Author: RR

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

RR

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

Splanchnic Venous Thrombosis is a Marker of Cancer and a Prognostic Factor for Cancer Survival

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. VTE is the third leading cause of cardiovascular mortality. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the following 12 months compared to the general population. It is however unknown if Splanchnic Venous Thrombosis (splanchnic veins carry blood through the liver and other abdominal organs) is a marker of occult cancer and a prognostic factor for cancer survival.

To address this question the authors from Denmark conducted a nationwide cohort study using Danish medical registries and included 1,191 patients with first time Splanchnic Venous Thrombosis (SVT) between 1994 and 2011, and followed them for subsequent cancer diagnosis, for a median of 1.6 years. They compared these results with the expected cancer risk in the general population. Additionally, to evaluate the impact of SVT on survival in those patients with cancer, the researchers compared survival in these cancer patients with a matched cohort of cancer patients without SVT. In the cohort of 1,191 patients with first time Splanchnic Venous Thrombosis (SVT), 183 patients were later diagnosed with cancer, of whom, 95 patients were diagnosed within 3 months of their SVT diagnosis. When compared to the general population, individuals diagnosed with SVT were 33 times more likely to be diagnosed with cancer within 3 months and their 3 month risk of developing cancer was 8%. The increased risk was for liver cancer, pancreatic cancer and myeloproliferative neoplasms and there was a continued twofold increase after one or more years of follow up. It was noted that Splanchnic Venous Thrombosis was also a poor prognostic factor for survival, in patients with liver and pancreatic cancer. The authors concluded that Splanchnic Venous Thrombosis (SVT) is a marker of occult malignancy, particularly liver cancer, pancreatic cancer and myeloproliferative neoplasms and SVT diagnosed in patients with liver or pancreatic cancer remains a poor prognostic factor. Therefore, patients presenting with Splanchnic Venous Thrombosis may require a more thorough diagnostic evaluation. Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival. Søgaard KK, Farkas DK, Pedersen L, et al. Blood, June 2015 DOI: 10.1182/blood-2015-03-631119

Modified GEMZAR® and ABRAXANE® Combination May Preserve Efficacy with Less Toxicity in Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2015, close to 49,000 people will be diagnosed with pancreatic cancer in the United States and over 40,000 people will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The benefit of a combination of GEMZAR® (Gemcitabine) and ABRAXANE® (nab-Paclitaxel regimen in first line treatment for metastatic pancreatic cancer was established following a open-label, randomized, phase III trial (MPACT trial) in which 861 patients with metastatic pancreatic cancer were randomized to receive either a combination of GEMZAR® and ABRAXANE® (n=431) or GEMZAR® alone (n=430). The treatment regimen consisted of GEMZAR® at 1000 mg/m2 IV and ABRAXANE® 125 mg/m2 IV, both administered on days 1, 8, and 15 of a 28 day cycle. There was a statistically significant prolongation of Overall Survival (OS) for patients in the combination group with a 28% reduction in the risk of death [HR= 0.72; P < 0.0001]. The median OS was 8.5 months in the combination group and 6.7 months in the single agent GEMZAR® group and the Progression Free Survival (PFS) in the combination group versus the single agent group was 5.5 months versus 3.7 months, respectively (HR= 0.69; P < 0.0001). In this study however, only 71% of the ABRAXANE® doses and 63% of the GEMZAR® doses were full doses, due to associated toxicities and 17% of the patients had grade 3 or 4 neuropathy.

To circumvent this toxicity, the authors at their institution adopted a modified regimen of GEMZAR® and ABRAXANE® for a similar patient population and the regimen consisted of GEMZAR® 1000 mg/m2 IV and ABRAXANE® 125 mg/m2 IV, both administered on days 1 and 15 of a 28 day cycle. They conducted a retrospective analysis of a prospectively maintained database of 69 patients treated with this modified regimen. A total of 47 patients were evaluable for responses and 63 patients were evaluable for toxicities. The median Progression Free Survival was 4.8 months and median Overall Survival was 11.1 months with the modified regimen. More importantly, the rate of grade 3 or 4 neuropathy was less than 2%. The rate of grade 3 or 4 neutropenia was 10%, and growth factor support was required in only 8% of the patients, compared with 26% for those in the MPACT trial. The authors concluded that a less intense biweekly regimen of GEMZAR® and ABRAXANE® preserves efficacy with significantly less toxicity as well as cost savings and should be a consideration, in the first line treatment of patients with metastatic pancreatic cancer. This study received a Merit Award at the 2015 Gastrointestinal Cancers Symposium. Modified gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer (MPC): A single-institution experience. Krishna K, Blazer MA, Wei L, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 366)

Late Breaking Abstract-ASCO 2015 Treating Cancer Based on Genomics Regardless of Tumor Type

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SUMMARY: KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti–PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic respons

The FDA approves IRESSA® for metastatic Non Small Cell Lung Cancer

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SUMMARY: The FDA on July 13, 2015 approved IRESSA® (Gefitinib) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA approved test. IRESSA was approved concurrently with a labeling expansion of the therascreen EGFR RGQ PCR Kit, a companion diagnostic test, for patient selection. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in NSCLC. In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced Non Small Cell Lung Cancer (NSCLC) patients, with Adenocarcinoma histology, and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), has changed the treatment paradigm, in favor of targeted therapy, for this patient subset. GILOTRIF® is an irreversible blocker of the ErbB family, which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. It is estimated that approximately 10% of Western patient population and 50% of Asian patients with NSCLC, harbor EGFR activating mutations. IRESSA® is an oral, EGFR Tyrosine Kinase Inhibitor (TKI), which works by blocking the activity of the EGFR tyrosine kinase enzyme responsible for regulating signaling pathways, implicated in the growth and survival of cancer cells. IRESSA® was granted Orphan Drug Designation by the FDA in August 2014 for the treatment of EGFR mutation positive NSCLC.

The approval of IRESSA® was based on the results of a Phase IV, single-arm, multicenter, open-label clinical study (IRESSA Follow-Up Measure or IFUM study) which included 106 treatment naïve-patients with metastatic EGFR mutation positive NSCLC who received IRESSA® 250mg PO daily. Treatment was given until disease progression or intolerable toxicity. Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS) and safety/tolerability. At the time of data cutoff, the investigator determined ORR was 70%, Duration of Response was 8.3 months, Disease Control Rate was 90.6%, median PFS was 9.7 months and median OS was19.2 months. This efficacy data was further supported by the IRESSA Pan-ASia Study (IPASS), a randomized phase III trial, which enrolled 1,217 treatment naïve advanced NSCLC patients with adenocarcinoma histology. Patients were randomized (1:1) to receive IRESSA® 250 mg PO daily or up to 6 cycles of combination chemotherapy with Carboplatin and Paclitaxel. The efficacy outcomes included Progression Free Survival (PFS) and Objective Response Rate (ORR). An exploratory analysis of a subset of 186 of 1217 patients (15%), who were determined to be EGFR mutation positive, had imaging studies available for evaluation (IRESSA® treated patients=88 and Carboplatin/Paclitaxel treated patients=98). The median PFS in the IRESSA® treated group was 10.9 months compared to 7.4 months for the Carboplatin/Paclitaxel treated patients (HR=0.54). The ORR was 67% with a Duration of Response (DoR) of 9.6 months for IRESSA® treated patients versus 41%, with a DoR of 5.5 months for Carboplatin/Paclitaxel treated patients. The most commonly reported adverse events for IRESSA® were diarrhea and skin toxicities including rash, acne, dry skin and pruritus. It was concluded that EGFR mutations are the strongest predictive biomarker for Progression Free Survival and tumor response to first line treatment with IRESSA®. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Douillard J-Y, Ostoros G, Cobo M, et al. Br J Cancer. 2014;110:55–62

GILOTRIF® Superior to TARCEVA® in Squamous Cell Carcinoma of the Lung

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with squamous cell histology have been a traditionally hard- to-treat patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer. Some of the advanced NSCLC tumors are dependent on the Epidermal Growth Factor Receptor (EGFR) for cell proliferation and survival, regardless of EGFR mutation status. TARCEVA® (Erlotinib) is a reversible EGFR Tyrosine Kinase Inhibitor and is presently approved by the FDA for the treatment of locally advanced or metastatic NSCLC, after failure of at least one prior chemotherapy regimen. GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. This kinase inhibitor is indicated for the first line treatment of patients with metastatic NSCLC, whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

The LUX-Lung 8 is a phase III trial in which 795 patients with Stage IIIB/IV Squamous Cell Carcinoma of the lung who had progressed on first line platinum based doublet therapy, were randomized 1:1 to receive GILOTRIF 40 mg PO daily (N=398) or TARCEVA 150 mg PO daily (N=397). Treatment was given until disease progression. The median age was 65 years. Majority of the patients were male, caucasian and ex-smokers. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), patient reported outcomes and safety. The Primary endpoint of Progression Free Survival (PFS) was met and reported in 2014 and favored GILOTRIF® over TARCEVA®. The authors in this analysis reported the Overall Survival data, as well as updated data on Progression Free Survival and other Secondary endpoints. The median Overall Survival was 7.9 months with GILOTRIF® and 6.8 months with TARCEVA® (HR=0.81; P=0.008). This meant a 19% reduction in the risk of death with GILOTRIF® when compared to TARCEVA® and this survival advantage was consistent across all time points. The updated median Progression Free Survival for GILOTRIF® was 2.6 months vs 1.9 months for TARCEVA® (HR=0.81; P=0.01). The Disease Control Rate was 50.5% for GILOTRIF® and 39.5% with TARCEVA® (P=0.002). Based on patient reported outcomes, symptoms including cough and dyspnea were better with GILOTRIF® compared to TARCEVA®. Incidence of severe adverse events was similar with both therapies, with patients on GILOTRIF® experiencing more grade 3 diarrhea and stomatitis and patients receiving TARCEVA® experiencing more grade 3 rash. The authors concluded that GILOTRIF® should be the TKI of choice in the second line treatment of patients with Squamous Cell Carcinoma of the lung, as it significantly improves Overall Survival, Progression Free Survival, Disease Control Rate and symptom control, with manageable toxicities, when compared to TARCEVA®. Afatinib (A) vs erlotinib (E) as second-line therapy of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following platinum-based chemotherapy: Overall survival (OS) analysis from the global phase III trial LUX-Lung 8 (LL8). Soria J, Felip E, Cobo M, et al. J Clin Oncol 33, 2015 (suppl; abstr 8002)

Choosing Appropriate Therapy in Chronic Myeloid Leukemia

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SUMMARY: Chronic Myeloid Leukemia (CML) constitutes approximately 10% of all new cases of leukemia. The American Cancer Society estimates that 6,660 new CML cases will be diagnosed in the United States in 2015 and about 1,140 people will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Gleevec® (Imatinib) inhibits the BCR-ABL tyrosine kinase and is the standard first line treatment, of Ph chromosome positive (Ph+) leukemias. Lack of response due to resistance to GLEEVEC® and in some instances drug intolerance, has led to the development of newer agents including Second and Third generation Tyrosine Kinase Inhibitors (TKIs). Resistance to Gleevec® and other TKIs sharing the same therapeutic target (BCR-ABL kinase), has been attributed to point mutations in the ABL kinase domain, amplification of the BCR-ABL gene as well as other BCR- ABL independent mechanisms such as upregulation of SRC kinases. Mutation analysis at the time of TKI failure, utilizing high sensitivity sequencing techniques such as Next Generation Sequencing, can give clinically relevant information related to low level mutations and compound mutations and this information in turn, can dictate choice of second line therapy. The Second generation TKIs, TASIGNA® (Nilotinib) and SPRYCEL® (Dasatinib) although initially approved for second line treatment of CML after GLEEVEC® resistance or intolerance, are now FDA approved for the treatment of newly diagnosed Chronic Phase CML. This approval was based on the rapid and superior Major Molecular Responses (MMR) noted, when compared to GLEEVEC®. Now, that the Second generation TKIs are being used as first line therapy, the choice of second line therapy after failure with Second generation TKIs has become more nebulous. It is clear however that, patients with primary cytogenetic resistance to first and second line therapy do not benefit from sequential therapy with Second generation TKIs and BCR-ABL mutation analysis should be performed in all patients who develop TKI resistant disease. Before switching from a Second to a Third generation TKI such as Ponatinib, the following considerations should be taken into account

BCR-ABL Mutations and Sensitivity to Second Generation TKIs

1) Patients with F317L/V/I/C mutations are more sensitive to TASIGNA® (Nilotinib) or BOSULIF® (Bosutinib) than to SPRYEL® (Dasatinib)

2) Patients with V299L mutation are more sensitive to TASIGNA® than to BOSULIF® or SPRYCEL®

3) Patients with Y253F/H, E255K/V, and F359V/I/C mutations are more sensitive to SPRYCEL® or BOSULIF® than to TASIGNA®

Tolerability of Second Generation TKIs

1) Patients who experience pleural effusion during SPRYCEL® treatment might better tolerate TASIGNA® or BOSULIF®

2) Patients who experience rash during treatment with TASIGNA® or BOSULIF® could be switched to SPRYCEL®

3) Some toxicities common with other TKIs such as pleural effusion and cardiac toxicity are less common with BOSULIF® and this agent also has activity against many BCR-ABL kinase domain mutations resistant to GLEEVEC®, SPRYCEL® and TASIGNA®, with the exception of T315I mutation.

It should be noted that Second generation TKI as third line therapy has limited value in majority of the patients with CML. ICLUSIG® (Ponatinib) is a Third generation kinase inhibitor approved for the treatment of patients with T315I positive CML or T315I-positive Philadelphia Chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL) and for whom no other TKI is indicated. Other treatment options include SYNRIBO® (Omacetaxine Mepesuccinate), a first-in-class Cephalotaxine and a semi synthetic purified Homoharringtonine (HHT) compound. Unlike Tyrosine Kinase Inhibitors , SYNRIBO® is a protein synthesis inhibitor and reduces the levels of multiple Oncoproteins including BCR-ABL, BCL-2, MCL-1 and promotes apoptosis of leukemic stem cells. This agent is presently approved for the treatment of Chronic or Accelerated phase Chronic Myeloid Leukemia (CML) with resistance and/or intolerance to two or more Tyrosine Kinase Inhibitors, with cytopenias being the most common toxicity. Allogeneic Hematopoietic Stem Cell transplantation should be considered for eligible patients with T315I mutation not responding to ICLUSIG®, those with mutations resistance to second and third generation TKIs and patients with Accelerated or Blast phase CML, following remission with TKIs. Use of Second- and Third-Generation Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia: An Evolving Treatment Paradigm. Jabbour E, Kantarjian H and Cortes J. Clinical Lymphoma, Myeloma & Leukemia 2015;15:323-334

IRESSA® (Gefitinib)

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The FDA on July 13, 2015 approved IRESSA® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA approved test. IRESSA® was approved concurrently with a labeling expansion of the therascreen EGFR RGQ PCR Kit, a companion diagnostic test, for patient selection. IRESSA® tablets are a product of AstraZeneca Pharmaceuticals LP.

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

Radiation Therapy Added to Androgen Deprivation Therapy Improves Overall Survival in Locally Advanced Prostate Cancer

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SUMMARY:Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. This is accomplished by either surgical castration (bilateral orchiectomy) or medical castration using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists given along with 2 weeks of first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) or NILANDRON® (Nilutamide), with the anti-androgen agents given to prevent testosterone flare. This large intergroup trial which was developed by the NCIC Clinical Trials Group in collaboration with the Medical Research Council and the National Cancer Institute US Cancer Therapy Evaluation Program, evaluated the benefits of adding Radiation Therapy (RT) to ADT, when compared to ADT alone, in patients with locally advanced prostate cancer. In this study, 1205 patients were randomly assigned to receive either ADT alone (N=602) or ADT plus RT (N=603). Eligible patients included those with T1-2 disease with either Prostate Specific Antigen (PSA) of more than 40 μg/L or PSA of 20-40 μg/L plus Gleason score of 8-10 or patients with T3-4, N0/NX, M0 prostate cancer. ADT consisted of either bilateral orchiectomy or LHRH agonists (plus 2 weeks of oral anti-androgen therapy to prevent testosterone flare), based on patient and physician preference, and ADT was continued for life. RT consisted of a dose of 64-69 Gy given in 35-39 fractions to the prostate gland and pelvis or prostate gland alone. The median age was 70 years and the median follow up was 8 years. Eighty seven percent of patients had T3-4 disease, 63% of patients had a PSA more than 20 μg/L and 18% had a Gleason score of more than 8. The Primary Endpoint was Overall Survival (OS), defined as the time from randomization to death from any cause. Secondary Endpoints included Time To Progression (TTP), improvement in Disease Specific Survival, quality of life and toxicity. The authors had previously reported the interim analysis findings of this intergroup trial and they noted that the addition of RT to ADT significantly improved overall survival, at a median follow up of 6 years (HR= 0.77; P=0.033). In this final analysis, at a median follow up of 8 years, the interim analysis findings were confirmed and the patients assigned to ADT plus RT had significantly improved Overall Survival compared to those who received ADT alone (HR=0.70; P<0.001), with a 30% reduction in the risk of death. Disease Specific Survival was also superior with ADT plus RT compared to ADT alone, with a 54% reduction in deaths from prostate cancer (HR=0.46; P <0 .001). There was a higher incidence of grade 1 and 2 bowel toxicities in patients who received ADT plus RT, but grade 3 bowel toxicities were rare and short term. The authors concluded that this long term follow up data suggests that the addition of Radiation Therapy to Androgen Deprivation Therapy significantly prolongs Overall and Disease Specific Survival, in patients with locally advanced prostate cancer. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. Mason MD, Parulekar WR, Sydes MR, et al. J Clin Oncol 2015; 33:2143-2150