Tag: General Medical Oncology & Hematology

Unique Toxicities of Immunotherapy for the Practicing Physician

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SUMMARY: Immunotherapy in cancer management includes Cancer Vaccines, Cytokine therapy, Adoptive Cell therapy and therapy with Check Point protein inhibitors such as YERVOY®, KEYTRUDA® and OPDIVO®. Toxicities related to these immunotherapeutic interventions are mediated by T cells resulting in exaggerated T cell response and potential damage to normal tissues. A brief summary of the more common adverse events associated with cancer immunotherapy, is listed below-

CANCER VACCINES

PROVENGE® (Sipuleucel-T) is an autologous, cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic Castrate Resistant (hormone-refractory) Prostate Cancer. This product is the only currently approved Cancer Vaccine and consists of autologous CD54+ cells activated with recombinant PAP/GM-CSF (Prostate Acid Phosphatase, an antigen expressed in the prostate cancer tissue, linked to immune cell activator, Granulocyte Macrophage-Colony Stimulating Factor). Vaccine therapies work by promoting type 1 or type 2 immune reactions. In type 1 immune reaction, T helper type 1 (Th1) lymphocytes secrete Interleukin-2 (IL-2), Interferon gamma, and lymphotoxin-alpha and facilitate intense phagocytic activity whereas in type 2 immunity, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and is characterized by high antibody titers. Cancer Vaccines are associated with minimal toxicities because the antigens associated with the tumor are overexpressed in the cancer cells and are not usually detectable in normal cells. Common side effects include local reactions, fever, chills, fatigue, rash, back pain and Melanoma vaccines are associated with vitiligo.

CYTOKINE THERAPY

Both INTRON® A (Interferon alfa-2b) and ROFERON® A (Interferon alfa-2a) are approved for a variety of malignant conditions as well as for Chronic Hepatitis B and C. In addition to fever, chills and flu like symptoms, two thirds of the patients have nausea and anorexia and up to 45% of the patients may experience symptoms of depression. Patients should be monitored for cytopenias, diarrhea, liver toxicities as well as thyroid dysfunction and autoimmune disorders may be exacerbated with Interferon.

PROLEUKIN® (High dose IL-2) is administered in an inpatient setting with cardiac monitoring, as patients often develop capillary leak syndrome and hypotension in addition to flu like symptoms and liver function abnormalities. This has been attributed to release of Nitric Oxide, IL-1, Tumor Necrosis Factor alpha, and IFN gamma. Patients may also develop autoimmune related thyroid dysfunction, cytopenias as well as neurotoxicity and will therefore require close monitoring.

ADOPTIVE CELL THERAPY

Unlike Cancer Vaccines, Adoptive T cell therapy is a type of passive immunization which involves the transfusion of autologous or allogeneic T cells into patients with malignancies. These tumor reactive T cells can be genetically engineered or grown ex vivo and their efficacy can be enhanced by other immunotherapies, such as Cancer Vaccines, Cytokine administration or in some instances cytotoxic chemotherapy and radiation therapy. BLINCYTO® (Blinatumomab) is a genetically engineered bispecific CD19 directed CD3 T-cell engager, approved by the FDA, that binds to CD19 (expressed on B-cells) and CD3 (expressed on T-cells). It is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL). Administration of BLINCYTO® or high dose IL-2 given along with T cells, can cause Cytokine Release Syndrome (CRS), associated with fever, tachycardia, vascular leak, oliguria, and hypotension. This has been attributed to IL-6 and ACTEMRA® (Tocilizumab), an IL-6 receptor antagonist may be of benefit for these patients along with IV fluids, nonsteroidal anti-inflammatory agents and vasopressors. Other toxicities that require monitoring include flu like symptoms, liver function abnormalities, B-cell aplasia, cytopenias and neurotoxicity.

THERAPY WITH CHECKPOINT INHIBITORS

The FDA approved checkpoint inhibitors include, YERVOY® (Ipilimumab) which targets CTLA-4, KEYTRUDA® (Pembrolizumab) and OPDIVO® (Nivolumab), which block checkpoint PD-1. The toxicities associated with YERVOY® are dose dependant. Some common side effects of check point inhibitors include skin rash, flu like symptoms, liver function abnormalities, diarrhea and colitis, cytopenias, thyroid and adrenal function abnormalities. Rare cases of pneumonitis, encephalitis, Guillain-Barré syndrome, and a myasthenia gravis–like syndrome have been reported. With close monitoring, early diagnosis and intervention with Corticosteroids, these toxicities can be alleviated. REMICADE® (Infliximab), a chimeric monoclonal antibody against Tumor Necrosis Factor alpha (TNF-alpha), should be offered to those whose colitis does not resolve within 3 days of high dose steroids or for relapse of colitis with steroid taper.

Toxicities of Immunotherapy for the Practitioner. Weber JS, Yang JC, Atkins MB, et al. J Clin Oncol 2015;33:2092-2099

VARUBI® Now Approved for Delayed Chemotherapy Induced Nausea and Vomiting

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SUMMARY: The U.S. Food and Drug Administration on September 2, 2015, approved VARUBI® (Rolapitant) to prevent delayed phase Chemotherapy Induced Nausea and Vomiting (CINV). Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems. VARUBI® is a substance P/Neurokinin-1 (NK-1) receptor antagonist.

The safety and efficacy of VARUBI® were established in three randomized, double-blind, controlled clinical trials where VARUBI® in combination with KYTRIL® (Granisetron) and Dexamethasone was compared with placebo, KYTRIL® and Dexamethasone (control therapy), in more than 2500 patients receiving a moderately or highly emetic chemotherapy regimen. HEC Study 1 and HEC Study 2 included Cisplatin Based Highly Emetogenic Chemotherapy (HEC). Chemotherapy regimens included more than 60 mg/m2 of Cisplatin. In HEC Study 1, 532 patients were randomized to receive either antiemetic regimen with VARUBI® (N =266) or control therapy (N =266). In HEC Study 2, a total of 555 patients were randomized to receive either antiemetic regimen with VARUBI® (N =278) or control therapy (N =277). MEC Study 3 included Moderately Emetogenic Chemotherapy and combinations of Anthracycline and Cyclophosphamide chemotherapy. A total of 1369 patients were randomized in this study to receive either antiemetic regimen with VARUBI® (N =684) or control therapy (N =685). Patients in these trials received either VARUBI® 180 mg PO or placebo at 1 to 2 hours before administration of Highly Emetogenic Chemotherapy. All patients received intravenous KYTRIL® 10 μg/kg IV and Dexamethasone 20 mg PO on day 1 and Dexamethasone 8 mg PO twice daily on days 2 to 4 for up to six cycles, with each cycle lasting a minimum of 14 days. The primary endpoint in all three studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) post chemotherapy.

It was noted that a significantly greater proportion of patients receiving antiemetic regimen with VARUBI® had complete responses in the delayed phase than did patients in the control therapy group – HEC Study 1: 72.7% vs 58.4% (P<0.001), HEC Study 2: 70.1% vs 61.9% (P=0.043) and MEC Study 3: 71.3% vs 61.6% (P<0.001). The most common adverse events in patients treated with VARUBI® included neutropenia, hiccups, decreased appetite and dizziness. It was concluded from these three trials that VARUBI® when combined with a 5-HT3 receptor antagonist such as KYTRIL® and a corticosteroid, significantly prevented delayed Chemotherapy Induced Nausea and Vomiting.

1) Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Rapoport BL, Chasen MR, Gridelli C, et al. The Lancet Oncology 2015;16:1079-1089

2) Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC). Schnadig ID, Modiano MR, Poma A, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 9633)

Hepatitis B Antiviral Prophylaxis for Cancer Patients with Solid Tumors Receiving Chemotherapy

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SUMMARY: The Centers for Disease Control and Prevention (CDC) estimates that there are 800,000 -1.4 million individuals with Chronic Hepatitis B (HBV) infection in the United States. Reactivation of HBV is a major concern in cancer patients who may be on chemotherapy or other immunosuppressive therapies, with the incidence of HBV reactivation ranging from 40%-60% in those who are positive for Hepatitis B surface antigen (HBsAg). HBV reactivation is preventable with prophylactic antiviral therapy, failing which it can result in delays in cancer treatment, as well as potentially fatal outcomes. Based on recently published data, showing the high risk for HBV reactivation among patients with hematological malignancies receiving B-cell-depleting agents such as RITUXAN® (Rituximab) or ARZERRA® (Ofatumumab), the FDA has urged health care providers to screen all patients for HBV infection, prior to starting therapy with these agents. HBV reactivation has been observed following chemotherapy for solid tumors, but the risk for reactivation in these settings has been unclear with insufficient evidence. The American Society of Clinical Oncology in 2010 rendered a Provisional Clinical Opinion (PCO), suggesting that there was insufficient evidence to determine the net benefits and harms of routine screening for HBV infection, in patients receiving chemotherapy and the recommendation was that screening be considered in those at increased risk for HBV infection or who receive highly immunosuppressive regimens.

This present study was conducted to determine the risk for HBV reactivation with and without antiviral prophylaxis and the benefit of prophylaxis in adults with solid tumors and chronic or resolved HBV infection. This meta-analysis included 26 original reports and the studies were independently reviewed by two investigators for study inclusion. HBV patients included in this study were receiving chemotherapy for any solid tumor with or without concomitant HBV prophylactic therapy. Study patients could receive long-term antiviral treatment or prophylaxis before chemotherapy initiation and the comparison was with those receiving chemotherapy without antiviral prophylaxis. The primary outcome was HBV reactivation as defined by a greater than 10-fold increase in HBV DNA levels from baseline or an absolute increase greater than 105 copies/mL in those with chronic HBV infection or the re-emergence of HBsAg when previously negative, in those with resolved HBV infection. Secondary outcomes included HBV-related hepatitis, interruption or delay in chemotherapy, acute liver failure with coagulopathy and hepatic encephalopathy and death.

It was noted that in patients with chronic HBV infection receiving chemotherapy, the risk for HBV reactivation without antiviral prophylaxis ranged from 4% to 68% (median, 25%). The risk for HBV reactivation, HBV-related hepatitis, and chemotherapy interruption was reduced by more than 80% with antiviral prophylaxis. Interestingly, in patients with resolved HBV infection receiving chemotherapy, there was still a risk of HBV reactivation, with this risk ranging from 0.3% to 9%. The authors in this meta-analysis addressed a very important question and concluded that the risk for HBV reactivation in patients with chronic HBV, on chemotherapy for solid tumors, is similar to the risk with other types of immunosuppressive therapy. Cancer patients should therefore be screened for HBV before chemotherapy is initiated for solid tumors and started on antiviral prophylaxis. Paul S, Saxena A, Terrin N, et al. Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016; 164:30-40.

The 2015 ASH CHOOSING WISELY® Campaign Five Hematologic Tests and Treatments to Question

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SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that, reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged 70 medical societies to identify 5 tests, procedures or treatments, within each specialty’s clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care without harming the patient. The ASH CHOOSING WISELY® Task Force comprised of 13 individuals, represents a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2015 ASH Choosing Wisely Campaign is an addition to the 10 prior recommendations made by ASH over the past 2 years. These top 5 recommendations were presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

Don’t image for suspected Pulmonary Embolism (PE) without moderate or high pre-test probability of PE

The American College of Radiology has recommended that assessment of the risk-benefit ratio is important especially with pulmonary embolism and imaging can be avoided for suspected PE, without moderate to high pre-test probability.

Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation

With Nearly 15% couples of patients receiving an infertility evaluation, the American Society for Reproductive Medicine has recommended that even though several population-based studies have found association of infertility or failure of assisted reproduction with thrombophilia, 2 large cohort studies have shown no association between thrombophilias such as Factor V Leiden or Prothrombin gene mutations and assisted reproduction failure or infertility. Further, thrombophilia is not a predictor of who will benefit from Low Molecular Weight Heparin (LMWH) treatment with respect to assisted reproduction and LMWH can be associated with adverse events.

Don’t perform repetitive Complete Blood Count (CBC) and chemistry testing in the face of clinical and lab stability

The Society for Hospital Medicine and Adult Hospital Medicine noted that ordering routine complete blood counts (CBCs) during hospitalization is common practice and is unnecessary. Critically ill patients do not have the bone marrow reserve or erythropoietin stimulus to compensate for iatrogenic blood loss. Reducing the frequency of CBC’s does not result in inferior outcomes and several studies have shown that there is no difference in readmission rates, length of hospital stay and rates of adverse events. In addition to the risks of phlebotomy, this practice is economically disadvantageous, as they may not be reimbursable and will be an additional avoidable cost to dispose the biohazard waste of the blood samples.

Don’t transfuse red blood cells for iron deficiency without hemodynamic instability

The American Association of Blood Banks has recommended against PRBC transfusions for patients with hemodynamically stable iron deficiency anemia. These patients when evaluated in the Emergency Department (ED) can be prescribed oral or IV iron with similar responses noted at 6-8 weeks. The compliance rate in those receiving oral iron may only be 50% due to GI side effects. Therefore parenteral iron may be a better treatment option for certain groups of patients seen in the ED.

Avoid using positron emission tomography (PET) or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome

Professional organizations like ASCO, ESMO and NCCN do not include surveillance PET in disease-specific guidelines because, routine use of intensive surveillance does not improve survival or enhance quality of life. Besides cost implications, CT scans may in fact expose patients to small doses of radiation.

The ASH Choosing Wisely® Campaign: Top 5 Non-ASH Choosing Wisely® Recommendations of Relevance to Hematology. Presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida.

ZOMETA® Administered Every 12 Weeks Is Non-inferior to Every 4 Weeks for Bone Metastases

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SUMMARY: Bones are the third most common site of metastatic disease and approximately 100,000 cases of bone metastasis are reported in the United States each year. Cancers originating in the breast, prostate, lung, thyroid and kidney, are more likely to metastasize to the bone. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. Amino-bisphosphonate, ZOMETA® has however largely replaced AREDIA®, because of its superior efficacy. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks during the first year, following diagnoses of bone metastases. However, the optimal treatment schedule following this initial phase of treatment has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential problems with bisphosphonate use.

CALGB 70604 (Alliance), is a randomized phase III study in which the efficacy of ZOMETA® administered every 4 weeks was compared with ZOMETA® administered every 12 weeks, in patients with breast cancer, prostate cancer or multiple myeloma, with bone metastases. In this non-inferiority trial, 1822 patients (Breast = 833, Prostate = 674, Myeloma= 270 and Other= 45) were randomly assigned 1:1, to receive ZOMETA® every 4 weeks or every 12 weeks for 2 years. The primary endpoint was incidence of any Skeletal Related Event (SRE) and secondary endpoints included skeletal morbidity rates, performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease was pre-planned. It was noted that for the primary endpoint, there was no significant difference between the two treatment groups with 29% of patients in both treatment groups experiencing at least one SRE (P=0.79). With regards to secondary endpoints, there were still no significant differences between the two treatment groups, including renal dysfunction and ONJ. The authors pointed out that toxicities such as ONJ and renal dysfunction are more likely to occur after 2 years of treatment.

It was concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA® administered every 4 weeks for 2 years, in patients with breast cancer, prostate cancer and multiple myeloma, with bone metastases. A less frequent dosing of ZOMETA® compared with the standard monthly dosing, may be more convenient for the patients and cost effective. CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer. Himelstein AL, Qin R, Novotny PJ, et al. J Clin Oncol 33, 2015 (suppl; abstr 9501)

FDA Approves First Biosimilar Product ZARXIO® – A Primer on Biosimilars

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SUMMARY: The U.S. FDA on March 6, 2015 approved ZARXIO® (Filgrastim-sndz), the first biosimilar product approved in the United States. A biosimilar product is a biological product that is approved based on its high similarity to an already approved biological product (also known as reference product). Biological products are made from living organisms including humans, animals and microorganisms such as bacteria or yeast and are manufactured through biotechnology, derived from natural sources or produced synthetically. Biological products have larger molecules with a complex structure than conventional drugs (also known as small molecule drugs). Unlike biological products, conventional drugs are made of pure chemical substances and their structures can be identified. A generic drug is a copy of brand name drug and has the same active ingredient and is the same as brand name drug in dosage form, safety and strength, route of administration, quality, performance characteristics and intended use. Therefore, brand name and the generic drugs are bioequivalent.

The Affordable Care Act in 2010 created an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to, or “interchangeable” with an FDA-licensed (FDA approved) biological product (reference product). The biosimilar must show that it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. A biosimilar product can only be approved by the FDA if it has the same mechanism of action, route of administration, dosage form and strength as the reference product, and only for the indications and conditions of use that have been approved for the reference product. Biosimilars are not as easy to manufacture as generics (copies of brand name drugs) because of the complexity of the structure of the biologic product and the process used to make a biologic product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

The FDA’s approval of ZARXIO® was based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data, that demonstrated ZARXIO® was biosimilar to NEUPOGEN®. ZARXIO® was approved as a biosimilar and not as an interchangeable product (Can only be substituted for the reference product after approval by the prescribing Health Care Provider). ZARXIO® is approved for the same indications as NEUPOGEN® and these indications include

• Patients with cancer receiving myelosuppressive chemotherapy

• Patients with Acute Myeloid Leukemia receiving induction or consolidation chemotherapy

• Patients with cancer undergoing Bone Marrow Transplantation

• Patients undergoing Autologous peripheral blood progenitor cell collection and therapy

• Patients with severe Chronic Neutropenia.

The most common expected side effects of ZARXIO® are bone and muscle aches, redness, swelling or itching at injection site. Less common, serious side effects include spleen rupture and serious allergic reactions. Unlike ZARXIO® which was approved via an abbreviated licensure pathway for biosimilars, GRANIX® (tbo-Filgrastim) was approved via the full Biologic License Application pathway, which presently limits GRANIX® use only for reducing the duration of severe neutropenia in patients non-myeloid malignancies, receiving myelosuppressive chemotherapy. The present Medicare reimbursement rules will be more favorable to ZARXIO® compared to GRANIX®, based on their approval process. FDA approves first biosimilar product ZARXIO®. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm

Fish Oil and Certain Species of Fish May Negate the Effects of Chemotherapy

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SUMMARY: It is estimated that approximately 20% of cancer patients in the US take Omega-3 fatty acids in the form of fish oil. Fish oil is a mixture of fatty acids produced from several species of fish and the two most abundant and important fatty acids in fish oil include EicosaPentaenoic Acid (EPA) and DocosaHexaenoic Acid (DHA). Fish oil content in presently available preparations is not standardized and does not require FDA approval. Preclinical studies have demonstrated that mouse tumors recruit mesenchymal stem cells that are specifically activated by platinum based chemotherapy and secrete 2 fatty acids, 12S-HHT and 16:4(n-3)). These fatty acids are called Platinum Induced Fatty Acids (PIFAs) and they have been shown to induce resistance to a broad range of chemotherapeutic agents, by activating a cytoprotective response in the tumor tissue. Fish oil has relevant levels of fatty acid 16:4(n-3) and preclinical models have shown that the fish oil neutralized the antitumor activity of chemotherapy, thus conferring drug resistance. With this preclinical information and given that cancer patients frequently use fish oil supplements, the authors evaluated the effect of fish oil intake in healthy volunteers, on the plasma levels of fatty acid 16:4(n-3), which has been shown to induce resistance to chemotherapeutic agents. The researchers first conducted a survey to determine what percentage of cancer patients undergoing treatment at a University Medical Center in the Netherlands were taking fish oil supplements. They also analyzed fatty acid 16:4(n-3) content, in 3 brands of fish oil supplements and 4 often consumed species of fish. The authors then randomly selected 30 healthy volunteers for the fish oil study and 20 healthy volunteers for the fish consumption study and the plasma levels of fatty acid 16:4(n-3) was measured after they consumed fish oil or fish, for a period of 2 weeks. They noted that 11% of the cancer patients in their study reported using omega-3 supplements. All fish oils tested contained amounts of fatty acid 16:4(n-3) ranging from 0.2 to 5.7 μM and this was adequate to induce chemoresistance to a variety of chemotherapeutic agents. They noted that there was a significant rise in the plasma 16:4(n-3) fatty acid levels in the healthy volunteers after they consumed fish oil supplements and fish, with high levels of fatty acid 16:4(n-3). Herring and Mackerel fish contained high levels of fatty acid 16:4(n-3), in contrast to Salmon and Tuna. The authors concluded that based on this preclinical data it is best to avoid fish oils and fish such as Herring and Mackerel in the 48 hours surrounding chemotherapy, as the high plasma 16:4(n-3) fatty acid levels may negate the effects of chemotherapy. These recommendations have been adopted by the Dutch Cancer Society and by the Dutch National Working Group for Oncologic Dieticians. Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil. Daenen LGM, Cirkel GA, Houthuijzen JM, et al. JAMA Oncol. 2015;1:350-358

Late Breaking Abstract – ASCO 2015 Adjuvant Whole Brain Radiation Therapy Not Recommended After Stereotactic RadioSurgery

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SUMMARY: Brain metastases from an extracranial primary, occur in approximately 15% of cancer patients and this is estimated to be about 400,000 to 600,000 patients annually. The incidence of brain metastases has been on the rise with the availability of more effective systemic therapies and better control of systemic disease. The most frequent malignancies associated with brain metastases include Lung cancer, Breast cancer and Melanoma. Majority of the patients with brain metastases have synchronous extracerebral metastases. A significant number of patients present with solitary or fewer than 3 brain metastases and they may be amenable to focal therapeutic interventions. However, Whole Brain Radiation Therapy (WBRT) has been the standard treatment strategy since the 1950’s. It is also well recognized that WBRT can be associated with neurocognitive dysfunction. Stereotactic RadioSurgery (SRS) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional radiation therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SRS include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator and CYBER KNIFE® which use Photons, to target the tumor tissue.

NCCTG N0574 is a federally funded, randomized phase III clinical trial, designed to determine whether cognitive deterioration occurred less frequently with SRS alone compared to SRS followed by WBRT, in patients with 1-3 brain metastases. In this study, 213 patients with 1-3 brain metastases, each measuring less than 3 cm by contrast MRI, were enrolled and randomized to SRS alone or SRS plus WBRT. All patients underwent cognitive testing before and after treatment. Sixty eight percent (68%) of the enrolled patients had a Lung primary and the median age was 60 years. Baseline characteristics were similar in both treatment groups. The median follow up was 7.2 months. The authors used several tools to assess cognitive dysfunction and the primary endpoint was the cognitive decline at 3 months following treatment. It was noted that at 3 months, with the addition of WBRT to SRS, 91.7% of patients experienced cognitive decline compared with 63.5% for those receiving SRS alone (P=0.0007) and there was statistically significant decline in immediate recall, delayed recall and verbal fluency, in the SRS plus WBRT group. Patients who received SRS plus WBRT also reported significantly worse Quality of Life. There was however better intracranial tumor control at 6 and 12 months with SRS plus WBRT compared to SRS alone (P< 0.001), but this local control had no significant impact on the median Overall Survival (OS), with similar OS outcomes noted in both treatment groups (P=0.93). The authors concluded that the addition of WBRT to SRS can result in significant decline in neurocognitive function, without any Overall Survival benefit, compared to SRS alone. It is therefore recommended that patients with newly diagnosed brain metastases amenable to SRS, be closely monitored after SRS, with consideration given to WBRT, at the time of symptomatic progression. NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Brown PD, Asher AL, Ballman KV, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA4)

Higher Risk of Fractures in Hematopoietic Stem Cell Transplant Recipients

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SUMMARY: According to the CIBMTR (Center for International Blood and Marrow Transplant Research), in 2012, over 11,000 Hematopoietic Stem Cell Transplants (HSCT) in the US were Autologous and over 7500 were Allogeneic. Multiple myeloma and Lymphoma accounted for 57% of all HSCTs and AML and Myelodysplasia accounted for 51% of Allogeneic HSCTs. There has been an increase in the number of Autologous and Allogeneic transplants for treatment of malignant diseases in elderly patients, with 39% of Autologous transplant recipients and 17% of Allogeneic transplant recipients between 2006-2012 reported to be older than 60 years of age. With increase in the number of long term survivors following transplantation, early and late complications of HSCT have been the focus of increasing attention. Morbidity and mortality as well as quality of life related to bone loss among long term survivors after HSCT, has been previously published. Factors contributing to bone loss in this patient population include intensive chemotherapy, total body irradiation, post-transplantation glucocorticoid use, reduced intake and metabolism of Calcium and Vitamin D, graft versus host disease, use of Cyclosporine-A and sedentary lifestyle after transplantation. Loss of Bone Mineral Density (BMD) occurs within 6 to 12 months after transplantation at all skeletal sites, followed by initial recovery of BMD in the lumbar spine and a slower recovery of BMD in the femur neck. This bone loss may persist for 48 to 120 months or even longer. The authors in this single institution, retrospective study, calculated the cumulative incidence rates of fractures among survivors of Autologous and Allogeneic Hematopoietic Stem Cell Transplantations (HSCT) and compared the rate of fractures to that of the general US population. Data was collected from 7,620 patients over 18 years of age who underwent HSCT at The University of Texas MD Anderson Cancer Center, from January 1997 to December 2011 and these patients were observed through December 2013. The authors then calculated the cumulative incidence of fractures, with death as a competing risk and the age and sex-specific fracture incidence rates were compared with those in the US general population, using estimated rates from the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey. Of the 7,620 patients who underwent HSCT, 56% were male and 51% underwent Autologous and 49% underwent Allogeneic stem cell transplantation. The most common reasons for HSCT were hematologic malignancies other than Multiple Myeloma (67%), Multiple Myeloma (22%) and other solid tumors (11%). The median follow up was 85 months. Fractures occurred in 8% of patients (N = 602) of whom 419 patients had an Autologous stem cell transplantation and 183 patients had Allogeneic stem cell transplantation. The incidence of fracture was higher in patients older than age 50 years, 5 times higher among patients with Multiple Myeloma compared to other hematologic malignancies and patients who underwent Autologous transplantation were 45% more likely to develop a fracture than those who underwent an Allogeneic transplantation. When age- and sex-specific fracture incidence rates after HSCT were compared with National Health Interview Survey data, females were at approximately 8 times greater risk and men 45-64 years old were at approximately 7-9 times greater risk of sustaining a fracture. The authors concluded that the incidence of fractures after HSCT is significantly higher and all patients undergoing HSCT should be considered to be at risk for post-transplantation bone loss. Measures to prevent bone loss and fractures include physical exercise, Vitamin D and Calcium supplementation, avoiding tobacco products, abstaining from excess alcohol intake and fall prevention. The authors recommend that patients undergoing HSCT should have a Dual Energy X-ray Absorptiometry scan performed at baseline and at 6 months following transplantation. Increased Incidence of Fractures in Recipients of Hematopoietic Stem-Cell Transplantation. Pundole XN, Barbo AG, Lin H, et al. J Clin Oncol 2015; 33:1364-1370

E-Cigarettes – A Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology

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SUMMARY: According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer. E-cigarettes or Electronic Nicotine Delivery Systems (ENDS) were first developed in China and introduced to the U.S. market in 2007. When a smoker inhales through the mouth piece of an E-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the E-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world's leading lung organizations were compelled to release a position statement on electronic cigarettes, specifically focusing on their potential adverse effects on human health and calling on government organizations to ban or restrict the use of E-cigarettes, until their impact on health is better understood. According to the National Youth Tobacco Survey, the use of e-cigarettes has tripled from 2013 to 2014 among middle school and high school students. Epidemiological data have shown that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction. E-cigarettes and other Electronic Nicotine Delivery Systems (ENDS), unlike combustible cigarettes and many other tobacco products are not currently regulated by the U.S. Food and Drug Administration.

The American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO) have therefore made the following recommendations in a joint statement to guide policymakers and have encouraged oncology health care providers, to recommend FDA-approved cessation medications instead of e-cigarettes, to individuals who are interested or trying to quit smoking combustible cigarettes.

1) The FDA Center for Tobacco Products should regulate all ENDS as well as e-liquids containing tobacco-derived nicotine whether they are sold together or separately. ENDS products such as synthetic nicotine that do not meet the statutory definition of tobacco products, should then be regulated by the FDA through other appropriate authorities.

2) Manufacturers of ENDS should be required to register with the FDA and report nicotine concentration and all product and ingredient listings.

3) In the interest of public health, the FDA should exercise its regulatory authority to require safety labels and health warning regarding nicotine addiction.

4) The FDA should restrict all youth oriented marketing of ENDS, to prevent youth from initiating use of ENDS products.

5) The age and identification of customers should be checked by the Internet and mail-order sales agencies of ENDS, at the point of purchase and delivery.

6) ENDS use should be prohibited in places where combustible tobacco product use is prohibited by federal, state, or local law, until the safety of secondhand aerosol exposure is established.

7) All e-liquid containers should be required to have childproof caps.

8) ENDS and liquids containing candy and other youth friendly flavors should be prohibited, unless there is evidence demonstrating these products do not encourage youth uptake.

9) Funding generated through tobacco product taxes, including any potential taxes levied on ENDS, should be used to help support research on ENDS and other tobacco related products, and should not preclude the allocation of federal funding for this research.

10) All information related to ENDS composition, use, and health effects should be disclosed, to enhance policy decisions for ENDS product regulation.

11) In the absence of federal ENDS regulation, state and local governments should implement related regulations to protect public health, including restricting the sale, distribution, marketing, and advertising of electronic nicotine delivery systems to youth.

Electronic Nicotine Delivery Systems: A Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology. Brandon TH, Goniewicz ML, Hanna NH, et al. Clin Cancer Res 2015; 21:1-12