5, 1976. [PUBMED Abstract]
8. Gershanovich ML, Danova LA, Ivin BA, et al.: Results of clinical study antitumor action of hydrazine sulfate. Nutr Cancer 3 (1): 7-12, 1981. [PUBMED Abstract]
9. Ochoa M, Wittes RE, Krakoff IH: Trial of hydrazine sulfate (NSC-150014) in patients with cancer. Cancer Chemother Rep 59 (6): 1151-4, 1975 Nov-Dec. [PUBMED Abstract]
10. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 59 (3): 406-10, 1987. [PUBMED Abstract]
11. Chlebowski RT, Heber D, Richardson B, et al.: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44 (2): 857-61, 1984. [PUBMED Abstract]
12. Herndon JE, Fleishman S, Kosty MP, et al.: A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials 18 (4): 286-300, 1997. [PUBMED Abstract]
13. Hainer MI, Tsai N, Komura ST, et al.: Fatal hepatorenal failure associated with hydrazine sulfate. Ann Intern Med 133 (11): 877-80, 2000. [PUBMED Abstract]
14. Nagappan R, Riddell T: Pyridoxine therapy in a patient with severe hydrazine sulfate toxicity. Crit Care Med 28 (6): 2116-8, 2000. [PUBMED Abstract]
15. Black M, Hussain H: Hydrazine, cancer, the Internet, isoniazid, and the liver. Ann Intern Med 133 (11): 911-3, 2000. [PUBMED Abstract]
16. Masaki H, Arai H, Torii K: Newly developed animal model with alcoholic liver damage induced by an inhibitor for gluconeogenesis, hydrazine sulfate. Gastroenterol Jpn 24 (5): 584, 1989. [PUBMED Abstract]
17. Suzuki H, Tominaga T, Mizuno H, et al.: Ethanol and hydrazine sulfate induced chronic hepatic injury in rats: the curative effect of administration of glucogenic amino acids. Alcohol Alcohol Suppl 1A: 111-7, 1993. [PUBMED Abstract]
18. Gold J: Incompatibility of hydrazine sulfate and pentobarbital in the treatment of tumor bearing animals. [Abstract] Proc Am Assoc Cancer Res 18: A-999, 250, 1977.
19. U.S. General Accounting Office: Cancer Drug Research: Contrary to Allegation, NIH Hydrazine Sulfate Studies Were Not Flawed. U.S. General Accounting Office, 1995, GAO-HEHS-95-141. Also available online. Last accessed April 11, 2016.

Several clinical case series conducted by Russian investigators have indicated that hydrazine sulfate has marginal anticancer activity, but these results are considered inconclusive due to the lack of control groups and insufficient information provided about study methodology. Well-controlled clinical studies conducted in the United States have shown no evidence of anticancer activity. In addition, evidence concerning the effectiveness of hydrazine sulfate as a treatment for cancer-related cachexia and anorexia is inconclusive. Furthermore, hydrazine sulfate has been shown to increase the incidence of several types of tumors in animals, and it has been classified as a potential carcinogen by the National Toxicology Program of the U.S. Department of Health and Human Services. The use of hydrazine sulfate as an anticancer drug outside the context of clinical trials has not been approved by the U.S. Food and Drug Administration and, thus, cannot be recommended.

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, 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 hydrazine sulfate 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 Hydrazine Sulfate. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/hydrazine-sulfate-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389456]

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 hydrazine sulfate?

   Hydrazine sulfate is a compound that has been studied as a treatment for cancer and for cancer-related anorexia (loss of appetite) and cachexia (loss of muscle mass and body weight).

2. What is the history of the discovery and use of hydrazine sulfate as a complementary or alternative treatment for cancer?

   It has been known since the early 1900s that hydrazine compounds are toxic to animals and to humans. More than 400 hydrazine-related compounds have been tested for their ability to kill cancer cells. One of these compounds, procarbazine, has been used to treat Hodgkin disease, melanoma, and lung cancer since the 1960s.

   In view of procarbazine’s anticancer activity, hydrazine sulfate (a compound similar to procarbazine) was studied for its effectiveness in fighting cancer beginning in the 1970s. Studies of hydrazine sulfate as a treatment for cancer-related cachexia also began during this time.

   Hydrazine compounds have also been used to make rocket fuel, as herbicides (chemicals that kill plants), and as chemical agents in boiler and cooling-tower water systems. Many scientists consider hydrazine sulfate and other similar substances to be cancer-causing agents and are concerned about the safety of using these compounds.

3. What is the theory behind the claim that hydrazine sulfate is useful in treating cancer?

   Two theories have been suggested to explain how hydrazine sulfate acts against cancer and cachexia:

   • Hydrazine sulfate may prevent the body from making sugar that cancer cells need to grow. It has been suggested that cachexia occurs because the cancer is using too much of the body’s sugar, preventing healthy cells from getting what they need to live. This causes tissues to die and muscle to waste away, and the patient loses weight.
   • Hydrazine sulfate may block tumor necrosis factor-alpha (TNF-alpha). This is a substance made by the body’s white blood cells to fight infection and tissue damage. High levels of TNF-alpha have been found in cancer patients. These high levels of TNF-alpha may cause loss of appetite, tiredness, and the breakdown of muscle tissue. As muscle breaks down, it makes sugar that the cancer cells use to grow. Blocking the TNF-alpha might stop tumor growth and prevent cachexia.
4. How is hydrazine sulfate administered?

   Hydrazine sulfate is taken by mouth in pills or capsules. There is no standard dose or length of treatment time.

5. Have any preclinical (laboratory or animal) studies been conducted using hydrazine sulfate?

   Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be safe and useful in humans. These preclinical studies are done before any testing in humans is begun. The following has been learned from preclinical studies of hydrazine sulfate:

   • In most studies with rats, mice, and hamsters, hydrazine sulfate caused an increase in lung, liver, and breast cancers.
   • When used alone against certain types of cancer (including melanoma, leukemia, bladder, breast, and prostate), hydrazine sulfate slowed tumor growth in some animal studies and showed no effect in others. In cases where tumor growth was slowed the most, the animals lost large amounts of weight. This finding does not support the proposed use of hydrazine sulfate to treat cachexia caused by cancer.
   • When hydrazine sulfate was combined with an anticancer drug, it seemed to improve the anticancer effects in rats and mice. When hydrazine sulfate was combined with an anticancer drug that affects the way cells use sugar, however, it helped in some studies and did not help in others.
   • Preclinical studies by the National Cancer Institute (NCI) found that hydrazine sulfate showed no anticancer activity except in one type of cancer in rats. The NCI decided not to continue studying the compound as a treatment for cancer. Studies of hydrazine sulfate as a treatment for cancer-related anorexia and cachexia continued.

   For more information on the preclinical studies, see the PDQ health professional version of Hydrazine Sulfate.

6. Have any clinical trials (research studies with people) of hydrazine sulfate been conducted?

   Clinical trials are a type of research study that tests how well new drugs or other treatments work in people. There have been many studies of hydrazine sulfate in patients with advanced cancer. Researchers looked at the following:

   • Tumor response and/or survival among patients with various types of cancer.
   • Changes in body weight.
   • Quality of life.
   • Changes in nutritional status and metabolism (chemical changes that take place in cells and make energy needed for life).

   Clinical trials of hydrazine sulfate have reported the following:

   • In the mid 1970s, clinical trials by a drug company found that a small number of patients who were treated with hydrazine sulfate for advanced cancer reported having a better appetite, losing less weight, feeling stronger, or having less pain. In some patients, the tumor got smaller or did not grow, or there was improvement in a cancer-related symptom. These clinical trials do not prove that hydrazine sulfate is effective for advanced cancer, however, because of weaknesses in study design. There was no control group (a group of patients who did not receive hydrazine sulfate) and half of the patients in the trial could not be counted in the results for reasons that include missing information, short treatment times, and receiving other treatment along with the hydrazine sulfate.
   • From the 1970s to the mid 1990s, Russian studies with hydrazine sulfate had mixed results. Little information was reported about the patients and their treatment and about the study design and methods. All of the patients in these studies also received standard treatment with surgery, chemotherapy, and/or radiation therapy. Therefore, it is not known if results were caused by hydrazine sulfate or one of the standard treatments, or both.
   • Clinical studies funded by the NCI in the 1970s found that hydrazine sulfate did not cause tumors to shrink or go away. Some patients reported small improvements in appetite, pain, and weight, but they did not last. These studies did not include control groups.
   • Four randomized controlled trials were done in the 1990s. A randomized trial is a study in which the patients are assigned by chance to separate groups to compare different treatments; neither the researchers nor the patients can choose which group. These trials compared hydrazine sulfate with a placebo (an inactive substance that looks like the treatment being tested). The results showed that hydrazine sulfate was not effective in treating cancer. In some cases, it was found to be harmful.
     • In three of the trials, lung cancer patients received either hydrazine sulfate or a placebo, along with anticancer drugs. The patients who received hydrazine sulfate did not live longer or have their tumors shrink any more than the placebo group. In one of the studies, patients who took hydrazine sulfate showed better nutritional status than patients in the placebo group, although the increase in body weight was small. In another of the studies, patients who received hydrazine sulfate had a worse quality of life than patients who received the same anticancer drugs plus the placebo. 1
     • A fourth trial found that patients with colorectal cancer who received only hydrazine sulfate lived for a shorter time than patients who received only a placebo.
   • Four other randomized controlled trials studied the effects of hydrazine sulfate on nutritional status and metabolism. The studies showed some benefit from hydrazine sulfate.
     • In 2 of the studies2, patients receiving hydrazine sulfate showed improvement in metabolism, appetite, and in either gaining weight or not losing weight.
     • In the other 2 clinical trials3, lung and colon cancer patients receiving hydrazine sulfate had less cancer-related muscle wasting.
7. Have any side effects or risks been reported from hydrazine sulfate?

   In general, the reported side effects of hydrazine sulfate treatment have been mild to moderate. Most side effects are reported to end when treatment with hydrazine sulfate is stopped. Some animal studies, however, suggest that hydrazine sulfate may be highly toxic (harmful) when combined with either alcohol or barbiturates (drugs with sedative and hypnotic effects).

   Most of the side effects caused by hydrazine sulfate have involved the nervous system and gastrointestinal tract. These side effects include the following:

   • Nausea and/or vomiting.
   • Dizziness.
   • Abnormal feelings in the arms and legs (such as burning or prickling).
   • Nerve inflammation.
   • Impaired fine motor function (such as trouble writing).
   • Dry skin and/or itching.
   • Being unable to sleep.
   • Abnormally low blood sugar.

   One case of fatal liver and kidney failure and one case of severe injury to the brain have been linked to the use of hydrazine sulfate.

8. Is hydrazine sulfate approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The FDA has not approved hydrazine sulfate for use as a cancer treatment in the United States.

   The FDA has approved the study of hydrazine sulfate in clinical trials. Information about ongoing clinical trials can be found on the NCI website.

   Dietary supplements are products meant to be added to the diet. They are not drugs and are not meant to treat, prevent, or cure diseases. The manufacturer is responsible for ensuring that the product is safe and that the label claims are truthful and not misleading. The FDA does not approve dietary supplements as safe or effective before they are sold.

References

1. Loprinzi CL, Goldberg RM, Su JQ, et al.: Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12 (6): 1126-9, 1994. [PUBMED Abstract]
2. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 59 (3): 406-10, 1987. [PUBMED Abstract]
3. Tayek JA, Heber D, Chlebowski RT: Effect of hydrazine sulphate on whole-body protein breakdown measured by 14C-lysine metabolism in lung cancer patients. Lancet 2 (8553): 241-4, 1987. [PUBMED Abstract]

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.

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Purpose of This Summary

This PDQ cancer information summary has current information about the use of hydrazine sulfate 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.

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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.

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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).

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The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Hydrazine Sulfate. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/hydrazine-sulfate-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389475]

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.

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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.)

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.

1. What is the Gonzalez regimen?

   The Gonzalez regimen is a complex treatment plan based on the role of enzymes, vitamins, minerals, and other dietary factors. The developer of the regimen, Dr. Nicholas Gonzalez, promoted it as a treatment for advanced pancreatic cancer. The Gonzalez regimen is currently available only to patients in one clinical practice. Supporters of the Gonzalez regimen say it fights cancer in these ways:

   • Helping the body get rid of cancer-causing toxins taken in from the environment and processed foods.
   • Balancing the part of the nervous system that controls automatic body functions such as heartbeat, blood pressure, digestion, and breathing.
   • Keeping the immune system healthy.

   Some key parts of the regimen include the following:

   • Taking a freeze-dried pancreatic enzyme that is made from pigs. This is said to be the main cancer-fighter in the regimen.
   • Taking a large number of nutritional supplements, including magnesium citrate, papaya, vitamins, and other minerals.
   • Eating a special diet of mainly organic foods.
   • Taking coffee enemas twice a day.
2. What is the history of the discovery and use of the Gonzalez regimen as a complementary and alternative treatment for cancer?

   In 1902, James Beard, a Scottish physician, suggested that pancreatic enzymes might control and kill cancer cells. Later, William Kelley, a dentist, further developed Dr. Beard’s ideas and published the results of his own practice. Impressed by these findings, Dr. Gonzalez began working closely with Dr. Kelley. The Gonzalez regimen combines the work of Dr. Gonzalez and Dr. Kelley with the theories and practice of Dr. Max Gerson. Dr. Gerson also treated cancer with diet and nutritional supplements.

3. What is the theory behind the claim that the Gonzalez regimen is useful in treating cancer?

   Supporters of the Gonzalez regimen believe that toxins (harmful substances) in the environment and in processed foods cause cancer to form in the body. These toxins are said to build up in tissues of the body, preventing important body processes from working correctly and letting cancer develop. The theory is that if these toxins could be destroyed and removed from the body, cancer would stop growing.

   The pancreas secretes enzymes, proteins that help digest food. The Gonzalez regimen is based on the theory that pancreatic enzymes also help the body get rid of toxins that lead to cancer. The coffee enemas are added because they are believed to improve the liver’s ability to remove toxins from the body.

   The diets used in the Gonzalez regimen are planned for each patient’s metabolic type. Metabolic typing is a theory that people fall into one of three groups based on the main type of food (protein, carb, or mixed) that their bodies need to stay healthy. Certain tests, including looking at the patient’s hair under a microscope, are used to decide a patient’s metabolic type. The theory is that a diet that is correct for the patient’s metabolic type will keep the body healthy and better able to prevent or fight cancer.

4. How is the Gonzalez regimen administered?

   The pancreatic enzyme is taken by mouth, in a capsule. Between 130 and 160 doses of other nutritional supplements are taken by mouth each day. The patients also eat a special diet and have coffee enemas twice a day.

5. Have any preclinical (laboratory or animal) studies been conducted using the Gonzalez regimen?

   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. These preclinical studies are done before any testing in humans is begun. Animal studies of the Gonzalez regimen looked at the effect of pancreatic enzymes in cancer treatment, but did not study the regimen as a whole. There has been preclinical testing on the effects of pancreatic enzymes in several cancers:

   • In 1999, an animal study tested the effect of different doses of pancreatic enzymes taken by mouth on the growth and metastasis (spread) of breast cancer in rats. Some of the rats received magnesium citrate in addition to the enzymes. Rats receiving the enzymes were compared to rats that did not receive the enzymes.
     • Results showed that the enzyme did not affect growth of the primary tumor (where the cancer started).
     • The cancer spread to the most places in the rats that received the highest dose of enzymes.
     • The cancer spread to the fewest places in the rats that received the lowest dose of enzymes plus magnesium citrate.
   • Another animal study looked at the effects of pancreatic enzymes on survival rates and tumor growth in rats with pancreatic cancer. Rats receiving the enzyme treatment lived longer, had smaller tumors and fewer signs of disease, and were more active than the rats in the control group, which did not receive the enzyme.
6. Have any clinical trials (research studies with people) of the Gonzalez regimen been conducted?

   Nicholas Gonzalez, a New York physician, first studied his regimen in 11 patients who had advanced pancreatic cancer. In 1993, he reported selected results of the study to the National Cancer Institute (NCI). Patients treated with the Gonzalez regimen lived a median of 17 months, which is longer than usual for patients with this disease. Most patients with advanced pancreatic cancer live less than a year.

   Because of the small number of patients in the study, and for other reasons, the NCI and the Office of Alternative Medicine (OAM) decided that the results were not clear and prospective studies were encouraged. In prospective studies, patients are followed forward in time. The NCI and the National Center for Complementary and Integrative Health (NCCIH) sponsored a second study with a much larger number of patients. This was a 7-year clinical study that included patients who had stage II, stage III, or stage IV pancreatic cancer that could not be removed by surgery.

   In this study, one group of patients followed the Gonzalez regimen while another group was given standard treatment (chemotherapy). Results in the two groups were compared to see if the Gonzalez regimen works better than the standard treatment and if it has bad side effects. Results of the study were reported in the peer-reviewed Journal of Clinical Oncology in April 2010. Patients treated with standard chemotherapy survived a median of 14 months and patients treated with the Gonzalez regimen survived a median of 4.3 months. Patients treated with chemotherapy reported a better quality of life than those treated with the Gonzalez regimen. Dr. Gonzalez published comments on his website to express concerns about how the trial was conducted. One concern was how well patients in the Gonzalez regimen group actually followed the regimen.

7. Have any side effects or risks been reported from the Gonzalez regimen?

   The reported side effects of treatment with the Gonzalez regimen are the following:

   • Gas, bloating, and digestion problems.
   • Flu-like symptoms.
   • Low-grade fever.
   • Muscle aches.
   • Skin rashes.

   There is no information on the side effects of the coffee enemas taken twice a day. Taking too many enemas of any kind can cause changes in normal blood chemistry, chemicals that occur naturally in the body and keep the muscles, heart, and other organs working properly.

8. Is the Gonzalez regimen approved by the US Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The FDA has not approved the Gonzalez regimen or any of its components as a cancer treatment.

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.

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Purpose of This Summary

This PDQ cancer information summary has current information about the use of Gonzalez Regimen 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).

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The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Gonzalez Regimen. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/gonzalez-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389246]

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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.)

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 Gonzalez regimen as a treatment for people with cancer. The summary includes a brief history of the science and philosophies of care that have influenced development of the regimen, the results of research and clinical studies, and side effects that have been associated with this treatment approach.

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.

The Gonzalez regimen combines prescribed diets, nutritional supplements, coffee enemas, and pancreatic enzymes in a cancer management program. The regimen is intended to detoxify the body, correct nervous system imbalances that might lead to impaired general health, and support natural immune processes. The pancreatic enzymes are thought to be the specific anticancer component of the Gonzalez program.[1–3]

Two major concepts underlie use of the Gonzalez regimen in cancer treatment. The first concept is that the pancreas, like the liver, is an organ that performs a detoxification function and that pancreatic enzymes help the body eliminate toxins and help normal cells repair damaged cells.[2] The second concept is that cancer and most other human illness are related to physiological imbalances created by environmental toxins either consumed in food or contacted in the environment.[2,3]

Proponents of the Gonzalez regimen believe that toxins from sources such as processed foods and environmental pollution are responsible for human cancers. These toxins are thought to accumulate in tissues and over time create imbalances in the autonomic nervous system, diminish the normal immune response, and give rise to cellular damage that can lead to cancer.[2,3] If these toxins could be neutralized and eliminated from the body, proponents believe, both early and established cancers would be halted, and general health would be restored.[2,3]

According to the developer of the Gonzalez regimen, the diets used in this regimen are chosen for each patient according to individual metabolic profiles established at the time of initial evaluation through various tests, including hair analysis. There are ten basic diets and 90 variations.[2] The diets emphasize organic foods. Each diet carries a particular focus and can range from strictly vegetarian diets to diets high in meat and fat. Variations in the diets correlate with the theory that imbalances in the autonomic nervous system are exacerbated by a diet that is inappropriate for the patient’s metabolic type.[2,3]

Nutritional supplements employed in the Gonzalez regimen include vitamins, minerals, trace elements, amino acids, and extracts of animal organs (e.g., thymus and liver extracts from sheep or cows). As with the dietary protocols, the nutritional supplements are intended to correct autonomic nervous system imbalances.[2,3]

The major feature of the Gonzalez regimen is freeze-dried porcine pancreatic enzyme (PPE) administered in capsule form as part of the nutritional supplementation aspect of the program. Obtained from pigs, PPE is considered to be the primary cancer-fighting component in the regimen and to contribute to the overall detoxification process.[2]

Proponents of the regimen believe that the pancreatic enzymes are delivered to the bloodstream and help the body eliminate and destroy abnormal cells, waste material, and abnormal proteins that are toxic to the body. As the body detoxifies, the cancerous tumors tend to shrink.[2]

Coffee enemas are also included as part of the detoxification process. The enemas are administered twice daily.[3] The use of coffee enemas is based on a belief that coffee introduced into the lower intestinal tract will improve liver function and stimulate emptying of the gallbladder, thereby enhancing the elimination of toxins and waste products from the body.[2,3]

The Gonzalez regimen is available only to private patients of its New York-based practitioner.

Pancreatic enzymes are sold in the United States as either prescription drugs indicated for pancreatic insufficiency [4] or over-the-counter (OTC) dietary supplements. As of 2004, those sold as prescription drugs must have a New Drug Approval from the US Food and Drug Administration (FDA) to be marketed legally in the United States. Pancreatic enzymes sold as OTC dietary supplements are regulated as foods, not drugs. Dietary supplements in the United States are therefore sold without a requirement of a market approval by the FDA, as long as they do not claim to treat or prevent a specific disease or condition. According to the developer of the Gonzalez regimen, most OTC preparations or other commercially available pancreatic enzymes are not effective against cancer.[3]

For the FDA, PPE falls under the category of a new prescription drug that is under investigation. To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. Only one group of investigators is known to have IND approval to study this pancreatic enzyme preparation as a treatment for cancer. The IND process is confidential, and the existence of an IND can be disclosed only by the applicant(s).

References

1. Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]
2. Gonzalez N: Dr. Nicholas Gonzalez on nutritional cancer therapy: a Moneychanger interview. The Moneychanger July 1995. Also available online. Last accessed April 11, 2016.
3. Gonzalez NJ: Pancreatic cancer, proteolytic enzyme therapy and detoxification [excerpts]. Clinical Pearls News November 1999. Also available online. Last accessed April 11, 2016.
4. Physician’s Desk Reference 2005. 59th ed. Thomson PDR, 2005.

The Gonzalez regimen was developed by Dr. Nicholas Gonzalez, who became interested in the use of pancreatic enzymes and dietary protocols as a possible treatment for cancer as a second-year medical student when he learned of a cancer treatment approach developed by a Texas dentist, William Donald Kelley, D.D.S. Dr. Kelley’s approach espoused, among other things, the use of pancreatic enzymes administered orally as anticancer agents.[1–5] The use of enzymes as a treatment for cancer was originally proposed nearly a century ago [6] and then resurfaced in the work of Dr. Max Gerson in the 1940s.[7] The Gonzalez regimen was developed from these earlier theories and approaches.

A key concept underlying the original use of pancreatic enzymes for cancer treatment is the trophoblastic theory of cancer.[8] When a human egg is fertilized by sperm, the early cell divisions produce a small ball of cells, which give rise to the blastocyst (preimplantation embryo). The blastocyst possesses a surrounding layer of cells known as the trophectoderm, which is made of individual cells called trophoblasts. Responsible for protecting the developing blastocyst and for mediating its attachment to the wall of the uterus, trophoblasts create the placenta. During the process of attaching the blastocyst to the uterine wall, trophoblasts express invasive qualities similar to those found in cancer cells. Trophoblasts, however, cease their invasive activity once the placenta is in place and functioning and then differentiate into other cell types.[8]

When Scottish embryologist Dr. John Beard [6] first observed the invasive activity of trophoblasts in 1902, he speculated on the similarities between these cells and cancer cells. In addition, he observed that trophoblast invasiveness begins to decline at about the same time that the pancreas in the developing fetus begins to function. He also theorized that maternal pancreatic enzymes might play a role in containing trophoblastic invasiveness in the uterus. These considerations led to his proposal that cancer cells, like trophoblasts, arise from primordial germ cells. Dr. Beard also thought that some of these primordial cells—carrying latent capacities for invading tissues—could escape and spread throughout the body of the developing fetus. He thought it was possible that pancreatic enzymes modulated the degree of trophoblastic invasiveness in the uterus, he suggested that these same enzymes play a role in either limiting or eliminating cancerous cells elsewhere in the body.[6,8] Dr. Beard worked before the advent of molecular biology and human genetics. Although unable to experimentally establish that pancreatic enzymes had anticancer effects, he published papers and a book about his theory between 1902 and 1911. Other scientists of the time raised significant objections to the trophoblastic theory of cancer, and it was never broadly accepted.[9]

As Dr. Beard had before him, Dr. Kelley also asserted that trophoblasts and cancer cells have a common origin in primordial germ cells. Dr. Kelley maintained, furthermore, that cancer was initiated when primordial germ cells migrated to a point in the body already weakened by toxic exposure and nervous system imbalance. At these presumably compromised sites, the germ cells met no opposition from the immune system and initiated an aggressive invasion of normal tissue, creating malignancy. Dr. Kelley’s treatment approach was based on the belief that primordial germ cells are the single cause of all cancers, no matter where they occur, and that pancreatic enzymes are able to suppress or destroy cancers.[1,5]

Dr. Gonzalez incorporated many of Dr. Beard’s and Dr. Kelley’s key points into his own treatment regimen. In addition, the Gonzalez regimen includes the rigorous dietary protocols, nutritional supplements, and coffee enemas that can be found in the earlier work of Dr. Max Gerson.[7] The Gonzalez regimen now includes use of pancreatic enzymes, along with nutritional supplements, coffee enemas, and prescriptive diets based on a theory of autonomic dominance.[2–4]

An example of the Gonzalez regimen for a patient with pancreatic adenocarcinoma would be the following:

The total number of capsules taken per day by each cancer patient on the Gonzalez regimen typically ranges from 130 to 160, taken with and away from meals.[2] In addition, the Gonzalez regimen uses coffee enemas on the premise that coffee absorbed through the intestinal wall will improve liver and gallbladder function and help increase the removal of toxic waste from tumor breakdown.[2,4] At this time there is no scientific evidence that coffee enemas have any specific effects on increased liver function, effects on tumor breakdown detoxification, or a role in the treatment of any cancer.

Doubts exist about the effectiveness of oral administration of pancreatic enzymes because pancreatic enzymes were not thought to be transported intact from the gut to the bloodstream. Evidence now suggests that intact digestive enzymes can be absorbed and resecreted by the pancreas, in a manner similar to the liver recycling of bile salts and hormones.[10–12]

References

1. Kelley WD: One Answer to Cancer. Cancer Coalition for Alternative Therapies, Inc. 1999. Also available online. Last accessed April 11, 2016.
2. Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]
3. Gonzalez N: Dr. Nicholas Gonzalez on nutritional cancer therapy: a Moneychanger interview. The Moneychanger July 1995. Also available online. Last accessed April 11, 2016.
4. Gonzalez NJ: Pancreatic cancer, proteolytic enzyme therapy and detoxification [excerpts]. Clinical Pearls News November 1999. Also available online. Last accessed April 11, 2016.
5. Kelley WD, Rohe F: Cancer: Curing the Incurable without Surgery, Chemotherapy, or Radiation. New World Promotions, 2005.
6. Beard J: The Enzyme Treatment of Cancer and its Scientific Basis. Chatto & Windus, 1911.
7. Gerson M: The cure of advanced cancer by diet therapy: a summary of 30 years of clinical experimentation. Physiol Chem Phys 10 (5): 449-64, 1978. [PUBMED Abstract]
8. Krebs ET Jr, Krebs ET Sr, Beard HH: The unitarian or trophoblastic thesis of cancer. Med Rec 163 (7): 149-74, 1950.
9. Cohen LA, Aliaga C, Pittman B, et al.: Oral enzyme therapy and experimental rat mammary tumor metastasis. Life Sci 65 (24): 2603-14, 1999. [PUBMED Abstract]
10. Leibow C, Rothman SS: Enteropancreatic circulation of digestive enzymes. Science 189 (4201): 472-4, 1975. [PUBMED Abstract]
11. Rothman S, Liebow C, Isenman L: Conservation of digestive enzymes. Physiol Rev 82 (1): 1-18, 2002. [PUBMED Abstract]
12. Isenman L, Liebow C, Rothman S: Transport of proteins across membranes–a paradigm in transition. Biochim Biophys Acta 1241 (3): 341-70, 1995. [PUBMED Abstract]

Directly relevant laboratory or animal data concerning the anticancer potential of the Gonzalez regimen are limited. Published animal studies focus on the role of pancreatic enzymes in cancer treatment rather than the regimen as a whole.

An animal study published in 1999 measured the ability of orally administered porcine pancreas preparation (PPP) to slow or halt the growth of cancer and to inhibit metastasis. Sixty Fischer F344 female rats were divided into five groups of 12 each. All groups were fed the same basic diet. After 5 days, R13762 transplantable rat mammary tumor was implanted into a mammary fat pad on each rat. The animals were maintained on their assigned diets for another 40 days. After the tumors had taken hold, two groups were given a high dose of PPP (20% by weight) and two groups were given a lower dose (2% by weight). The fifth group was used as a control and received no enzymes. In addition, one group from each of the PPP-dosed rat groups was also given a magnesium citrate supplement because magnesium is often given with PPP in clinical practice.[1]

Results showed that PPP had no effect on tumor growth, and PPP alone did not show any significant effect on the amount of metastases. However, when the rate of metastases in the rats dosed at the 20% rate was compared with those dosed at 2%, it was noted that there was an increase in metastases in the rats given a higher dose of PPP. The lowest rate of metastases was seen in the rats given the 2% dose plus magnesium citrate.[1]

In another study, the effects of porcine pancreatic enzyme (PPE) extracts on survival and tumor growth were examined in 5- to 6-week-old male beige X-linked immunodeficient mice. In the survival study, two groups of mice received pancreatic cancer cells AsPc1 injected into their pancreas. The treatment group (14 mice) received PPE in water at a dose of 400 mg/kg of body weight, which corresponds to the dose used in patients receiving the Gonzalez regimen. The control group (13 mice) was given only water. After death, the pancreas was removed and measured for volume and weight. The median survival rates for the treatment group and the control group were 43.5 days and 35 days, respectively. At day 35, the survival rates were 79% in the treatment group and 38% in the control group. In addition, the control mice showed reduced activity as compared with the treatment group, which showed normal activity and no signs of disease. In general, the size of tumors and the rate of invasion in the liver and peritoneum correlated with length of survival time.[2]

In the tumor growth segment of this study, a second group of 30 mice was taken through the same procedures. Tumor size and weight were measured in two mice from each group on day 52, and again in two mice from the control group and five mice from the treatment group on day 60. Ascites were much more apparent in the control group than in the treatment group. Physical activity among the treated mice was much greater than in the control group. Results showed that the treatment group had significantly smaller tumors than the control group in both weight and volume. The mean tumor weight was 1.2 g in the control group and 0.75 g in the treatment group. The tumor volume was 0.42 cm3 in the treatment group and 0.91 cm3 in the control group. All mice in the control group showed steatorrhea, hyperglycosuria, hyperbilirubinuria, and ketonuria in the early stages of tumor growth, whereas in the treated group only a few mice showed these abnormalities in the final stages. There were no differences in the tumors of the treatment and control groups in the expression of growth factors, epidermal growth factor receptor, or apoptotic rate.[2]

References

1. Cohen LA, Aliaga C, Pittman B, et al.: Oral enzyme therapy and experimental rat mammary tumor metastasis. Life Sci 65 (24): 2603-14, 1999. [PUBMED Abstract]
2. Saruc M, Standop S, Standop J, et al.: Pancreatic enzyme extract improves survival in murine pancreatic cancer. Pancreas 28 (4): 401-12, 2004. [PUBMED Abstract]

The anticancer efficacy of the Gonzalez regimen has been investigated in two human studies (CPMC-IRB-8544 [1]), both involving patients with pancreatic cancer.

The first study, a prospective nonconsecutive case series conducted by the developer and an associate, included 11 patients diagnosed with adenocarcinoma of the pancreas (stage II through stage IV). None of the patients had received chemotherapy or radiation therapy, and none had undergone surgical resection with curative intent. All the patients had pancreatic tumors that were either unresected or partially resected. Survival from the time of diagnosis was the only study endpoint, and all 11 patients (including one who left the study) were included in this survival analysis.

The investigators reported a median survival time of 17 months and a mean survival time of 25.2 months for these patients. Nine patients (82%) survived 1 year, five patients (45%) survived 2 years, and four patients (36%) survived 3 years. At the time the study was reported, two patients were alive: one who had survived 3 years, and one had survived 4 years. The researchers concluded that the 1-year and 2-year survival percentages for this group of patients were superior to those observed for other U.S. patients diagnosed with adenocarcinoma of the pancreas (1-year survival, all stages = 25%; 2-year survival, all stages = 10%).[1]

The small number of patients in this study and the absence of a control group are limitations that raise doubts about the reliability of its findings. It is possible that important, unidentified differences between these patients and other patients diagnosed with stage II to stage IV pancreatic cancer contributed to the relatively long survival. The investigators report that 25 additional patients with pancreatic cancer were seen during the study period but were excluded from study participation. Eleven of these patients were excluded on the basis of comorbidities, previous treatment, or delay between diagnosis and beginning the program; 14 otherwise eligible patients were excluded on the grounds that they chose not to start the program, complied only briefly, or predicted noncompliance.[1]

The second study is a nonrandomized prospective case-control observational study sponsored by the National Center for Complementary and Integrative Health and the National Cancer Institute in which median survival and quality of life were found to be better in patients treated with gemcitabine-based (i.e., other drugs may be included) chemotherapy than for patients treated with the Gonzalez regimen. This study was originally planned for randomization but changed after few patients elected to participate in the randomized trial. The same eligibility criteria were used to select patients for both treatment arms. The results of this study were reported in the peer-reviewed Journal of Clinical Oncology.[2] According to the report, 70 patients were evaluated for the study and 55 were enrolled: 23 in the gemcitabine arm and 32 in the enzyme treatment arm. The enzyme treatment included orally ingested proteolytic enzymes, nutritional supplements, detoxification, and an organic diet (as used in the pilot study by Gonzalez and Isaacs).[1] Patients received three pancreatic enzyme capsules and two magnesium citrate capsules with each meal. The patients also took specified numbers of capsules with magnesium citrate and Papaya Plus every 4 hours on an empty stomach. The dose for patients with stage II disease was 69 enzyme capsules per day, and the dose for patients with stages III or stage IV was 81 capsules per day. After day 16, patients had a 5-day rest period and then resumed treatment on day 22. Patients in the experimental arm received proteolytic treatment under the care of a practitioner familiar with the regimen; those in the chemotherapy arm received treatment by the oncologist they selected.[2] Treatment could be adjusted by the physician, and it could be increased for cancer  progression. The gemcitabine treatment patients received various gemcitabine-containing regimens, with 19 of the 23 patients receiving a combination of gemcitabine, capecitabine, and docetaxel. The two groups had similar clinical characteristics. The median survival for the patients in the gemcitabine arm was 14 months and, on the enzyme arm, 4.3 months. The quality of life as measured by the FACT-PA was also better in the chemotherapy arm. The paper does not list Dr. Gonzalez as an author, and does not identify him as participating in the study; however, Dr. Gonzalez published comments on his website indicating his participation in the study and detailing his concerns about how the study was conducted, including patient compliance with the prescribed treatment in the enzyme arm.[3]

No data concerning the effectiveness of the Gonzalez regimen for the treatment of cancer patients with other types of cancer have been reported, despite claims that a variety of cancers can be treated. In addition, there is no safety or efficacy information on the regimen in children. No clinical trials of this regimen have been conducted in children, and this extremely difficult regimen may be prohibitive in young children.

References

1. Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]
2. Chabot JA, Tsai WY, Fine RL, et al.: Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol 28 (12): 2058-63, 2010. [PUBMED Abstract]
3. Gonzalez Nicholas: Journal of Clinical Oncology Article Rebuttal. New York, NY, 2009. Available online. Last accessed April 11, 2016.

The developer of the Gonzalez regimen has reported the following adverse effects associated with the regimen: intestinal gas; occasional bloating and indigestion, apparently related to ingestion of porcine pancreatic enzyme; and flu-like syndromes, allegedly associated with detoxification, including low-grade fever, nonspecific myalgia (muscle aches), and nonspecific skin rashes.[1,2] The cases found in the literature on coffee enema are not adequate to support an adverse effect from coffee enemas alone. There are rare reports of adverse events unrelated to the coffee enemas in patients receiving them. It should be remembered that clinically significant changes in blood chemistries can occur with excessive use of enemas of any kind.[3–6]

References

1. Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]
2. Gonzalez NJ: Pancreatic cancer, proteolytic enzyme therapy and detoxification [excerpts]. Clinical Pearls News November 1999. Also available online. Last accessed April 11, 2016.
3. Green S: A critique of the rationale for cancer treatment with coffee enemas and diet. JAMA 268 (22): 3224-7, 1992. [PUBMED Abstract]
4. Margolin KA, Green MR: Polymicrobial enteric septicemia from coffee enemas. West J Med 140 (3): 460, 1984. [PUBMED Abstract]
5. Brown BT: Treating cancer with coffee enemas and diet. JAMA 269 (13): 1635-6, 1993. [PUBMED Abstract]
6. Eisele JW, Reay DT: Deaths related to coffee enemas. JAMA 244 (14): 1608-9, 1980. [PUBMED Abstract]

Existing clinical data concerning the effectiveness of the Gonzalez regimen as a treatment for cancer are limited and inconclusive. One clinical study, a nonconsecutive case series involving 11 patients with pancreatic cancer, has been reported.[1] Another clinical study involving 55 patients with pancreatic cancer was published in the peer-reviewed Journal of Clinical Oncology in August 2009.[2] No data concerning the effectiveness of the Gonzalez regimen in patients with other types of cancer have been reported.

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:

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 an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

References

1. Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]
2. Chabot JA, Tsai WY, Fine RL, et al.: Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol 28 (12): 2058-63, 2010. [PUBMED Abstract]

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 Gonzalez Regimen 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.

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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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The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Gonzalez Regimen. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/gonzalez-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389287]

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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 Gerson therapy as a treatment for people with cancer. The summary includes a brief history of the development of the Gerson therapy; a review of laboratory, animal, and human studies; and possible side effects associated with the use of this treatment.

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 websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

The Gerson therapy is a complex regimen advocated by its supporters to treat cancer and other degenerative diseases. It consists of a specialized diet to “detoxify” the body and rebuild the immune system, adding vitamin and mineral supplements to help in these processes. Coffee enemas are an essential part of the regimen. The therapy is named for its developer, Max Gerson, a German physician who emigrated to the United States and started a medical practice in New York City in 1938.[1,2]

The Gerson therapy is rooted in the belief that cancer is a disease of the whole organism, the tumor being only a symptom of a diseased body. Gerson considered cancer to be an accumulation of several damaging factors that combine to cause the deterioration of the entire metabolic system. The goal of the Gerson therapy is to bring the body back to its normal metabolic state, or as near to this state as possible, and to keep the metabolism in natural equilibrium.[1,2]

Gerson observed that cancer patients exhibited markedly degenerated organs, especially the liver, presumably caused by the clearing of toxic materials of an unknown type that the disease produced. He also noted that the situation became worse after chemotherapy, probably because of more toxic products entering the bloodstream. Gerson’s regimen focused on helping the liver rid the body of toxic substances while restoring and maintaining healthy liver function.[1,2]

According to Gerson, during the detoxification process that results from the Gerson diet, the liver becomes progressively overburdened as the body rids itself of toxic substances formed by the breakdown of cancer cells. Coffee enemas, pancreatic enzymes, and crude liver extract are used to help the liver deal with the burden of removing toxic substances.[1–4]

Total control of everything that enters and leaves the body is the governing principle of the Gerson regimen. Its three main components are strict diet, nutritional supplements, and regular enemas.

The diet is strictly vegetarian for at least 6 weeks and consists of specific fruits and vegetables, eaten either raw or stewed in their own juices. No animal protein is allowed. Some whole grains such as oatmeal are included. Flaxseed oil is allowed only because it aids in the body’s use of vitamin A.[2] No other fat such as cooking oil and no salt or spices of any kind are allowed. A glass of freshly prepared juice from vegetables and fruits must be consumed every hour for 13 hours throughout the day. The vegetables and fruits used on the diet are very high in potassium and very low in sodium.

Food preparation is also controlled. Food may be prepared only in cast-iron pots and pans; no aluminum cookware is allowed. Juices must be prepared using a specific type of juicer that crushes the fruit or vegetable rather than grinding it into pulp. Gerson advocated organically produced food, with all fruits, vegetables, and grains grown and raised in soil free of pesticides and contaminants and enriched only with natural fertilizers.[2]

The protein and dairy restriction may be lifted to include buttermilk; however, this restriction may continue through the entire course of the therapy, depending on the individual patient. Some changes in the original diet have occurred over time, but the initiation phase of the diet has always been a vegetarian diet.[2]

Taking specific vitamin and mineral supplements plus pancreatic enzymes is the second component of the regimen. Although there have been additions and substitutions to the basic list of supplements, there have been few changes since the 1940s. The typical range of supplements includes the following:

The potassium solution (potassium dissolved in water) is to help increase the ratio of potassium to sodium in the cells. Lugol’s solution, which consists of 5 g of iodine and 10 g of potassium iodide dissolved in water, is given to increase the body’s metabolic rate. The potassium solution and Lugol’s solution are both added to the hourly juice intake.[1–4]

Originally, Gerson thought that using crude liver extract and juice (made by processing fresh calf and veal livers) would help maintain liver function. The extract and juice were given to patients via injection with the vitamin B12. In 1989, the use of injectable crude liver extract was banned by the U.S. Food and Drug Administration because it was found to be contaminated with Campylobacter.[1,2] Desiccated liver capsules replaced the crude extract, but this has now been replaced by coenzyme Q10.[2] As mentioned above, flaxseed oil is used to help the body utilize vitamin A. Pancreatic enzymes are given to assist in the digestion and the elimination of the breakdown products in the colon.

Coffee (or chamomile) enemas are the third component of the Gerson therapy. Coffee enemas supposedly dilate the bile duct in the liver, thereby allowing the liver to release the breakdown products more easily and speed their removal to the intestine. At the beginning of therapy, a patient may take four or more coffee enemas per day. Literature suggests that coffee enemas help relieve the pain associated with gastrointestinal cancers; however, there is only anecdotal evidence to suggest that the enemas actually dilate the bile ducts.[5,6]

Central to the therapy is an abundance of potassium and the lack of sodium. Gerson had observed that as soon as his cancer patients started on the diet regimen, they released large amounts of sodium in their urine. He noticed that cells in the patients’ bodies that had been bloated with fluid started to shrink as the fluid was released.[1] After studying the research in cancer cell biology available to him at the time and noting the ratio of potassium to sodium in cancer cells versus healthy cells, he deduced that the reason for this sodium excretion was that the diet regimen was correcting generalized tissue damage caused by excess sodium. Healthy cells had a high ratio of potassium to sodium; diseased cells had a low ratio of potassium to sodium or an abundance of sodium.[1]

The implications of this observation led Gerson to believe that part of the process of recovery from cancer was the replacement of excess sodium by potassium in damaged tissues.[7] This belief is the theoretical basis for Gerson’s choice of high-potassium, low-sodium fruits and vegetables in his prescribed diet: a high intake of potassium was needed to restore a normal ratio of potassium to sodium in the cell.

The Gerson therapy is the basis for other CAM therapies that include cleansing enemas or special diets as part of their regimens, most notably the Gonzalez regimen. (Refer to the PDQ summary on the Gonzalez Regimen for more information.)

References

1. Gerson M: A Cancer Therapy: Results of Fifty Cases and The Cure of Advanced Cancer by Diet Therapy. The Gerson Institute, 2002.
2. Gerson C, Walker M: The Gerson Therapy: The Amazing Nutritional Program for Cancer and Other Illnesses. Kensington Publishing Corp, 2001.
3. Gerson M: Effects of a combined dietary regime on patients with malignant tumors. Exp Med Surg 7 (4): 299-317, illust, 1949. [PUBMED Abstract]
4. Gerson M: The cure of advanced cancer by diet therapy: a summary of 30 years of clinical experimentation. Physiol Chem Phys 10 (5): 449-64, 1978. [PUBMED Abstract]
5. Green S: A critique of the rationale for cancer treatment with coffee enemas and diet. JAMA 268 (22): 3224-7, 1992. [PUBMED Abstract]
6. Brown BT: Treating cancer with coffee enemas and diet. JAMA 269 (13): 1635-6, 1993. [PUBMED Abstract]
7. Cope FW: A medical application of the Ling association-induction hypothesis: the high potassium, low sodium diet of the Gerson cancer therapy. Physiol Chem Phys 10 (5): 465-8, 1978. [PUBMED Abstract]

Max Gerson immigrated to the United States from Germany. In 1938, after passing the New York state medical board examinations, he started a practice in New York City. While in Germany, Gerson had suffered from severe migraine headaches and developed a vegetarian diet as a way to cure his migraines. The diet was based on his study of the history of medicine and his respect for the writings of Paracelsus (1490–1541), who said that diet must be the basis of medical therapy; however, Gerson noted that diet is only one part of a treatment regimen.[1] The special diet cured his migraines, and after seeing its success in one of his patients suffering from lupus vulgaris, he prescribed the diet for others suffering from the same disease. He conducted a successful clinical trial in Germany using the vegetarian diet.[1] His most noted patient was the wife of Albert Schweitzer, M.D., whom he reported curing. The accolades he received from Dr. Schweitzer may have persuaded the medical community to seriously consider the Gerson therapy and perhaps led to Gerson’s 1946 appearance with five of his patients before a congressional committee considering a bill to increase funding for cancer research.[2]

When Gerson began prescribing his regimen for patients, he did not consider his therapy a cure for cancer. In 1958, after treating patients with his regimen for more than 15 years, Gerson published his complete theory, including the results of 50 cases. He started referring to his regimen as an “effective treatment for cancer, even in advanced cases.”[1,3]

The practice of changing diet or fasting to cure or ameliorate the effects of disease has a long history, as does the practice of giving enemas to flush the body, thus keeping the body clear of toxins.[4] There are no reported results of clinical trials examining the efficacy of either of these practices in the treatment of cancer or how these practices would affect a treatment. Evolving evidence supports the idea that a plant-based diet plays a role in cancer prevention.

Gerson theorized that the use of pancreatic enzymes would reduce demands on the liver and pancreas, already in a weakened state, to manufacture the enzymes necessary to convert food into usable nutrients; this would help stabilize the nutritional needs of the body while it undergoes the detoxification process.[1,5] Gerson’s therapy was widely considered impossible because it was thought that pancreatic enzymes were reduced to their components in the intestinal tract. However, it has been reported that these enzymes are not broken down but are released into the bloodstream and used again in the digestive process.[6,7]

Controversy about the efficacy of the Gerson therapy continued throughout Gerson’s life. In 1946 and 1949, two articles in the Journal of the American Medical Association concluded that the treatment was of no value.[8,9] The National Cancer Institute (NCI) reviewed Gerson’s data from ten case histories in 1947 and 50 case histories in 1959. NCI concluded that in most cases, basic criteria for evaluating clinical benefit were not met. NCI concluded that the data demonstrated no benefit.[2] In 1972, the American Cancer Society (ACS) published a statement summarizing the negative assessments of Gerson’s treatment.[10] Another statement published by ACS in 1991 concerned various “metabolic therapies” (defined as treatments that depend on changing metabolism through diet, enemas, and supplements given at clinics in Tijuana, Mexico) and reemphasized the lack of scientific evidence on the efficacy of the Gerson regimen.[11]

Gerson died in 1959, leaving behind no systematic way to continue offering his treatment. His malpractice insurance had been canceled in 1953, and in 1958 he was suspended for 2 years from the New York County Medical Society.[10] In 1977, his daughter, Charlotte Gerson Straus, who had continued to lecture widely about the Gerson therapy, cofounded the Gerson Institute with Norman Fritz. Located in San Diego, the Gerson Institute does not own or operate treatment facilities but maintains a licensing program for treatment centers such as the Centro Hospitalario Internacional Pacifico and Mexico’s Center for Integrative Medicine and the Gerson Hospital (CHIPSA) in Baja California, Mexico. CHIPSA refers to Max Gerson as the founder of “immunonutrition,” their term for Gerson’s idea of cleansing the body while building up the immune system through diet and supplementation.

References

1. Gerson M: A Cancer Therapy: Results of Fifty Cases and The Cure of Advanced Cancer by Diet Therapy. The Gerson Institute, 2002.
2. US Congress, Office of Technology Assessment: Unconventional Cancer Treatments. U.S. Government Printing Office, 1990. OTA-H-405.
3. Gerson M: The cure of advanced cancer by diet therapy: a summary of 30 years of clinical experimentation. Physiol Chem Phys 10 (5): 449-64, 1978. [PUBMED Abstract]
4. Ernst E: Colonic irrigation and the theory of autointoxication: a triumph of ignorance over science. J Clin Gastroenterol 24 (4): 196-8, 1997. [PUBMED Abstract]
5. Gerson C, Walker M: The Gerson Therapy: The Amazing Nutritional Program for Cancer and Other Illnesses. Kensington Publishing Corp, 2001.
6. Rothman S, Liebow C, Isenman L: Conservation of digestive enzymes. Physiol Rev 82 (1): 1-18, 2002. [PUBMED Abstract]
7. Isenman L, Liebow C, Rothman S: Transport of proteins across membranes–a paradigm in transition. Biochim Biophys Acta 1241 (3): 341-70, 1995. [PUBMED Abstract]
8. Gerson’s cancer treatment. JAMA 132 (11): 645-6, 1946.
9. Council on Pharmacy and Chemistry: Report of the council: cancer and the need for facts. JAMA 139 (2): 93-8, 1949.
10. Unproven methods of cancer management. Gerson method of treatment for cancer. CA Cancer J Clin 23 (5): 314-7, 1973 Sep-Oct. [PUBMED Abstract]
11. Questionable cancer practices in Tijuana and other Mexican border clinics. CA Cancer J Clin 41 (5): 310-9, 1991 Sep-Oct. [PUBMED Abstract]

There are no in vivo studies in animal models of the Gerson diet in the scientific literature.

Gerson’s book [1] and articles in English [2,3] are primarily reports of the details of the Gerson regimen, supplemented with case reports of patients seen in his clinical practice. His book presents an extended discourse on the empirical and scientific foundation for his treatment regimen and an expansive description of the treatment and diet followed by 50 patients selected from 30 years of clinical practice. Gerson’s published cases encompass a variety of cancer types. The reports are extended case notes, with occasional x-rays of the patients over time. Although some attempt at follow-up is made, it is not systematic and consists chiefly of anecdotal reports and conversations with patients by mail or phone.

A preliminary study conducted between 1983 and 1984 attempted to collect any available retrospective data on three nonallopathic treatments offered in clinics in Tijuana, Mexico: Gerson, Hoxsey, and Contreras.[4] The authors did not have access to medical records and relied on patient interviews for all information. The self-reporting was incomplete and inconsistent, lacking precise information in areas such as how far the disease had advanced. In the Gerson segment, only 18 of the 38 patients stayed in the study for 5 years or until they died; their mean survival was 9 months from the beginning of the study. The other 20 patients were lost to follow-up. At 5 years, 17 of the 18 had died, and one patient with advanced non-Hodgkin lymphoma was alive but not disease free. Overall, this study did not offer meaningful data to support the clinical efficacy of the approaches studied.

A 1990 noncontrolled, self-selected, matched-pairs study conducted in Austria used a diet regimen based on the Gerson therapy to evaluate diet as an adjuvant to surgery. This diet was ovolactovegetarian.[5] The Gerson regimen is basically strictly vegetarian (no eggs or milk) and does not introduce food other than buttermilk until 6 or 8 weeks into the regimen, if at all, depending on the patient.

Two groups of patients who had undergone surgery—18 patients with colorectal cancer with metastases to the liver and 38 with breast cancer—were treated. Each of the two groups was divided into a diet group and a nondiet group. All patients continued with whatever prescribed conventional regimen was required after their surgery. Results in the matched pairs with colorectal cancer showed an increased survival time in three of the nine patients in the diet group (28.6 months) as compared with four of the nine patients (16.2 months) in the nondiet group. In the breast cancer matched pairs, side effects of chemotherapy and pain and pleural effusion were lower in the diet group. No statistically significant information was generated in this small number of patients; however, the authors stated that the diet regimen appeared to have beneficial effects that required further study.[5]

The Gerson Research Organization published a retrospective survival analysis of their melanoma patients treated with the Gerson approach, which was compared with published survival data according to stage. The analysis showed a survival advantage for melanoma patients with stage IIIA disease and stage IV disease with no visceral metastases, who were treated with the Gerson approach.[6] However, there has been no report of a prospective clinical trial confirming the findings of this retrospective analysis.

The study looked at records of 153 patients with stage I–IV melanoma treated with the Gerson diet. Of the 14 stage I–II patients, all were disease-free at 17 years posttreatment; however, this number was too small for a statistical comparison with other cohorts. For stage III patients, the 5-year survival rate was 71% compared with rates of 27% to 42% reported in the literature. The stage IV patients had the largest survival advantage. The 5-year survival rate for these 18 patients was 39%, compared with 6% in the published literature. The analysis did not include 53 patients who were lost to follow-up, which could have influenced the survival comparisons.[6]

A small best-case series [7] suggests that the evidence presented supports the development and conduct of a more definite clinical study on the Gerson regimen.

No conclusions about the effectiveness of the Gerson therapy, either as an adjuvant to other cancer therapies or as a cure, can be drawn from any of the studies reported above.

References

1. Gerson M: A Cancer Therapy: Results of Fifty Cases and The Cure of Advanced Cancer by Diet Therapy. The Gerson Institute, 2002.
2. Gerson M: Effects of a combined dietary regime on patients with malignant tumors. Exp Med Surg 7 (4): 299-317, illust, 1949. [PUBMED Abstract]
3. Gerson M: The cure of advanced cancer by diet therapy: a summary of 30 years of clinical experimentation. Physiol Chem Phys 10 (5): 449-64, 1978. [PUBMED Abstract]
4. Austin S, Dale EB, DeKadt S: Long term follow-up of cancer patients using Contreras, Hoxsey and Gerson therapies. J Naturopathic Med 5 (1): 74-6, 1994.
5. Lechner P, Kroneberger L Jr: Experiences with the use of diet therapy in surgical oncology. Aktuel Ernahrungsmed 2 (15): 72-8, 1990.
6. Hildenbrand GL, Hildenbrand LC, Bradford K, et al.: Five-year survival rates of melanoma patients treated by diet therapy after the manner of Gerson: a retrospective review. Altern Ther Health Med 1 (4): 29-37, 1995. [PUBMED Abstract]
7. Molassiotis A, Peat P: Surviving against all odds: analysis of 6 case studies of patients with cancer who followed the Gerson therapy. Integr Cancer Ther 6 (1): 80-8, 2007. [PUBMED Abstract]

Case reports of adverse events associated with coffee enemas raise concern about their use. Three deaths that seem related to coffee enemas have been reported in the literature. Salmonella enteridis group D and Campylobacter fetus intestinalis were cultured from stool and blood of one patient who died shortly after treatment at the Gerson Institute clinic. This death could not be directly linked to the practice of coffee enemas because more tests could not be performed.[1]

Case reports of two more deaths following treatment at the Gerson Institute were both attributed to electrolyte imbalance after autopsies were performed showing no active inflammation of the colon.[2]

A third case report of electrolyte imbalance that did not result in death describes a patient who developed hyperkalemia while undergoing Gerson therapy.[3] No other reports of adverse effects have been identified.

References

1. Margolin KA, Green MR: Polymicrobial enteric septicemia from coffee enemas. West J Med 140 (3): 460, 1984. [PUBMED Abstract]
2. Eisele JW, Reay DT: Deaths related to coffee enemas. JAMA 244 (14): 1608-9, 1980. [PUBMED Abstract]
3. Nagasaki A, Takamine W, Takasu N: Severe hyperkalemia associated with “alternative” nutritional cancer therapy. Clin Nutr 24 (5): 864-5, 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:

Evidence from studies that do not meet these requirements is considered extremely weak. In addition to scoring individual studies, an overall level of evidence assessment is usually made.

Because no prospective, controlled study of the use of the Gerson therapy in cancer patients has been reported in a peer-reviewed scientific journal, no level of evidence analysis is possible for this approach. The data that are available are not sufficient to warrant claims that the Gerson therapy is effective as an adjuvant to other cancer therapies or as a cure. At this time, the use of the Gerson therapy in the treatment of cancer patients cannot be recommended outside the context of well-designed clinical trials.

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, 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 Gerson therapy 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,
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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 Gerson Therapy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/gerson-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389464]

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.

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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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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 the Gerson therapy?

   The Gerson therapy has been used by some people to treat cancer and other diseases. It is based on the role of minerals, enzymes, and other dietary factors. There are 3 key parts to the therapy:

   • Diet: Organic fruits, vegetables, and whole grains to give the body plenty of vitamins, minerals, enzymes, and other nutrients. The fruits and vegetables are low in sodium (salt) and high in potassium.
   • Supplementation: The addition of certain substances to the diet to help correct cell metabolism (the chemical changes that take place in a cell to make energy and basic materials needed for the body’s life processes).
   • Detoxification: Treatments, including enemas, to remove toxic (harmful) substances from the body.
2. What is the history of the discovery and use of the Gerson therapy as a complementary or alternative treatment for cancer?

   The Gerson therapy was named after Dr. Max B. Gerson (1881-1959), who first used it to treat his migraine headaches. In the 1930’s, Dr. Gerson’s therapy became known to the public as a treatment for a type of tuberculosis (TB). The Gerson therapy was later used to treat other conditions, including cancer.

3. What is the theory behind the claim that the Gerson therapy is useful in treating cancer?

   The Gerson therapy is based on the idea that cancer develops when there are changes in cell metabolism because of the buildup of toxic substances in the body. Dr. Gerson said the disease process makes more toxins and the liver becomes overworked. According to Dr. Gerson, people with cancer also have too much sodium and too little potassium in the cells in their bodies, which causes tissue damage and weakened organs.

   The goal of the Gerson therapy is to restore the body to health by repairing the liver and returning the metabolism to its normal state. According to Dr. Gerson, this can be done by removing toxins from the body and building up the immune system with diet and supplements. The enemas are said to widen the bile ducts of the liver so toxins can be released. According to Dr. Gerson, the liver is further overworked as the treatment regimen breaks down cancer cells and rids the body of toxins. Pancreatic enzymes are given to decrease the demands on the weakened liver and pancreas to make enzymes for digestion. An organic diet and nutritional supplements are used to boost the immune system and support the body as the regimen cleans the body of toxins. Foods low in sodium and high in potassium are said to help correct the tissue damage caused by having too much sodium in the cells.

4. How is the Gerson therapy administered?

   The Gerson therapy requires that the many details of its treatment plan be followed exactly. Some key parts of the regimen include the following:

   • Drinking 13 glasses of juice a day. The juice must be freshly made from organic fruits and vegetables and be taken once every hour.
   • Eating vegetarian meals of organically grown fruits, vegetables, and whole grains.
   • Taking a number of supplements, including:
     • Potassium.
     • Lugol’s Solution (potassium iodide, iodine, and water).
     • Coenzyme Q10 injected with vitamin B12. (The original regimen used crude liver extract instead of coenzyme Q10.)
     • Vitamins A, C, and B3 (niacin).
     • Flaxseed oil.
     • Pancreatic enzymes.
     • Pepsin (a stomach enzyme).
   • Taking coffee or chamomile enemas regularly to remove toxins from the body.
   • Preparing food without salt, spices, or oils, and without using aluminum cookware or utensils.
5. Have any preclinical (laboratory or animal) studies been conducted using the Gerson therapy?

   No results of laboratory or animal studies have been published in scientific journals.

6. Have any clinical trials (research studies with people) of the Gerson therapy been conducted?

   Most of the published information on the use of the Gerson therapy reports on retrospective studies (reviews of past cases). Dr. Gerson published case histories (detailed reports of the diagnosis, treatment, and follow-up of individual patients) of 50 of his patients. He treated several different types of cancer in his practice. The reports include Dr. Gerson’s notes, with some X-rays of the patients over time. The follow-up was contact with patients by mail or phone and included anecdotal reports (incomplete descriptions of the medical and treatment histories of one or more patients).

   In 1947 and 1959, the National Cancer Institute (NCI) reviewed the cases of a total of 60 patients treated by Dr. Gerson. The NCI found that the available information did not prove the regimen had benefit.

   The following studies of the Gerson therapy were published:

   • In 1983-1984, a retrospective study of 38 patients treated with the Gerson therapy was done. Medical records were not available to the authors of the study; information came from patient interviews. These case reviews did not provide information that supports the usefulness of the Gerson therapy for treating cancer.
   • In 1990, a study of a diet regimen similar to the Gerson therapy was done in Austria. The patients received standard treatment along with the special diet. The authors of the study reported that the diet appeared to help patients live longer than usual and have fewer side effects. The authors said it needed further study.
   • In 1995, the Gerson Research Organization did a retrospective study of their melanoma patients who were treated with the Gerson therapy. The study reported that patients who had stage III or stage IV melanoma lived longer than usual for patients with these stages of melanoma. There have been no clinical trials that support the findings of this retrospective study.
   • A case review of 6 patients with metastatic cancer who used the Gerson therapy reported that the regimen helped patients in some ways, both physically and psychologically. Based on these results, the reviewers recommended that clinical trials of the Gerson therapy be conducted.
7. Have any side effects or risks been reported from use of the Gerson therapy?

   Reports of three deaths that may be related to coffee enemas have been published. Taking too many enemas of any kind can cause changes in normal blood chemistry, chemicals that occur naturally in the body and keep the muscles, heart, and other organs working properly.

8. Is the Gerson therapy approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The Gerson therapy has not been approved by the FDA for use as a treatment for cancer or any other disease.

   For most cancer patients, nutrition guidelines include eating a well-balanced diet with plenty of fruits, vegetables, and whole-grain products. However, general guidelines such as these may have to be changed to meet the specific needs of an individual patient. Patients should talk with their health care providers about an appropriate diet to follow. Information about diet during cancer treatment is also available from the Cancer Information Service (1-800-4-CANCER) and in Nutrition During Cancer Treatment.

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 Gerson therapy 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 Gerson Therapy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/gerson-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389408]

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 cartilage as a treatment for people with cancer. The summary includes a brief history of cartilage research, the results of clinical studies, and possible side effects of cartilage 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.

Bovine (cow) cartilage and shark cartilage have been investigated as treatments for people with cancer, psoriasis, arthritis, and a number of other medical conditions for more than 30 years.[1–19] At least some of the interest in cartilage as a treatment for people with cancer arose from the mistaken belief that sharks, whose skeletons are made primarily of cartilage, are not affected by this disease.[16,20,21] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these animals.[20–23] Nonetheless, several substances that have antitumor activity have been identified in cartilage.[2–4,7,15–19,24–49] More than half a dozen clinical studies of cartilage as a treatment for people with cancer have already been conducted.[2–4,6–9,15–18,49,50] Additional clinical studies, MDA-ID-99303 and AETERNA-AE-MM-00-02 have been completed.[6,15,50]

The absence of blood vessels in cartilage led to the hypothesis that cartilage cells (also known as chondrocytes) produce one or more substances that inhibit blood vessel formation.[27–30,35,36,48] The formation of new blood vessels or angiogenesis is necessary for tumors to grow larger than a few millimeters in diameter (i.e., larger than approximately 100,000 to 1,000,000 cells) because tumors, like normal tissues, must obtain most of their oxygen and nutrients from blood.[33,34,41,51–54] A developing tumor, therefore, cannot continue to grow unless it establishes connections to the circulatory system of its host. It has been reported that tumors can initiate the process of angiogenesis when they contain as few as 100 cells.[53] Inhibition of angiogenesis at this early stage may, in some instances, lead to complete tumor regression.[53] The possibility that cartilage could be a source of one or more types of angiogenesis inhibitors for the treatment of cancer has prompted much research.

The major structural components of cartilage include several types of the protein collagen and several types of glycosaminoglycans, which are polysaccharides.[19,29,30,39,48,54,55] Chondroitin sulfate is the major glycosaminoglycan in cartilage.[39,54] Although there is no evidence that the collagens in cartilage, or their breakdown products, can inhibit angiogenesis, there is evidence that shark cartilage contains at least one angiogenesis inhibitor that has a glycosaminoglycan component (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information).[46] Other data indicate that most of the antiangiogenic activity in cartilage is not associated with the major structural components.[26,30,48]

Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune-system-stimulating properties,[1,2,14,16,56,57] and it has been suggested that either they or some of their breakdown products are toxic to tumor cells.[2,3,24] Thus, the antitumor potential of cartilage may involve more than one mechanism of action.

Cartilage products are sold commercially in the United States as dietary supplements. More than 40 different brand names of shark cartilage alone are available to consumers.[17] In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because manufacturers of cartilage products are not required to show evidence of anticancer or other biologic effects, it is unclear whether any of these products have therapeutic potential. In addition, individual products may vary considerably from lot to lot because standard manufacturing processes do not exist, and binding agents and fillers may be added during production.[17] The FDA has not approved the use of cartilage as a treatment for people with cancer or any other medical condition. The FDA is notifying consumers of a refund program for purchasers of Lane Labs-USA, Inc.’s shark cartilage product, BeneFin. Consumers are eligible for a partial refund of the purchase price and any shipping and handling costs if this product was purchased between September 22, 1999 and July 12, 2004.

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. IND status has been granted to at least four groups of investigators to study cartilage as a treatment for people with cancer; one of these trials, MDA-ID-99303, is now completed.[7,18,58] Because the IND application process is confidential and because the existence of an IND can be disclosed only by the applicants, it is not known whether other applications have been made.

In animal studies, cartilage products have been administered in a variety of ways. In some studies, oral administration of either liquid or powdered forms has been used.[19,39,40,43,44,59,15,47] In other studies, cartilage products have been given by injection (intravenous or intraperitoneal), applied topically, or placed in slow-release plastic pellets that were surgically implanted.[26–28,32,33,35,38,40,42,44,46,48] Most of the latter studies investigated the effects of cartilage products on the development of blood vessels in the chorioallantoic membrane of chicken embryos, the cornea of rabbits, or the conjunctiva of mice.[26–28,32,35,38,40,42,44,46,48]

In human studies (MDA-ID-99303, AETERNA-AE-MM-00-02, and NCCTG-971151), cartilage products have been administered topically or orally, or they have been given by enema or subcutaneous injection.[2–4,6–9,15,16,18,60] For oral administration, liquid, powdered, and pill forms have been used as described in the following completed trials: MDA-ID-99303, NCCTG-971151, AETERNA-AE-RC-99-02, and AETERNA-AE-MM-00-02.[2–4,6–9,15,16,18] The dose and duration of cartilage treatment have varied in human studies, in part because different types of products have been tested.

In this summary, the brand name (i.e., registered or trademarked name) of the cartilage product(s) used in individual studies will be identified wherever possible.

References

1. Prudden JF, Balassa LL: The biological activity of bovine cartilage preparations. Clinical demonstration of their potent anti-inflammatory capacity with supplementary notes on certain relevant fundamental supportive studies. Semin Arthritis Rheum 3 (4): 287-321, 1974 Summer. [PUBMED Abstract]
2. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract]
3. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract]
4. Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
5. Dupont E, Savard PE, Jourdain C, et al.: Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg 2 (3): 146-52, 1998. [PUBMED Abstract]
6. Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001. [PUBMED Abstract]
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8. Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
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10. Iandoli R: Shark cartilage in the treatment of psoriasis. Dermatologia Clinica 21 (part 1): 39-42, 2001.
11. Milner M: A guide to the use of shark cartilage in the treatment of arthritis and other inflammatory joint diseases. American Chiropractor 21 (4): 40-2, 1999.
12. Himmel PB, Seligman TM: Treatment of systemic sclerosis with shark cartilage extract. Journal of Orthomolecular Medicine 14 (2): 73-7, 1999. Also available online. Last accessed April 8, 2016.
13. Sorbera LA, Castañer RM, Leeson PA: AE-941. Oncolytic, antipsoriatic, treatment of age-related macular degeneration, angiogenesis inhibitor. Drugs Future 25 (6): 551-7, 2000.
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24. Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985. [PUBMED Abstract]
25. Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986. [PUBMED Abstract]
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30. Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995. [PUBMED Abstract]
31. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977. [PUBMED Abstract]
32. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976. [PUBMED Abstract]
33. Langer R, Conn H, Vacanti J, et al.: Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci U S A 77 (7): 4331-5, 1980. [PUBMED Abstract]
34. Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985. [PUBMED Abstract]
35. Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987. [PUBMED Abstract]
36. Hiraki Y, Inoue H, Iyama K, et al.: Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem 272 (51): 32419-26, 1997. [PUBMED Abstract]
37. Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst 67 (1): 65-73, 1981. [PUBMED Abstract]
38. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983. [PUBMED Abstract]
39. Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res 54 (2): 178-82, 1997. [PUBMED Abstract]
40. Sheu JR, Fu CC, Tsai ML, et al.: Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Res 18 (6A): 4435-41, 1998 Nov-Dec. [PUBMED Abstract]
41. McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy 16 (2): 237-44, 1996 Mar-Apr. [PUBMED Abstract]
42. Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 51 (3): 181-6, 1990. [PUBMED Abstract]
43. Morris GM, Coderre JA, Micca PL, et al.: Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage. Br J Radiol 73 (868): 429-34, 2000. [PUBMED Abstract]
44. Dupont E, Falardeau P, Mousa SA, et al.: Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19 (2): 145-53, 2002. [PUBMED Abstract]
45. Béliveau R, Gingras D, Kruger EA, et al.: The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Clin Cancer Res 8 (4): 1242-50, 2002. [PUBMED Abstract]
46. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [PUBMED Abstract]
47. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [PUBMED Abstract]
48. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999. [PUBMED Abstract]
49. Batist G, Champagne P, Hariton C, et al.: Dose-survival relationship in a phase II study of Neovastat in refractory renal cell carcinoma patients. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1907, 2002.
50. Loprinzi CL, Levitt R, Barton DL, et al.: Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 104 (1): 176-82, 2005. [PUBMED Abstract]
51. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992. [PUBMED Abstract]
52. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994. [PUBMED Abstract]
53. Li CY, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92 (2): 143-7, 2000. [PUBMED Abstract]
54. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. Garland Publishing, 1994.
55. Cremer MA, Rosloniec EF, Kang AH: The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med 76 (3-4): 275-88, 1998. [PUBMED Abstract]
56. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract]
57. Houck JC, Jacob RA, Deangelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632-8, 1962. [PUBMED Abstract]
58. Simone CB, Simone NL, Simone CB: Shark cartilage for cancer. Lancet 351 (9113): 1440, 1998. [PUBMED Abstract]
59. Horsman MR, Alsner J, Overgaard J: The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 37 (5): 441-5, 1998. [PUBMED Abstract]
60. Gingras D, Batist G, Béliveau R: AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1 (3): 341-7, 2001. [PUBMED Abstract]

The therapeutic potential of cartilage has been investigated for more than 30 years. As noted previously (refer to the General Information section of this summary for more information), cartilage products have been tested as treatments for people with cancer, psoriasis, and arthritis. Cartilage products have also been studied as enhancers of wound repair and as treatments for people with osteoporosis, ulcerative colitis, regional enteritis, acne, scleroderma, hemorrhoids, severe anal itching, and the dermatitis caused by poison oak and poison ivy.[1–5]

Early studies of cartilage’s therapeutic potential utilized extracts of bovine (cow) cartilage. The ability of these extracts to suppress inflammation was first described in the early 1960s.[1] The first report that bovine cartilage contains at least one angiogenesis inhibitor was published in the mid-1970s.[6] The use of bovine cartilage extracts to treat patients with cancer and the ability of these extracts to kill cancer cells directly and to stimulate animal immune systems were first described in the mid- to late-1980s.[7–10]

The first report that shark cartilage contains at least one angiogenesis inhibitor was published in the early 1980s,[11] and the only published report of a clinical trial of shark cartilage as a treatment for people with cancer appeared in the late 1990s.[12] The more recent interest in shark cartilage is due, in part, to the greater abundance of cartilage in this animal and its apparently higher level of antiangiogenic activity. Approximately 6% of the body weight of a shark is composed of cartilage, compared with less than 1% of the body weight of a cow.[13] In addition, on a weight-for-weight basis, shark cartilage contains approximately 1,000 times more antiangiogenic activity than bovine cartilage.[11]

As indicated previously (refer to the Overview and General Information sections of this summary for more information), at least three different mechanisms of action have been proposed to explain the anticancer potential of cartilage: 1) it is toxic to cancer cells; 2) it stimulates the immune system; and 3) it inhibits angiogenesis. Only limited evidence is available to support the first two mechanisms of action; however, the evidence in favor of the third mechanism is more substantial (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information).

The process of angiogenesis requires at least four coordinated steps, each of which may be a target for inhibition. First, tumors must communicate with the endothelial cells that line the inside of nearby blood vessels. This communication takes place, in part, through the secretion of angiogenesis factors such as vascular endothelial growth factor.[14–18] Second, the activated endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels.[15,17–20] Third, the dividing endothelial cells must migrate toward the tumor.[15–20] To accomplish this, they must produce enzymes called matrix metalloproteinases, which will help them carve a pathway through the tissue elements that separate them from the tumor.[18–22] Fourth, the new endothelial cells must form the hollow tubes that will become the new blood vessels.[17,18] Some angiogenesis inhibitors may be able to block more than one step in this process.

Cartilage is relatively resistant to invasion by tumor cells,[23–30] and tumor cells use matrix metalloproteinases when they migrate during the process of metastasis.[21,25,31,32] Therefore, if the angiogenesis inhibitors in cartilage are also inhibitors of matrix metalloproteinases, then the same molecules may be able to block both angiogenesis and metastasis. Shark tissues other than cartilage have also been reported to produce antitumor substances.[33–36]

References

1. Houck JC, Jacob RA, Deangelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632-8, 1962. [PUBMED Abstract]
2. Prudden JF, Balassa LL: The biological activity of bovine cartilage preparations. Clinical demonstration of their potent anti-inflammatory capacity with supplementary notes on certain relevant fundamental supportive studies. Semin Arthritis Rheum 3 (4): 287-321, 1974 Summer. [PUBMED Abstract]
3. Prudden JF, Migel P, Hanson P, et al.: The discovery of a potent pure chemical wound-healing accelerator. Am J Surg 119 (5): 560-4, 1970. [PUBMED Abstract]
4. Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. WW Norton & Company, 1998, pp 197-200.
5. Fontenele JB, Araújo GB, de Alencar JW, et al.: The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Biol Pharm Bull 20 (11): 1151-4, 1997. [PUBMED Abstract]
6. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976. [PUBMED Abstract]
7. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract]
8. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract]
9. Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985. [PUBMED Abstract]
10. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract]
11. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983. [PUBMED Abstract]
12. Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998. [PUBMED Abstract]
13. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995. [PUBMED Abstract]
14. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992. [PUBMED Abstract]
15. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994. [PUBMED Abstract]
16. Li CY, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92 (2): 143-7, 2000. [PUBMED Abstract]
17. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. Garland Publishing, 1994.
18. Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15 (3): 180-9, 1997. [PUBMED Abstract]
19. Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103 (9): 1237-41, 1999. [PUBMED Abstract]
20. Haas TL, Madri JA: Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 9 (3-4): 70-7, 1999 Apr-May. [PUBMED Abstract]
21. McCawley LJ, Matrisian LM: Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6 (4): 149-56, 2000. [PUBMED Abstract]
22. Mandal M, Mandal A, Das S, et al.: Clinical implications of matrix metalloproteinases. Mol Cell Biochem 252 (1-2): 305-29, 2003. [PUBMED Abstract]
23. Takigawa M, Pan HO, Enomoto M, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Res 10 (2A): 311-5, 1990 Mar-Apr. [PUBMED Abstract]
24. Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995. [PUBMED Abstract]
25. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977. [PUBMED Abstract]
26. Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985. [PUBMED Abstract]
27. Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987. [PUBMED Abstract]
28. Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst 67 (1): 65-73, 1981. [PUBMED Abstract]
29. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [PUBMED Abstract]
30. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999. [PUBMED Abstract]
31. Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986. [PUBMED Abstract]
32. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [PUBMED Abstract]
33. Pettit GR, Ode RH: Antineoplastic agents L: isolation and characterization of sphyrnastatins 1 and 2 from the hammerhead shark Sphyrna lewini. J Pharm Sci 66 (5): 757-8, 1977. [PUBMED Abstract]
34. Sigel MM, Fugmann RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Res 28 (7): 1457-9, 1968. [PUBMED Abstract]
35. Snodgrass MJ, Burke JD, Meetz GD: Inhibitory effect of shark serum on the Lewis lung carcinoma. J Natl Cancer Inst 56 (5): 981-4, 1976. [PUBMED Abstract]
36. Pugliese PT, Heinerman J: Devour Disease with Shark Liver Oil. Impakt Communications, 1999.

The antitumor potential of cartilage has been investigated extensively in laboratory and animal studies. Some of these studies have assessed the toxicity of cartilage products toward cancer cells in vitro.[1–5]

Powdered Cartilage Products

In one study, cells from 22 freshly isolated human tumors (nine ovary, three lung, two brain, two breast, and one each of sarcoma, melanoma, colon, pancreas, cervix, and testis) and three human cultured cell lines (breast cancer, colon cancer, and myeloma) were treated with Catrix, which is a commercially available powdered preparation of bovine (cow) cartilage.[1,3,4] In the study, the growth of all three cultured cell lines and cells from approximately 70% of the tumor specimens were inhibited by 50% or more when Catrix was used at high concentrations (1–5 mg/mL of culture fluid). However, it is unclear whether the inhibitory effect of Catrix in this study was specific to the growth of cancer cells because the preparation’s effect on the growth of normal cells was not tested. In addition, the cytotoxic component of Catrix has not been identified, and it has not been shown that equivalent inhibitory concentrations of this component can be achieved in the bloodstreams of patients who may be treated with either injected or oral formulations of this product. (Refer to the Human/Clinical Studies section of this summary for more information.)

A commercially available preparation of powdered shark cartilage (no brand name given) was reported to have no effect on the growth of human astrocytoma cells in vitro.[2] The shark cartilage product tested in this study, however, was examined at only one concentration (0.75 mg/mL).[2]

The immune system–stimulating potential of cartilage has also been investigated in laboratory and animal studies.[6] In one study, Catrix was shown to stimulate the production of antibodies by mouse B cells (B lymphocytes) both in vitro and in vivo. However, increased antibody production in vivo was observed only when Catrix was administered by intraperitoneal or intravenous injection. It was not observed when oral formulations of Catrix were used.[6] In most experiments, the proliferation of mouse B cells (i.e., normal, nonmalignant cells) in vitro was increasingly inhibited as the concentration of Catrix was increased (tested concentration range, 1–20 mg/mL). Catrix has also been reported to stimulate the activity of mouse macrophages in vivo,[3] but results demonstrating this effect have not been published.

The effects of shark cartilage on the immune system were also reported in two studies that used the same purified protein fraction that had exhibited the most immunostimulatory effects when tested.[7,8] One study explored the effects of this fraction on tumor immune response by observing the infiltration of this fraction on CD4 and CD8 lymphocytes in a murine tumor model. An increase in the ratio of CD4/CD8 lymphocytes was seen in tumor-infiltrating lymphocytes but not in peripheral blood lymphocytes.[8] The second study exploring immune system response measured antibody response, cytotoxic assay, lymphocyte transformation, and intratumor T-cell ratio in mice. The fraction exhibited the ability to augment delayed-type hypersensitivity response against sheep red blood cells in mice and to decrease the cytotoxic activity of natural killer cells. In addition, this fraction showed a strong inhibitory effect on human brain microvascular endothelial cell proliferation and migration in the fibrin matrix.[7]

Additional in vivo studies of the antitumor potential of shark cartilage have been published in the peer-reviewed scientific literature.[9–11] In one study, oral administration of powdered shark cartilage (no brand name given) was shown to inhibit chemically induced angiogenesis in the mesenteric membrane of rats.[9] In another study, oral administration of powdered shark cartilage (no brand name given) was shown to reduce the growth of GS-9L gliosarcomas in rats.[10] It was reported in a third study that oral administration of two powdered shark cartilage products, Sharkilage and MIA Shark Powder, did not inhibit the growth or the metastasis of SCCVII squamous cell carcinomas in mice.[11]

A large number of laboratory and animal studies concerning the antiangiogenic potential of cartilage have been published.[2,9,12–32] Overall, these studies have revealed the presence of at least three angiogenesis inhibitors in bovine cartilage [13,14,16–18,21,23,33] and at least two in shark cartilage.[2,9,25,26]

Aqueous Extracts of Cartilage

A liquid (i.e., aqueous) extract of shark cartilage called AE-941/Neovastat has also been reported to inhibit the growth of a variety of cancer cell types in vitro.[5] These results have not been published in a peer-reviewed scientific journal and are not consistent with other results obtained by the same group of investigators.[27,34]

Three angiogenesis inhibitors in bovine cartilage have been very well characterized.[13,14,16–18,21,23,33] They are relatively small proteins with molecular masses that range from 23,000 to 28,000.[13,14,16,23] These proteins, called cartilage-derived inhibitor (CDI), cartilage-derived antitumor factor (CATF), and cartilage-derived collagenase inhibitor (CDCI) by the researchers who purified them,[13,14,21] have been shown to block endothelial cell proliferation in vitro and new blood vessel formation in the chorioallantoic membrane of chicken embryos.[14,16–18,21,23,33] Two of the proteins (CDI and CDCI) have been shown to inhibit matrix metalloproteinase activity in vitro,[13,14,16,18] and one (CDI) has been shown to inhibit endothelial cell migration in vitro.[14,16] These proteins do not block the proliferation of normal cells or of tumor cells in vitro.[14,16,17,21,33] When the amino acid sequences of CDI, CATF, and CDCI were determined, it was discovered that they were the same as those of proteins known otherwise as tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), chondromodulin I, and TIMP-2, respectively.[13,14,18,23,33]

A possible fourth angiogenesis inhibitor in bovine cartilage has been purified not from cartilage but from the culture fluid of bovine chondrocytes grown in the laboratory.[15] This inhibitor, which has been named chondrocyte-derived inhibitor (ChDI), is a protein that has a molecular mass of approximately 36,000. It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[15,16,33] but the relationship between these proteins is unclear because amino acid sequence information for ChDI is not available. Thus, whether CDI/TIMP-1 is a breakdown product of ChDI or whether ChDI is truly the fourth angiogenesis inhibitor identified in bovine cartilage is unknown.

As indicated previously, shark cartilage, like bovine cartilage, contains more than one type of angiogenesis inhibitor. One shark cartilage inhibitor, named U-995, reportedly contains two small proteins, one with a molecular mass of approximately 14,000 and the other with a molecular mass of approximately 10,000.[25] Both proteins have shown antiangiogenic activity when tested individually. The exact relationship between these two proteins and their relationship to the larger bovine angiogenesis inhibitors are not known because amino acid sequence information for U-995 is not available. U-995 has been reported to inhibit endothelial cell proliferation, endothelial cell migration, matrix metalloproteinase activity in vitro, and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos.[25] It does not appear to inhibit the proliferation of other types of normal cells or of cancer cells in vitro. Intraperitoneal but not oral administration of U-995 has been shown to inhibit the growth of mouse sarcoma-180 tumors implanted subcutaneously on the backs of mice and the formation of lung metastases of mouse B16-F10 melanoma cells injected into the tail veins of mice.[25]

The second angiogenesis inhibitor identified in shark cartilage appears to have been studied independently by three groups of investigators.[2,26,35] This inhibitor, which was named SCF2 by one of the groups,[35] is a proteoglycan that has a molecular mass of about 10,000. Proteoglycans are combinations of glycosaminoglycans and protein.[30] The principal glycosaminoglycan in SCF2 is keratan sulfate.[35] SCF2 has been shown to block endothelial cell proliferation in vitro,[2,26,35] the formation of new blood vessels in the chorioallantoic membrane of chicken embryos,[2,26] and tumor-induced angiogenesis in the corneas of rabbits.[2,26]

Other studies have demonstrated that AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[12,27,28,34,36–39] but the molecular basis for this activity has not been defined. Therefore, whether AE-941/Neovastat contains U-995 and/or SCF2 or some other angiogenesis inhibitor is not known. It has been reported that AE-941/Neovastat inhibits endothelial cell proliferation and matrix metalloproteinase activity in vitro and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos.[12,27,31] In addition, AE-941/Neovastat has been shown to induce endothelial cell apoptosis by activating caspases, enzymes important in the promotion and regulation of apoptosis.[32,34,38] It also appears to inhibit the action of vascular endothelial growth factor, thus interfering with the communication between tumor cells and nearby blood vessels.[28,34,37,38] AE-941/Neovastat may also inhibit angiogenesis through promotion of tissue plasminogen activator (tPA) activity. Neovastat stimulates tPA expression in endothelial cells through an increase in the transcription of the tPA gene.[40] This transcriptional activation is associated with activation of c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-kappa B) signaling pathways to an extent similar to tumor necrosis factor-alpha (TNF-alpha).[40] Furthermore, AE-941/Neovastat has been reported to inhibit the growth of DA3 mammary adenocarcinoma cells and the metastasis of Lewis lung carcinoma cells in vivo in mice.[5,27,34,41] In the Lewis lung carcinoma experiments, AE-941/Neovastat enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[5,27,34,41] All the aspects of preclinical development have been reviewed.[42]

The cartilage-derived antiangiogenic substance troponin I (TnI) has been isolated from human cartilage and has been produced by the cloning and expression of cDNA of human cartilage. It has been shown to specifically inhibit angiogenesis in vivo and in vitro and tumor metastasis in vivo.[43] The active site of Tnl has been located in the amino acid residues of 96 to 116. The synthetic peptide Glu94-Leu123 (pTnl) has been shown to be a potent inhibitor of endothelial cell tube formation and endothelial cell division and to inhibit pancreatic cancer metastases in an in vivo liver metastases model.[44]

References

1. Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985. [PUBMED Abstract]
2. McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy 16 (2): 237-44, 1996 Mar-Apr. [PUBMED Abstract]
3. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract]
4. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract]
5. AE 941–Neovastat. Drugs R D 1 (2): 135-6, 1999. [PUBMED Abstract]
6. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract]
7. Hassan ZM, Feyzi R, Sheikhian A, et al.: Low molecular weight fraction of shark cartilage can modulate immune responses and abolish angiogenesis. Int Immunopharmacol 5 (6): 961-70, 2005. [PUBMED Abstract]
8. Feyzi R, Hassan ZM, Mostafaie A: Modulation of CD(4)(+) and CD(8)(+) tumor infiltrating lymphocytes by a fraction isolated from shark cartilage: shark cartilage modulates anti-tumor immunity. Int Immunopharmacol 3 (7): 921-6, 2003. [PUBMED Abstract]
9. Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res 54 (2): 178-82, 1997. [PUBMED Abstract]
10. Morris GM, Coderre JA, Micca PL, et al.: Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage. Br J Radiol 73 (868): 429-34, 2000. [PUBMED Abstract]
11. Horsman MR, Alsner J, Overgaard J: The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 37 (5): 441-5, 1998. [PUBMED Abstract]
12. Dupont E, Savard PE, Jourdain C, et al.: Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg 2 (3): 146-52, 1998. [PUBMED Abstract]
13. Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986. [PUBMED Abstract]
14. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990. [PUBMED Abstract]
15. Moses MA, Sudhalter J, Langer R: Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes. J Cell Biol 119 (2): 475-82, 1992. [PUBMED Abstract]
16. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr. [PUBMED Abstract]
17. Takigawa M, Pan HO, Enomoto M, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Res 10 (2A): 311-5, 1990 Mar-Apr. [PUBMED Abstract]
18. Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995. [PUBMED Abstract]
19. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976. [PUBMED Abstract]
20. Langer R, Conn H, Vacanti J, et al.: Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci U S A 77 (7): 4331-5, 1980. [PUBMED Abstract]
21. Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985. [PUBMED Abstract]
22. Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987. [PUBMED Abstract]
23. Hiraki Y, Inoue H, Iyama K, et al.: Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem 272 (51): 32419-26, 1997. [PUBMED Abstract]
24. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983. [PUBMED Abstract]
25. Sheu JR, Fu CC, Tsai ML, et al.: Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Res 18 (6A): 4435-41, 1998 Nov-Dec. [PUBMED Abstract]
26. Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 51 (3): 181-6, 1990. [PUBMED Abstract]
27. Dupont E, Falardeau P, Mousa SA, et al.: Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19 (2): 145-53, 2002. [PUBMED Abstract]
28. Béliveau R, Gingras D, Kruger EA, et al.: The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Clin Cancer Res 8 (4): 1242-50, 2002. [PUBMED Abstract]
29. Cho J, Kim Y: Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY) 4 (6): 521-5, 2002. [PUBMED Abstract]
30. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. Garland Publishing, 1994.
31. Gingras D, Renaud A, Mousseau N, et al.: Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound. Anticancer Res 21 (1A): 145-55, 2001 Jan-Feb. [PUBMED Abstract]
32. Boivin D, Gendron S, Beaulieu E, et al.: The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis. Mol Cancer Ther 1 (10): 795-802, 2002. [PUBMED Abstract]
33. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999. [PUBMED Abstract]
34. Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001. [PUBMED Abstract]
35. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [PUBMED Abstract]
36. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003. [PUBMED Abstract]
37. Gingras D, Batist G, Béliveau R: AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1 (3): 341-7, 2001. [PUBMED Abstract]
38. Gingras D, Boivin D, Deckers C, et al.: Neovastat–a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14 (2): 91-6, 2003. [PUBMED Abstract]
39. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002. [PUBMED Abstract]
40. Gingras D, Nyalendo C, Di Tomasso G, et al.: Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent. Biochem Biophys Res Commun 320 (1): 205-12, 2004. [PUBMED Abstract]
41. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [PUBMED Abstract]
42. Dredge K: AE-941 (AEterna). Curr Opin Investig Drugs 5 (6): 668-77, 2004. [PUBMED Abstract]
43. Moses MA, Wiederschain D, Wu I, et al.: Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A 96 (6): 2645-50, 1999. [PUBMED Abstract]
44. Kern BE, Balcom JH, Antoniu BA, et al.: Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. J Gastrointest Surg 7 (8): 961-8; discussion 969, 2003. [PUBMED Abstract]

Since the early 1970s, at least a dozen clinical trials (MDA-ID-99303, NCCTG-971151, and AETERNA-AE-MM-00-02) of cartilage as a treatment for people with cancer have been (or are being) conducted;[1–15] (refer to the table at the end of this section) however, results from only seven studies have been published in peer-reviewed scientific journals.[1,2,4,8,9,16] It is not clear whether any of the patients in these studies were children.

In the first randomized trial published in a peer-reviewed scientific journal, 83 incurable breast cancer and colorectal cancer patients were randomly assigned to receive either shark cartilage or placebo, in addition to standard care. No difference was observed in survival or quality of life between those receiving shark cartilage and those receiving placebo.[8] Additional clinical studies are under way; however, the cumulative evidence is inconclusive regarding the effectiveness of cartilage as a treatment for people with cancer.

Powdered Cartilage Products

Two of the three published clinical studies evaluated the use of Catrix, the previously mentioned (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information) powdered preparation of bovine (cow) cartilage, as a treatment for various solid tumors.[1,2] One of these studies was a case series that included 31 patients;[1] the other was a phase II clinical trial that included 9 patients.[2]

In the case series,[1] all patients were treated with subcutaneously injected and/or oral Catrix; however, three patients (one with squamous cell carcinoma of the skin and two with basal cell carcinoma of the skin) were also treated with topical preparations. The individual dose, the total dose, and the duration of Catrix treatment in this series varied from patient to patient; however, the minimum treatment duration was 7 months, and the maximum duration was more than 10 years. Eighteen patients had been treated with conventional therapy (surgery, chemotherapy, radiation therapy, hormonal therapy) within 1 year of the start of Catrix treatment; nine patients received conventional therapy concurrently with Catrix treatment; and seven patients received conventional therapy both prior to and during Catrix treatment. It was reported that 19 patients had a complete response, 10 patients had a partial response, and 1 patient had stable disease following Catrix treatment. The remaining patient did not respond to cartilage therapy. Eight of the patients with a complete response received no prior or concurrent conventional therapy. Approximately half of the patients with a complete response eventually experienced recurrent cancer.

This clinical study had several weaknesses that could have affected its outcome, including the absence of a control group and the receipt of prior and/or concurrent conventional therapy by most patients.

Partial results of a third clinical study of Catrix are described in an abstract submitted for presentation at a scientific conference,[3] but complete results of this study have not been published in a peer-reviewed scientific journal. In the study, 35 patients with metastatic renal cell carcinoma were divided into four groups, and the individuals in each group were treated with identical doses of subcutaneously injected and/or oral Catrix. Three partial responses and no complete responses were observed among 22 evaluable patients who were treated with Catrix for more than 3 months. Following Catrix therapy, 2 of the 22 evaluable patients were reported to have stable disease, and 17 were reported to have progressive disease. No relationship between Catrix dose and tumor response could be established in this study.

The third published study of cartilage as a treatment for people with cancer was a phase I/II trial that tested the safety and the efficacy of orally administered Cartilade, a commercially available powdered preparation of shark cartilage, in 60 patients with various types of advanced solid tumors.[4] All but one patient in this trial had been treated previously with conventional therapy. According to the design of the study, no additional anticancer treatment could be given concurrently with Cartilade therapy. No complete responses or partial responses were observed among 50 evaluable patients who were treated with Cartilade for at least 6 weeks. However, stable disease that lasted 12 weeks or more was reported for 10 of the 50 patients. All ten of these patients eventually experienced progressive disease.

Partial results of three other clinical studies of powdered shark cartilage are described in two abstracts submitted for presentation at scientific conferences,[5,6] but complete results of these studies have not been published in peer-reviewed scientific journals. All three studies were phase II clinical trials that involved patients with advanced disease; two of the studies were conducted by the same group of investigators.[5] These three studies enrolled 20 patients with breast cancer,[5] 12 patients with prostate cancer,[5] and 12 patients with primary brain tumors.[6] All patients had been treated previously with conventional therapy. No other anticancer treatment was allowed concurrently with cartilage therapy. In two of the studies,[5] the name of the cartilage product was not identified; however, in the third study,[6] the commercially available product BeneFin was used. Ten patients in each study completed at least 8 weeks of treatment and therefore were considered evaluable for response. No complete responses or partial responses were observed in any of the studies. Two evaluable patients in the breast cancer study were reported to have stable disease that lasted 8 weeks or more; two evaluable patients in the brain tumor study had stable disease that lasted 20 weeks or more; and three evaluable patients in the prostate cancer study had stable disease that also lasted 20 weeks or more.

Aqueous Extracts of Cartilage

In the phase II trial,[2] Catrix was administered by subcutaneous injection only. All patients in this trial had progressive disease following radiation therapy and/or chemotherapy. Identical individual doses of Catrix were administered to each patient, but the duration of treatment and the total delivered dose varied because of disease progression or death. The minimum duration of Catrix treatment in this study was 4 weeks. One patient (with metastatic renal cell carcinoma) reportedly had a complete response that lasted more than 39 weeks. The remaining eight patients did not respond to Catrix treatment. The researchers in this trial also investigated whether Catrix had an effect on immune system function in these patients. No consistent trend or change in the numbers, percentages, or ratios of white blood cells (i.e., total lymphocyte counts, total T cell counts, total B cell counts, percentage of T cells, percentage of B cells, and ratio of helper T cells to cytotoxic T cells) was observed, though increased numbers of T cells were found in three patients.

The safety and the efficacy of AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has also been examined in clinical studies.[9–11,15,17] It has been reported that AE-941/Neovastat has little toxicity.[10,11,15] In addition, there is evidence from a randomized clinical trial that examined the effect of AE-941/Neovastat on angiogenesis associated with surgical wound repair that this product contains at least one antiangiogenic component that is orally bioavailable.[17]

AE-941/Neovastat was administered to 331 patients with advanced solid tumors (including lung, prostate, breast, and kidney tumors) in two phase I/II trials.[10] The results of these trials, however, have not been fully reported. A retrospective analysis involving a subgroup of patients with advanced non-small cell lung cancer (NSCLC) suggests that AE-941/Neovastat is able to lengthen the survival of patients with this disease.[10] Furthermore, in a prospective analysis involving 22 patients with refractory renal cell carcinoma, survival was longer in patients treated with 240 mL/day AE-941/Neovastat than in patients treated with only 60 mL/day.[7,10,16]

In 2003, the results of a phase I/II trial of AE-941/Neovastat in 80 patients with advanced NSCLC reported that there was a significant survival advantage for patients receiving the highest doses (2.6 mL/kg/day) of AE-941/Neovastat. A survival analysis of 48 patients with unresectable stage IIIA, IIIB, or IV NSCLC showed a median survival advantage of P = .0026 in patients receiving the highest doses. The trial was principally conducted to explore the safety and efficacy of orally administered AE-941/Neovastat when administered in escalating doses (30, 60, 120, and 240 mL/day). No dose-limiting toxicity was found, and no tumor response was observed.[9]

In 2001, a phase II trial (AETERNA-AE-MM-00-02) of AE-941/Neovastat was initiated in patients with relapsed or refractory multiple myeloma. This trial closed approximately 1 year later, and no results have been reported.[18]

Two randomized phase III trials of AE-941/Neovastat in patients with advanced cancer have been approved by the U.S. Food and Drug Administration (FDA). In one trial (MDA-ID-99303), which is completed, treatment with oral AE-941/Neovastat plus chemotherapy and radiation therapy was compared with treatment with placebo plus the same chemotherapy and radiation therapy in patients with stage III NSCLC. In the second trial, which closed to patient recruitment in 2002, treatment with oral AE-941/Neovastat was compared with treatment with placebo in patients with metastatic renal cell carcinoma. Results from this second phase III trial have not been reported in the peer-reviewed scientific literature.[19] Despite AE-941/Neovastat being granted orphan drug status by the FDA in 2002 for use in the treatment of renal cell carcinoma, the company that produces AE-941/Neovastat, Aeterna Laboratories, announced in early 2004 that this application would be discontinued in favor of a focus on the treatment of NSCLC.[19,20]

In 2010, the results of a randomized, double-blind, placebo-controlled phase III trial aimed at assessing the effect of adding AE-941 to chemotherapy and radiation therapy on the overall survival of patients with nonresectable stage III NSCLC were reported. A total of 379 eligible patients received induction chemotherapy followed by concurrent chemotherapy with chest radiation therapy; participating centers used one of two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. No statistically significant difference in overall survival was observed between the group (n = 188) receiving chemotherapy and radiation therapy plus AE-941 (120 mL administered orally twice daily) and the group receiving chemotherapy and radiation therapy plus placebo (n = 191). Both AE-941 and placebo were well tolerated.[21]

Cartilage Use in Cancer Treatment: Clinical Studies With Therapeutic Endpointsa,b

Reference Citation(s)	Type of Study	Type(s) of Cancer	Cartilage Product (Source)	No. of Patients: Treated; Control	Strongest Benefit Reportedc	Concurrent Therapyd	Level of Evidence Scoree
No. = number; NSCLC = non-small cell lung cancer; wk = week.
aSee text and the NCI Dictionary of Cancer Terms for additional information and definition of terms.
bOther clinical studies have been conducted, but no results have been reported.
cStrongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
dChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy given/allowed at the same time as cartilage therapy.
eFor information about Levels of Evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
fStudy results reported in review article or abstract form only; insufficient information presented for Level of Evidence analysis.
gInsufficient information available to describe these studies separately.
[8]	Phase III randomized, placebo-controlled, double-blind trial (2 arms)	Breast and colorectal	BeneFin (shark)	42; 41	No statistically significant difference	No	1i
[21]	Randomized controlled phase III trial	NSCLC	AE-941 (shark)	188; 191	None	Cisplatin and vinorelbine; carboplatin and paclitaxel	1iA
[1]	Nonconsecutive case series	Various advanced or recurrent	Catrix (bovine)	31; None	Complete response, 19 patients	Yes	3iiiDiii
[2]	Phase II trial	Various metastatic	Catrix (bovine)	9; None	Complete response, 1 patient, metastatic renal cell carcinoma	No	3iiiDiii
[3]	Phase II trial	Metastatic renal cell	Catrix (bovine)	35; None	Partial response, 3 of 22 evaluable patients	Unknown	Nonef
[10,16]	Two phase I/II trialsg	Various advanced, refractory solid tumors	AE-941/ Neovastat (shark)	331; None	Improved survival, higher versus lower doses, patients with stage III/IV non-small cell lung cancer (unplanned retrospective analysis), and patients with refractory renal cell carcinoma (prospective analysis)	Unknown	Nonef
[9]	Phase I/II trial	Advanced non-small cell lung cancer	AT-941/Neovastat (shark)	80; None	No dose-limiting toxicity found. Improved survival time in patients receiving the highest doses when survival analysis was conducted, and stable disease for greater number of patients receiving higher doses. No tumor response observed.	Yes or refused standard therapy	None
[4]	Phase I/II trial	Various advanced solid tumors	Cartilade (shark)	60; None	Stable disease for 12 wk or more, 10 of 50 evaluable patients	No	3iiiDiii
[5]	Phase II trial	Metastatic, refractory breast	Unknown (shark)	20; None	Stable disease for 8 wk or more, 2 of 10 evaluable patients	No	Nonef
[5]	Phase II trial	Metastatic, hormone- refractory prostate	Unknown (shark)	12; None	Stable disease for 20 wk or more, 3 of 10 evaluable patients	No	Nonef
[6]	Phase II trial	Various advanced brain	BeneFin (shark)	12; None	Stable disease for 20 wk or more, 2 of 10 evaluable patients	No	Nonef

References

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract]
2. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract]
3. Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
4. Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998. [PUBMED Abstract]
5. Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
6. Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
7. Batist G, Champagne P, Hariton C, et al.: Dose-survival relationship in a phase II study of Neovastat in refractory renal cell carcinoma patients. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1907, 2002.
8. Loprinzi CL, Levitt R, Barton DL, et al.: Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 104 (1): 176-82, 2005. [PUBMED Abstract]
9. Latreille J, Batist G, Laberge F, et al.: Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer. Clin Lung Cancer 4 (4): 231-6, 2003. [PUBMED Abstract]
10. Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001. [PUBMED Abstract]
11. AE 941–Neovastat. Drugs R D 1 (2): 135-6, 1999. [PUBMED Abstract]
12. Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. WW Norton & Company, 1998, pp 197-200.
13. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1 (6): 414-16, 1995.
14. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995. [PUBMED Abstract]
15. AE 941. Drugs R D 5 (2): 83-9, 2004. [PUBMED Abstract]
16. Batist G, Patenaude F, Champagne P, et al.: Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels. Ann Oncol 13 (8): 1259-63, 2002. [PUBMED Abstract]
17. Berbari P, Thibodeau A, Germain L, et al.: Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. J Surg Res 87 (1): 108-13, 1999. [PUBMED Abstract]
18. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002. [PUBMED Abstract]
19. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003. [PUBMED Abstract]
20. New treatment option for postmenopausal women with early breast cancer. Expert Rev Anticancer Ther 2 (6): 617, 2002. [PUBMED Abstract]
21. Lu C, Lee JJ, Komaki R, et al.: Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst 102 (12): 859-65, 2010. [PUBMED Abstract]

The side effects associated with cartilage therapy are generally described as mild to moderate in severity. Inflammation at injection sites, dysgeusia, fatigue, nausea, dyspepsia, fever, dizziness, and edema of the scrotum have been reported after treatment with the bovine (cow) cartilage product Catrix.[1–3] Nausea, vomiting, abdominal cramping and/or bloating, constipation, hypotension, hyperglycemia, generalized weakness, and hypercalcemia have been associated with the use of powdered shark cartilage.[4–6] The high level of calcium in shark cartilage may contribute to the development of hypercalcemia.[5,7] In addition, one case of hepatitis has been associated with the use of powdered shark cartilage.[8] Nausea, vomiting, and dyspepsia are the most commonly reported side effects following treatment with AE-941/Neovastat, the aqueous extract of shark cartilage.[9]

References

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract]
2. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract]
3. Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
4. Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998. [PUBMED Abstract]
5. Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
6. Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
7. Jungi WF: Dangerous nutrition. Support Care Cancer 11 (4): 197-8, 2003. [PUBMED Abstract]
8. Ashar B, Vargo E: Shark cartilage-induced hepatitis. Ann Intern Med 125 (9): 780-1, 1996. [PUBMED Abstract]
9. Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001. [PUBMED Abstract]

Although at least a dozen clinical studies of cartilage as a treatment for people with cancer have been conducted since the early 1970s, relatively few results have been reported in the peer-reviewed scientific literature. There are small amounts of reported data from phase III clinical trials. Additional clinical studies are now under way. At present, the use of cartilage (bovine [cow] or shark) as a treatment for people with cancer cannot be recommended outside the context of well-designed clinical trials.

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, 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 cartilage (bovine and shark) 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 Cartilage (Bovine and Shark). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/cartilage-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389205]

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1. What is cartilage?

   Cartilage is a type of tough, flexible connective tissue that forms parts of the skeleton in many animals. Cartilage contains cells called chondrocytes, which are surrounded by collagen (a fibrous protein) and proteoglycans, which are made of protein and carbohydrate.

   Products containing cartilage are sold in the United States as dietary supplements. Companies that make cartilage products may not have a process in place to check that all batches they make are exactly the same. This means different batches of a cartilage product may contain different amounts or strengths of ingredients. Different binding agents (substances that make loose mixtures stick together) and fillers may be used in different batches. Therefore, the results of a particular clinical trial may be true only for the batch that was used in the study.

2. What is the history of the discovery and use of cartilage as a complementary or alternative treatment for cancer?

   Cartilage from cows (bovine cartilage) and sharks has been studied as a treatment for cancer and other medical conditions for more than 30 years. It was once believed that sharks, whose skeletons are made mostly from cartilage, do not develop cancer. This caused interest in cartilage as a possible treatment for cancer. Although malignant tumors are rare in sharks, cancers have been found in these animals.

   Early studies used extracts of bovine cartilage.

   • In the 1960s, it was first reported that bovine cartilage decreased inflammation (redness, swelling, pain, and feeling of heat).
   • In the 1970s, it was first reported that bovine cartilage contains a substance that blocks angiogenesis (the forming of new blood vessels). If blood vessel growth into a tumor can be blocked, the tumor will stop growing or shrink.
   • In the 1980s, researchers first described laboratory and animal studies and clinical trials (research studies in people) testing bovine cartilage as a treatment for cancer.

   Interest in using shark cartilage grew because it was believed that shark cartilage may be more active than bovine cartilage in preventing new blood vessels from being formed. Since a shark’s skeleton is made mostly of cartilage, shark cartilage is more plentiful than bovine cartilage.

   • In the 1980s, it was first published that shark cartilage contains a substance that blocks blood vessel growth.
   • In 1998 and 2005, there were published reports of clinical trials of shark cartilage as a treatment for cancer.

   (See Question 5 for more information about the laboratory and animal studies. See Question 6 for more information about the clinical trials.)

3. What is the theory behind the claim that cartilage is useful in treating cancer?

   Three theories have been suggested to explain how cartilage acts against cancer:

   • As cartilage is broken down by the body, it releases products that kill cancer cells.
   • Cartilage increases the action of the body’s immune system to kill cancer cells.
   • Cartilage makes substances that block tumor angiogenesis (the growth of new blood vessels that feed a tumor and help it grow).

   Based on laboratory and animal studies, the third theory may be most likely. Cartilage does not contain blood vessels, so cancer cannot easily grow in it. It is suggested that a cancer treatment using cartilage may keep blood vessels from forming in a tumor, causing the tumor to stop growing or shrink.

4. How is cartilage administered?

   In animal studies, cartilage products have been given by mouth; injected into a vein or the abdomen; applied to the skin; or placed in slow-release plastic pellets that were surgically implanted (put into the body).

   In studies with people, cartilage products have been given by mouth; applied to the skin; injected under the skin; or given by enema (injected as a liquid into the rectum). The dose and length of time the cartilage treatment was given was different for each study, in part because different types of products were used.

5. Have any preclinical (laboratory or animal) studies been conducted using cartilage?

   A number of preclinical studies have been done with cartilage. Preclinical studies in a laboratory or using animals are done to find out if a drug, procedure, or treatment is likely to be safe and useful in humans. These preclinical studies are done before testing in humans is begun. 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.

   Preclinical studies of cartilage looked at whether bovine and shark cartilage products can kill cancer cells in the laboratory, make the immune system more active against cancer, and prevent blood vessels from forming.

   Powdered cartilage

   The following have been reported from preclinical studies of the effect of powdered cartilage on cancer cells in vitro (outside of the body):

   • In a published laboratory study, a powdered form of bovine cartilage called Catrix slowed the growth of human cancer cells by half or more. It is not clear if Catrix had this effect only on cancer cells, because its effect the growth of normal cells was not tested. It is also not known if the dose used in the laboratory study could safely be used in people.
   • In a published laboratory study of powdered shark cartilage, there was no effect on the growth of human astrocytoma cells (cancer cells that begin in the brain or spinal cord).

   The following have been reported from preclinical studies of the effect of powdered cartilage on the immune system:

   • One published study reported that Catrix injected into mice caused their immune systems to be more active. This effect did not happen when Catrix was given by mouth.
   • A laboratory study on the effect of shark cartilage on a tumor model reported an increase in tumor-fighting immune cells in the tumor but not in the blood.
   • A study on the effect of shark cartilage on immune system response in mice reported a number of different effects, both helpful and harmful. It increased antibody response but decreased the activity of natural killer cells (tumor-fighting white blood cells). The study also reported a decrease in blood vessel growth.

   A large number of laboratory and animal studies on the effect of powdered cartilage on angiogenesis have been published. The following have been reported from these studies:

   • Powdered shark cartilage given by mouth to rats decreased the growth of abdominal tissue cells.
   • Powdered shark cartilage given by mouth to rats decreased the growth of gliosarcomas, a type of brain cancer.
   • Two powdered shark cartilage products (Sharkilage and MIA Shark Powder) given by mouth to mice did not stop the growth or spread of squamous cell skin cancer.
   • Three substances that prevent blood vessel growth were found in bovine cartilage. These substances have not shown an effect on the growth of normal cells or tumor cells.
   • Two substances that prevent blood vessel growth were found in shark cartilage. These substances have not shown an effect on the growth of normal cells or tumor cells.

   Liquid cartilage

   The following have been reported from preclinical studies of liquid cartilage products:

   • In a laboratory study, a liquid form of shark cartilage called AE-941/Neovastat was reported to stop the growth of a number of cancer cell types. The results have not been published in a scientific journal.
   • Several studies have shown that AE-941/Neovastat blocks the growth of new blood vessels.
   • AE-941/Neovastat given by mouth to mice slowed the growth of breast cancer cells and the spread of lung cancer. In the lung cancer study, AE-941/Neovastat increased the effect of the anticancer drug cisplatin.
   • A substance made from human cartilage slowed the spread of pancreatic cancer cells in an animal study and prevented blood vessel growth in both animal and laboratory studies.
6. Have any clinical trials (research studies with people) been conducted using cartilage?

   Clinical trials are a type of research study that tests how well new drugs or other treatments work in people. Since the 1970s, there have been at least a dozen clinical studies of cartilage as a treatment for cancer.

   There has been one randomized clinical trial of cartilage as cancer treatment published in a peer-reviewed scientific journal. This trial compared treatment using a form of shark cartilage to treatment using a placebo (an inactive substance that looks the same as, and is given the same way as, the substance being tested). Patients also received standard care. In 83 patients having either advanced breast or advanced colon cancer, there was no difference in the quality of life or survival rate between the group that received the shark cartilage product and the group that received the placebo.

   Powdered cartilage

   The following have been reported from clinical trials of powdered cartilage products:

   • Case series (a collection of detailed information about individual patients) of 31 patients who were treated with Catrix by injection and/or by mouth:

     The cancer went into remission (signs and symptoms of cancer went away) in 19 patients and then recurred (came back) in about half of them. Some of these patients also received standard cancer treatment and there was no control group (a group of patients who do not receive the treatment being studied, to show if the treatment being studied makes a difference). For these reasons, the effectiveness of cartilage as a cancer treatment is not proven by this case series.

   • A clinical trial of Cartilade by mouth in 60 patients with advanced cancer:

     All but 1 patient had been treated with standard therapy before the trial. The cancer stopped growing in 10 of the patients for 12 weeks or more and then began to grow again. The cancer did not shrink or go into remission in any of the patients.

   Liquid cartilage

   The following have been reported from clinical trials of liquid cartilage products:

   • A clinical trial of Catrix in 9 patients whose cancers did not respond to radiation therapy and/or chemotherapy:

     Catrix was given by injection. One patient’s cancer went into remission for more than 39 weeks and the other 8 patients did not respond to treatment with Catrix.

   • Clinical studies on the safety of the liquid shark cartilage product AE-941/Neovastat have reported that it has little harmful effect.
   • A randomized clinical trial studied the effect of AE-941/Neovastat on blood vessel growth related to wound healing after surgery. This study reported that one of the ingredients that prevents blood vessel growth can be absorbed and used by the body when taken by mouth.
   • A clinical trial of oral AE-941/Neovastat in 379 patients with advanced non-small cell lung cancer reported that there was no difference in how long patients lived between the group receiving the shark cartilage product and chemoradiotherapy compared to the group receiving the placebo and chemoradiotherapy. Both kinds of treatment were well tolerated.

   For more detailed information about these clinical trials and others that are ongoing or have not fully reported, see the health professional version.

7. Have any side effects or risks been reported from cartilage?

   The side effects of cartilage treatment are usually mild or moderate.

   The most common side effects of treatment with the bovine cartilage product Catrix include the following:

   • Inflammation at the injection location.
   • A bad taste in the mouth.
   • Feeling very tired.
   • Nausea.
   • Upset stomach.
   • Fever.
   • Feeling dizzy.
   • Swelling of the scrotum (the sac that contains the testicles).

   The most common side effects of treatment with the shark cartilage include the following:

   • Nausea.
   • Vomiting.
   • Abdominal cramps and/or bloating.
   • Constipation.
   • Lower than normal blood pressure.
   • Higher than normal blood sugar.
   • General weakness.
   • A higher than normal level of calcium in the blood.

   Nausea, vomiting, and upset stomach are the side effects reported most often from treatment with the shark cartilage product AE–941/Neovastat.

   There has been one report of hepatitis occurring in a person who used shark cartilage.

8. Is cartilage approved by the US Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The US Food and Drug Administration (FDA) has not approved cartilage as a treatment for cancer. A number of cartilage products are sold in the United States as dietary supplements. Dietary supplements are products meant to be added to the diet. They are not drugs and are not meant to treat, prevent, or cure diseases. The manufacturer is responsible for ensuring that the product is safe and that the label claims are truthful and not misleading. The FDA does not approve dietary supplements as safe or effective before they are sold.

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 cartilage (bovine and shark) 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 Cartilage (Bovine and Shark). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/cartilage-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389175]

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.

1. What is Cancell?

   Cancell is also called Sheridan’s Formula, Jim’s Juice, JS–114, JS–101, 126–F, and “Cancell-like” products (Cantron and Protocel). It is a liquid that was promoted as a treatment for cancer and other diseases. Cancell was made using different mixtures of ingredients, mainly by two companies, since the late 1930s.

   None of the common chemicals in these products is known to be effective in treating any type of cancer.

   Since 1989, it has been illegal in the United States to make, sell, or give Cancell as a treatment for any disease. Mixtures similar to Cancell, such as Cantron and Protocel, are available as dietary supplements. (See Question 8.)

2. What is the history of the discovery and use of Cancell as a complementary or alternative treatment for cancer?

   Cancell was first made in the late 1930s by James V. Sheridan, a biochemist who called the mixture Entelev and gave it free to cancer patients. In 1984, another company began making Entelev under the name Cancell. That company gave it free to patients with cancer, AIDS (acquired immunodeficiency syndrome), and other conditions.

3. What is the theory behind the claim that Cancell is useful in treating cancer?

   The exact ingredients used to make Cancell are not known. One sample of the liquid mixture Cancell was found to contain 12 different ingredients, none of which is known to be helpful in treating any type of cancer. The U.S. Food and Drug Administration (FDA) has listed the following ingredients in Cancell:

   • Inositol.
   • Nitric acid.
   • Sodium sulfite.
   • Potassium hydroxide.
   • Sulfuric acid.
   • Catechol.

   The first maker of Cancell said the ingredients work together by changing cancer cells so they are seen by the body as “foreign” and are destroyed. The second maker stated that Cancell changes cancer cells so they “self-digest” and are replaced by normal cells. The waste matter made by this self-digestion was said to be passed from the body in urine, sweat, and other body fluids.

4. How is Cancell administered?

   Cancell has been taken by mouth, inserted into the rectum, or applied to the skin of the wrist or the ball of the foot. Patients taking Cancell were advised by the makers to take bromelain to help digestion and to avoid high doses of vitamin C and vitamin E. Makers of Cancell stated that vitamins raise the energy of the cell while Cancell lowers it.

5. Have any preclinical (laboratory or animal) studies been conducted using Cancell?

   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. These preclinical studies are done before any testing in humans is begun. 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.

   The National Cancer Institute (NCI) did animal studies on Cancell in 1978 and 1980 and laboratory studies in 1990 and 1991. Laboratory studies using human tumor cells concluded that Cancell could not be taken in doses high enough to kill cancer cells in the body. The NCI decided that Cancell did not show enough anticancer activity to continue the studies. See the PDQ health professional summary on Cancell/Cantron/Protocel for details on the results of these studies.

   The makers of Cancell reported doing animal studies with the liquid mixtures, but none of these studies have been published in peer-reviewed scientific journals. No information has been given on these studies, beyond stating that some of the studies tested the toxicity (harmful and unwanted side effects) of Cancell.

6. Have any clinical trials (research studies with people) been conducted using Cancell?

   No clinical trials of Cancell have been reported. The makers of Cancell have stated that more than 15,000 patients have used the mixture and that it is safe and effective in treating 50% to 80% of all cancers. Their findings have not been published in peer-reviewed scientific journals. Testimonials (information given by people who state that they have been helped by a particular treatment or product) and anecdotal reports (incomplete descriptions of the medical and treatment histories of one or more patients) have been made available by the manufacturers.

7. Have any side effects or risks been reported from Cancell?

   The company that made Cancell stated that the side effects of the mixture include feeling tired during the first few weeks of treatment. Nausea is also a reported side effect. One patient who took more than the maker’s advised dose reported diarrhea that lasted for a few hours.

8. Is Cancell approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   Cancell is not approved for use in the United States. In 1989, the U.S. Food and Drug Administration judged Cancell to be a new, unapproved drug. The FDA requested and received a court order making it illegal for manufacturers to send Cancell across state lines. The mixture may no longer be made, sold, or given to patients as a treatment for cancer or other diseases.

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 Cancell/Cantron/Protocel 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 Cancell/Cantron/Protocel. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/patient/cancell-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389431]

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 Cancell/Cantron/Protocel as a treatment in people with cancer. The discussion in the summary is limited to Cancell/Cantron/Protocel as it was originally conceived; the “vibrationally tuned” distilled water also distributed under the name Cancell will not be discussed.

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.

Cancell/Cantron/Protocel, also known by the names Sheridan’s Formula, Jim’s Juice, JS-114, JS-101, 126-F, and the “Cancell-like” products Cantron and Protocel, is a liquid that has been produced in various forms principally by two manufacturers since the late 1930s.[1–3] It has been promoted as an effective therapy for cancer and a wide range of other diseases including AIDS, collagen disease, lupus, scleroderma, cystic fibrosis, multiple sclerosis, adult-onset diabetes mellitus, emphysema, Parkinson disease, hemophilia, hypotension, hypertension, and some forms of epilepsy and mental illness.[1,3]

The exact composition of Cancell/Cantron/Protocel is unknown. The U.S. Food and Drug Administration (FDA) has listed the components as inositol, nitric acid, sodium sulfite, potassium hydroxide, sulfuric acid, and catechol.[1,2] The original manufacturer also identified “crocinic acid” as a component;[1] however, information about the nature and origin of this chemical has not been provided, and it does not appear to be a known compound. An independent analysis of one formulation of Cancell/Cantron/Protocel found 12 different compounds, none of which is known to be effective in treating any form of cancer.[1]

Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. Entelev, which is the original name of the mixture, was assigned an IND number (IND #20258) by the FDA in 1982.[4] The IND currently remains inactive because information about the product’s composition and studies showing its therapeutic effectiveness in animals have not been provided to the FDA.[1] In 1989, the FDA was granted a permanent injunction against both principal manufacturers of Cancell/Cantron/Protocel prohibiting them or their agents from distributing the mixture, which was judged an unapproved new drug.

Cancell/Cantron/Protocel has been administered orally, rectally, and topically.[1] Topical skin application is accomplished by dampening a cotton pad with the liquid and taping the moistened pad to the wrist or the ball of the foot after first treating the area with dimethyl sulfoxide. Cancer patients have also been advised to take bromelain, which is a digestive aid, and to avoid high intakes of vitamins C and E while undergoing treatment with Cancell/Cantron/Protocel.[1,3]

References

1. Questionable methods of cancer management: Cancell/Entelev. CA Cancer J Clin 43 (1): 57-62, 1993 Jan-Feb. [PUBMED Abstract]
2. Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. WW Norton & Company, 1998.
3. Cancell Alternative Cancer Treatment. Cottonwood, Ariz: Winter Works, 2002. Available online. Last accessed April 8, 2016.
4. U.S. District Court for the Eastern District of Michigan: Complaint for Permanent Injunction: United States of America, Plaintiff, v. James V. Sheridan and Edmund J. Sopcak, Defendants. 21st February, 1989.

Cancell/Cantron/Protocel was developed in the 1950s by a chemist who called it Entelev and provided it free of charge to patients with terminal cancer.[1,2] In 1984, production was taken over by a second manufacturer who distributed the mixture free of charge under the trademarked name Cancell to individuals with cancer, AIDS, and other conditions.[1,2]

The two principal manufacturers of Cancell/Cantron/Protocel have offered somewhat different explanations for cancer development, but their theories about how the mixture works are quite similar. According to the original manufacturer, human cells can be normal, cancerous, or primitive.[1] Each of these cellular forms is distinguished by the degree of oxygen utilization in cellular metabolism. Normal cells use aerobic metabolism (glycolysis plus additional biochemical reactions that require oxygen) to produce the energy needed for growth and maintenance. Primitive cells only use glycolysis, which is a much less efficient way to produce energy. It was proposed that normal cells become cancerous when, in response to certain damaging conditions such as chronic energy stress (a demand for energy greater than the cell’s ability to produce it), they reach a critical point and begin to rely mainly on glycolysis to produce energy. According to this theory, cancerous cells still maintain many of the features of normal cells and cannot be recognized by the body as foreign. According to the original manufacturer, Cancell/Cantron/Protocel causes cancer cells to become completely primitive, i.e., their residual aerobic metabolism is inhibited and they produce energy solely by glycolysis. The resulting primitive cells are then seen by the body as foreign and destroyed. While the aerobic metabolism of normal cells is also inhibited by Cancell/Cantron/Protocel, they are too far removed from the critical point to become cancerous or completely primitive.[1]

The second manufacturer suggested that a bacterium called Progenitor cryptocides is involved in cancer development.[1] According to this theory, P. cryptocides becomes activated in individuals whose bodies are damaged by an improper diet. Once activated, this bacterium helps cause damaged normal cells to shift their energy production from aerobic metabolism to glycolysis. When the demand for energy exceeds the damaged normal cell’s ability to produce it, the cell mutates and becomes cancerous. Once again, Cancell/Cantron/Protocel forces cancerous cells into a completely primitive state where they self-digest and are replaced by normal cells. The waste material produced by this self-digestion process is discarded by the body in a variety of ways: in urine, stool, vaginal discharge, or perspiration; it may also be vomited or coughed up.[1]

The idea that cancer cells show increased levels of glycolysis compared with normal cells is widely accepted, but this change in metabolism is not believed to be a fundamental cause of cancer development.[3–5] In addition, there is no scientific evidence that Cancell/Cantron/Protocel or any of its components can cause cells to produce energy solely by glycolysis or is able to treat cancer effectively.[1,6] Furthermore, there is no evidence to support the existence of the bacterium P. cryptocides.[7]

References

1. Questionable methods of cancer management: Cancell/Entelev. CA Cancer J Clin 43 (1): 57-62, 1993 Jan-Feb. [PUBMED Abstract]
2. Cancell Alternative Cancer Treatment. Cottonwood, Ariz: Winter Works, 2002. Available online. Last accessed April 8, 2016.
3. Mathupala SP, Rempel A, Pedersen PL: Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J Bioenerg Biomembr 29 (4): 339-43, 1997. [PUBMED Abstract]
4. Dang CV, Semenza GL: Oncogenic alterations of metabolism. Trends Biochem Sci 24 (2): 68-72, 1999. [PUBMED Abstract]
5. Dills WL: Nutritional and physiological consequences of tumour glycolysis. Parasitology 107 (Suppl): S177-86, 1993. [PUBMED Abstract]
6. Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. WW Norton & Company, 1998.
7. Unproven methods of cancer management. Livingston-Wheeler therapy. CA Cancer J Clin 41 (3): A7-12, 1991 May-Jun. [PUBMED Abstract]

In 1978 and 1980, the National Cancer Institute (NCI) tested Cancell/Cantron/Protocel in animal studies and determined that the mixture lacked substantial antitumor activity.[1]

In 1990 and 1991, samples of Cancell/Cantron/Protocel were evaluated in NCI’s in vitro NCI-60 DTP Human Tumor Cell Line Screen. In the screen, the cell lines are grown in artificial media under conditions that do not truly mimic the in vivo situation in animals or humans. The important information used in assessing a drug’s effectiveness in the NCI in vitro screen includes drug concentrations necessary to achieve the following:

The log₁₀ values for GI50, TGI, and LC50 for the 60 cell lines are available online.

The variations in log₁₀ values for GI50 are 0.4 to 1.8 (mean = 1.15), equivalent to concentrations of 2.5 to 63 μg/mL (mean = 14); the variations in log₁₀ values for TGI are 1.0 to 2.5 (mean = 1.62), equivalent to 10 to 320 μg/mL (mean = 41); and the variations in log₁₀ values for LC50 are 1.6 to 3.9 (mean = 3.17), equivalent to 39 to 7,943 μg/mL (mean = 1,479).

Cancell/Cantron/Protocel Tumor Cell Line Screen Results

Parameter Measured	60 Cell-line Range (μg/mL)	Mean (μg/mL)
50% growth inhibition (GI50)	2.5–63	14
Total growth inhibition (TGI)	10–320	41
Concentration for 50% lethality (LC50)	39–7,943	1,479
Maximum theoretical human plasma concentration (for comparison)	—	29 (calculated)

Based on the manufacturer’s recommended doses of a marketed brand of Cancell/Cantron/Protocel it has been calculated that under idealized conditions of absolutely no loss of the constituents after administration to a patient (i.e., 100% bioavailability, meaning no loss due to degradation, absorption in the body, or rapid excretion—an unlikely situation), the maximum concentration that could be achieved in the plasma of an average 154-lb male is 29 μg/mL (antilog of 1.46). Thus, under these highly idealized conditions Cancell/Cantron/Protocel may exhibit some mild inhibitory effect on the growth of some cancer cells, but it would not be expected to inhibit their growth completely or to kill them. There is little evidence that any of the constituents of Cancell/Cantron/Protocel would be available in the bloodstream of a patient.

Activity was seen in two-thirds of the cell lines, though at levels that would be roughly 275 times higher than the theoretical maximum concentration achievable in serum. Therefore, the in vitro effects are likely due to nonspecific effects of changes in salt concentration. Furthermore, cells in the NCI Tumor Cell Line Screen are grown in artificial media under conditions that do not truly mimic the in vivo situation in animals or humans, and results obtained with the screen may not accurately reflect possible effects in humans. To place the findings for Cancell/Cantron/Protocel in perspective, any conventional drug exhibiting this low level of in vitro activity in the NCI human cancer cell line screen would normally not be investigated further by NCI.

The principal manufacturers of Cancell/Cantron/Protocel have stated that they have performed numerous animal experiments with the mixture involving tens of thousands of mice.[1,2] Results of these experiments, however, have not been published in peer-reviewed scientific journals and no information beyond stating that some of the experiments tested the toxicity of Cancell/Cantron/Protocel has been provided.

References

1. Questionable methods of cancer management: Cancell/Entelev. CA Cancer J Clin 43 (1): 57-62, 1993 Jan-Feb. [PUBMED Abstract]
2. Cancell Alternative Cancer Treatment. Cottonwood, Ariz: Winter Works, 2002. Available online. Last accessed April 8, 2016.

The principal manufacturers of Cancell/Cantron/Protocel have stated that the mixture has been used by thousands of patients and that it is safe and effective in treating 50% to 80% of cancers.[1,2] The degree of effectiveness is said to vary with the type of malignancy. These findings, however, have not been published in peer-reviewed scientific journals and only testimonials and anecdotal reports have been provided. No clinical trials of Cancell/Cantron/Protocel have been reported.

References

1. Questionable methods of cancer management: Cancell/Entelev. CA Cancer J Clin 43 (1): 57-62, 1993 Jan-Feb. [PUBMED Abstract]
2. Cancell Alternative Cancer Treatment. Cottonwood, Ariz: Winter Works, 2002. Available online. Last accessed April 8, 2016.

The reported side effects of Cancell/Cantron/Protocel include temporary, moderate fatigue during the first few weeks of treatment and nausea.[1,2] One patient who exceeded the manufacturer’s dose recommendations experienced diarrhea for a few hours but was reported to be fine the next day.[2]

References

1. Questionable methods of cancer management: Cancell/Entelev. CA Cancer J Clin 43 (1): 57-62, 1993 Jan-Feb. [PUBMED Abstract]
2. Cancell Alternative Cancer Treatment. Cottonwood, Ariz: Winter Works, 2002. Available online. Last accessed April 8, 2016.

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:

No levels of evidence analysis could be performed for Cancell/Cantron/Protocel because no study of its use in humans has been published in a peer-reviewed scientific journal. 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.

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Cancell/Cantron/Protocel in the treatment of people with cancer in situ. 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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The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cancell/Cantron/Protocel. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /treatment_cam/hp/cancell-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389343]

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