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), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. There is now growing body of evidence suggesting superior outcomes when advanced NSCLC patients with specific genomic alterations receive targeted therapies.
Approximately 1% – 2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. The ROS protein and the ALK protein have similar structure and function and are sensitive to Tyrosine Kinase Inhibitors such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib). ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase– Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. XALKORI® is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In a previously published expansion cohort of the phase 1 study by Shaw and colleagues ( NEJM 2014; 371:1963-1971), XALKORI® showed significant activity in patients with in patients with advanced ROS1rearranged NSCLC. The authors in this publication provided additional evidence that ROS1 gene rearrangement is an actionable target in NSCLC, by conducting a retrospective study in centers that tested for ROS1 rearrangement and evaluated the outcomes of ROS1-positive NSCLC patients, who had been treated with XALKORI®. They included 32 patients with NSCLC whose tumors showed ROS1 rearrangement and who had received off-label treatment with XALKORI®. The median age was 50.5 years. They noted an overall response rate of 80% and a disease control rate, 86.7%. The median Progression Free Survival (PFS) was 9.1 months, and the PFS rate at 12 months was 44%. This impressive efficacy data again validates that similar to EGFR mutations and ALK rearrangements, ROS1 gene rearrangements are molecular drivers and patients with NSCLC with adenocarcinoma histology should be tested for ROS1. Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 Cohort. Mazières J, Zalcman G, Crinò L, J Clin Oncol. 2015;33:992-999
Author: RR
CYRAMZA® (Ramucirumab)
The FDA on April 24, 2015 approved CYRAMZA® for use in combination with FOLFIRI for the treatment of patients with metastatic ColoRectal Cancer (mCRC), whose disease has progressed on a first line Bevacizumab, Oxaliplatin and Fluoropyrimidine containing regimen. CYRAMZA® is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands. CYRAMZA® was approved earlier in 2014 for the treatment of patients with advanced Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma and in December 2014, for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC). CYRAMZA® injection for intravenous infusion, is a product of Eli Lilly and Company.
FDA Approves CYRAMZA® for Metastatic ColoRectal Cancer
SUMMARY: The FDA on April 24, 2015 approved CYRAMZA® for use in combination with FOLFIRI for the treatment of patients with metastatic ColoRectal Cancer (mCRC), whose disease has progressed on a first line AVASTIN® (Bevacizumab), ELOXATIN® (Oxaliplatin) and Fluoropyrimidine containing regimen. The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. With the availability of new active agents for the treatment of CRC, improving Overall Survival for patients with advanced disease, by prudently planning a treatment strategy and properly sequencing these agents, has become increasing relevant. 
CYRAMZA® (Ramucirumab) is a recombinant human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D and thus inhibits ligand-induced proliferation and migration of endothelial cells. This is unlike AVASTIN®, which inhibits VEGF-A. Several studies have demonstrated that continuing VEGF inhibition along with standard second-line chemotherapy beyond disease progression has a significant advantage, in patients with mCRC. Two observational studies (BRiTE and ARIES) as well as an open label phase III study have all shown improvement in median Overall Survival (OS) when AVASTIN® was continued beyond first progression and given along with second line chemotherapy. In the VELOUR trial, FOLFIRI in combination with ZALTRAP® (Aflibercept), a VEGF-A, VEGF-B and Placental Growth Factor inhibitor, when given as second line therapy for those patients with mCRC who had progressed on AVASTIN® plus ELOXATIN® containing regimen, resulted in a significant improvement in the median PFS and OS.
The RAISE trial is a double-blind, phase III study in which 1072 patients with mCRC who progressed on or after first-line treatment with AVASTIN®, ELOXATIN® and a Fluoropyrimidine were randomized to receive FOLFIRI given along with antiangiogenic agent CYRAMZA® (N = 536) or placebo (N = 536), every 2 weeks. The FOLFIRI regimen consisted of CAMPTOSAR® (Irinotecan) 180 mg/m2 IV, Folinic Acid 400 mg/m2 IV and 5-FU 400 mg/m2 IV bolus followed by 5-FU 2400 mg/m2 continuous IV infusion over 46 to 48 hours. CYRAMZA® was administered at a dose of 8 mg/kg IV every 2 weeks. The median age of patients was 62 years, about 50% harbored KRAS mutations and 99% of the patients had an ECOG performance status of 0 or 1. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and toxicity. There was a statistically significant Overall Survival improvement in patients receiving FOLFIRI plus CYRAMZA® compared to those receiving FOLFIRI plus placebo with a median OS of 13.3 and 11.7 months for patients on the FOLFIRI plus CYRAMZA® and FOLFIRI plus placebo arms, respectively (HR=0.85; P=0.023). The median PFS with FOLFIRI and CYRAMZA® was 5.7 months versus 4.5 months with FOLFIRI and placebo (HR= 0.79; P=0.001). There was no statistically significant difference in Objective Response Rate noted in the two treatment groups. Compared to the placebo group, more patients receiving CYRAMZA®, experienced grade 3 or more adverse events such as neutropenia (38.4% vs 23.3%) and hypertension (10.8% vs 2.8%). Other adverse events associated with CYRAMZA® included hemorrhage (43.9% vs 22.7% with placebo) and proteinuria (17% vs 4.5% with placebo). The authors concluded that CYRAMZA® is a new treatment option for second line treatment of patients with metastatic ColoRectal Cancer, including those with KRAS mutations. Tabernero J, Cohn AL, Obermannova R, et al. RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp). 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 512.
E-Cigarettes – A Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology
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
ABRAXANE® Superior to TAXOL® in High Risk Breast Cancer Including Triple Negative Tumors
SUMMARY:Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Taxanes, which include TAXOL® (Paclitaxel) and TAXOTERE® (Docetaxel) have an important role in the treatment of breast cancer and have been shown in numerous clinical studies to improve survival in patients with early-stage breast cancer and select group of patients with metastatic breast cancer.
ABRAXANE® (Nab-paclitaxel) is a solvent free, albumin-encapsulated nanoparticle formulation of the taxane, Paclitaxel. By virtue of its formulation, unlike TAXOL®, hypersensitivity reactions are uncommon with ABRAXANE® and can therefore be rapidly infused and premedications are not needed. Further, higher tumor drug concentrations are achieved with ABRAXANE® compared to conventional Paclitaxel (TAXOL®). Previously published studies have shown that ABRAXANE® is superior to TAXOL® in metastatic breast cancer. GeparSepto trial is a randomized phase III study in which weekly ABRAXANE® was compared head to head with weekly TAXOL® in a neoadjuvant setting. This study enrolled 1204 treatment naïve, high risk patients, with clinical T2-T4d invasive breast carcinoma. Eligible patients included those with unilateral, bilateral, operable or inoperable breast cancer. The median age was 49 years, median tumor size was 3 cm, 23% of the patients had triple-negative disease and 33% had HER-2 positive tumors. Patients were randomized 1:1 to receive either ABRAXANE® 125 mg/m2 IV or TAXOL® 80 mg/m2 IV, weekly for 12 weeks followed by 4 cycles of Epirubicin 90 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV. Patients with HER-2 positive tumors also received HERCEPTIN® (Trastuzumab) and PERJETA® (Pertuzumab). The primary endpoint was pathologic Complete Response (pCR), defined as absence of microscopic residual invasive or noninvasive viable tumor cells in all resected specimens of the breast and axilla. This endpoint was chosen because pathologic Complete Response serves as a surrogate marker for long-term efficacy and outcomes. In this trial, the researchers noted a pathologic Complete Response rate of 38% with ABRAXANE® compared to 29% with TAXOL® (P<0.01). On subgroup analysis, this benefit was even more evident in patients with triple negative breast cancer (N=275), with a pCR rate of 48.2% in the ABRAXANE® group compared with 25.7% in the TAXOL® group (P <0.001). The incidence of peripheral neuropathy was higher in the ABRAXANE® group compared to TAXOL® group and this was attributed to higher weekly doses of ABRAXANE® administered. It is felt that a lower dose of weekly ABRAXANE® (100 mg/m2) would result in a decrease in the incidence of peripheral neuropathy, without compromising efficacy. The authors concluded that ABRAXANE® is superior to TAXOL® in early stage, high risk patients with breast cancer and this benefit is even more evident in those patients with triple negative disease, which comprises about 15% of all breast cancers. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S2-07.
Indolent Non-Follicular B-Cell Lymphoma Treatment Guidelines
SUMMARY: Indolent Non-Follicular B-Cell Lymphoma (INFBCL) are mature B cell lymphoproliferative disorders and include Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).
NMZL, LPL, and SLL
Recommendations for Diagnosis:
1) Excision biopsy of material from the primary disease site (ie, lymph node)
2) Fine Needle Aspiration biopsy is not recommended for the diagnosis or sub-typing. Computed Tomography (CT)-guided core biopsy can be an alternative diagnostic approach when thoracotomy or laparotomy are needed for lymph node biopsy.
3) A definitive diagnosis of LPL can only be made using bone marrow material.
Recommendations for Staging and Pretreatment Evaluation:
1) Complete history and physical examination, assessing Performance Status and B symptoms
2) Lab tests including CBC, CMP, LDH, B2-Microglobulin, hemolysis workup if anemic, SPEP, UPEP with immunofixation, serology for Hepatitis B,C and HIV, Flow Cytometry if peripheral blood shows abnormal lymphocytes or absolute lymphocytosis present and bone marrow aspirate and biopsy
3) CT of the neck, chest, abdomen, and pelvis (FDG-PET is not routinely indicated for this group of lymphomas as the avidity of FDG uptake is lower)
4) In LPL with monoclonal protein in the urine or serum, a fat pad biopsy for Congo red staining and an ultrasound cardiac scan are recommended when Amyloidosis is suspected
5) ECHO or MUGA scan, if treatment with anthracyclines are planned
6) Pregnancy testing in women of child-bearing age and counseling for the preservation of fertility
Recommendations regarding treatment initiation
1) Initiation of Chemotherapy or Immunotherapy should be based on the identification of symptoms as defined by the GELF or BNLI criteria.
2) Monoclonal protein-related symptoms such as hyperviscosity syndrome, renal failure, vasculitis and a lymphocyte doubling time of less than 6 months in those with leukemia, are indications for treatment.
3) Chemoimmunotherapy or Chemotherapy alone as early treatment is not recommended in asymptomatic advanced disease and observation alone is recommended in patients who do not meet the criteria for treatment with Chemotherapy or Immunotherapy
Recommendations for First Line Therapy
1) Patients with stage I or nonbulky stage II disease should be promptly treated with involved field Radiotherapy (RT) with or without chemotherapy. Observation alone may be a reasonable alternative if the potential toxicity of RT outweighs the potential benefits, particularly in elderly patients or if the patient refuses RT.
2) FLUDARA® (Fludarabine) plus RITUXAN® (Rituximab) – FR or TREANDA® (Bendamustine) plus RITUXAN® (BR) is the recommended first line therapy.
3) The combination of FLUDARA®, Cyclophosphamide and RITUXAN® (FCR) should be recommended to patients less than 70 years of age without significant comorbidities, and TREANDA® plus RITUXAN® should be preferred for patients 70 years or older with significant comorbidities.
Recommendations for Postinduction Therapy
Maintenance RITUXAN® is not recommended and patients with a partial response (PR) with no symptoms or signs of active disease, should be observed without additional treatment until progression.
Recommendations for Patients with Relapse
BR combination is the preferred treatment and new combinations of RITUXAN® with REVLIMID® (Lenalidomide) or VELCADE® (Bortezomib) should be considered experimental
ENMZL of MALT Lymphoma of Gastric Mucosa (Gastric MALToma)
MALT lymphoma histology is the most frequent among Marginal Zone Lymphomas and the most common extranodal MALT lymphoma involves the gastrointestinal tract.
Recommendations for Diagnosis:
1) Biopsy of material from the primary disease site
2) A molecular genetic analysis of lymphoma tissue for the detection of t(11;18) is recommended to identify disease that is unlikely to respond to antibiotic therapy
3) The presence of active Helicobacter pylori (Hp) infection must be determined using histologic testing. In the case of negative results, serology testing, stool antigen testing, or the urea breath test is recommended
Recommendations for Staging and Pretreatment Evaluation:
1) A detailed description of the extent of gastric lesions, gastric wall infiltration, and involvement of the perigastric lymph nodes, with ultrasound-guided endoscopy.
2) Along with the conventional staging procedures, additional investigations should include CT of the neck, chest, abdomen and pelvis and bone marrow biopsy
3) Staging classification should use the Ann Arbor staging system modified according to the Paris staging system
Recommendations for First Line Therapy
1) The first-line treatment of Hp-positive patients with gastric MALT lymphoma is Hp eradication therapy, independent of the disease stage. Surgery should only be considered for patients with perforation or bleeding, not amenable to endoscopy
2) Patients with Hp-negative localized gastric MALT lymphoma can also be treated with eradication therapy although the chance of a response is low and disease status should be closely monitored during therapy
3) After successful Hp eradication, consolidation chemotherapy is not indicated
Recommendations for non-responding and relapsed Patients
1) Radiation therapy is recommended for patients with stage IE-IIE gastric MALT lymphoma
2) RITUXAN® plus chemotherapy is recommended for those with other disease stages
SMZL (Splenic Lymphoma With Circulating Villous Lymphocytes)
Recommendations for Diagnosis:
1) SMZL can be diagnosed by splenectomy and examination of the splenic tissue
2) SMZL can also be diagnosed by a combination of bone marrow biopsy and an immunocytochemistry profile (intrasinusoidal infiltration by CD20+ cells), peripheral blood and bone marrow aspirate morphology as well as flow cytometry.
Recommendations for Staging and Pretreatment Evaluation:
1) Complete history and physical examination assessing performance status and B symptoms
2) Lab tests should include CBC, CMP, LDH, B2-Microglobulin, hemolysis workup if anemic, SPEP, UPEP with immunofixation, cryoglobulin and cryocrit. Serology for Hepatitis B,C and HIV, flow cytometry if peripheral blood shows abnormal lymphocytes or absolute lymphocytosis present and bone marrow aspirate and biopsy
3) CT of the neck, chest, abdomen, and pelvis (FDG-PET is not routinely indicated for this group of lymphomas as the avidity of FDG uptake is lower)
4) Pregnancy testing in women of child-bearing age and counseling for the preservation of fertility
Recommendations regarding treatment initiation
Patients with SMZL should be initiated on therapy if there is progressive or symptomatic splenomegaly, hemoglobin less than 10 g/dL, neutrophils less than 1000/μL, progressive thrombocytopenia, systemic symptoms, progressive nodal disease and autoimmune hemolytic anemia.
Recommendations for First Line Therapy
1) Patients who are HCV positive with no indications for anti-lymphoma therapy, should be treated for HCV infection.
2) For those requiring therapy for lymphoma, the options include splenectomy, chemotherapy alone, RITUXAN® alone, or chemoimmunotherapy. Chemoimmunotherapy is indicated for good PS patients with disseminated disease. Combinations therapies with proven efficacy include RITUXAN® in combination with Chlorambucil, CVP (Cyclophosphamide, Vincristine, Prednisone), FLUDARA® or 2-CDA (Cladribine).
3) Splenectomy should be recommended when patients present with splenomegaly-related cytopenias in the absence of a high percentage of leukemic cells in the peripheral blood, heavy bone marrow infiltration, and diffuse nodal disease. In patients who are HCV positive, splenectomy should be considered only after the exclusion of a severe chronic liver disease.
4) Single agent RITUXAN® may be considered for patients without disseminated disease and for patients with contraindications to surgery or chemoimmunotherapy.
Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation Guidelines for the Management of Indolent, Nonfollicular B-Cell Lymphoma (Marginal Zone, Lymphoplasmacytic, and Small Lymphocytic Lymphoma). Tarella C, Arcaini L, Baldini L, et al. Clinical Lymphoma, Myeloma & Leukemia. 2015; 15:75–85
Platelet Transfusions Detrimental in TTP and HIT
SUMMARY: Patients with Thrombotic Thrombocytopenic Purpura (TTP), Heparin Induced Thrombocytopenia (HIT) and Immune Thrombocytopenic Purpura (ITP) often receive prophylactic platelet transfusions even though there are no data to support this practice. These transfusions are often given preemptively to reduce the risk for spontaneous bleeding in patients who are thrombocytopenic. Thrombocytopenia refers to a platelet count below the lower limit of the normal range used by the laboratory performing the count. In the United States, a little over 2 million platelet units are transfused annually.
The known risks associated with platelet transfusion include febrile and allergic reactions, Transfusion Related Acute Lung Injury and infections. The authors in this study utilized a Nationwide Inpatient Sample of patients over a 5 year period from 2007-2011and evaluated the risks associated with platelet transfusions. 
They identified 10,624 hospitalizations with TTP and platelet transfusions were reported in 10.1%, 6,332 hospitalizations with HIT and 7.1% received platelet transfusions and 79,980 admissions with ITP and 25.8% received platelet transfusions. The Odds Ratio (OR) was calculated after adjusting for age, gender, clinical severity and acuity. (An Odds Ratio is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure). The researchers noted some alarming findings. Platelet transfusions in TTP were associated with higher odds of arterial thrombosis (OR=5.8), Acute Myocardial Infarction (OR=2.0) and mortality (OR=2.0). Platelet transfusions in HIT were associated with higher odds of arterial thrombosis (OR=3.4) and mortality (OR=5.2). Platelet transfusions in TTP or HIT however, was not associated with venous thrombosis. There were no increased risks among patients with ITP, who received platelet transfusions. The authors concluded that until future trials provide additional information, platelet transfusions should be considered a relative contraindication in patients with TTP and HIT and should only be used in situations where severe or potentially life threatening bleeding is refractory to other therapies. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Goel R, Ness PM, Takemoto CM, et al. Blood. 2015;125:1470-1476.
Higher Serum Vitamin D Levels May Improve Survival in Patients with Advanced Colon Cancer
SUMMARY: The American Cancer Society estimates that approximately 133,000 new cases of colorectal cancer will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. There is a growing body of evidence suggesting that Vitamin D has colon cancer preventing properties and may induce antitumor immunity. A recent study by Song and colleagues (Gut. 2015;64:260-271) showed that high plasma level 25-Hydroxy Vitamin D [25(OH)D] was associated with lower risk of colorectal cancer with intense immune reaction, supporting that vitamin D through tumor-host interaction may play a role in cancer immunoprevention. 
There appears to be a strong association between plasma 25(OH)D level and colorectal cancer (CRC) specific mortality, with better outcomes in patients with Stage I-III CRC, who had higher plasma levels of 25(OH)D (Zgaga L, et al. J Clin Oncol 2014;32:2430-2439). The researchers in this present study conducted a prospective analysis of data from CALGB 80405 trial and evaluated the relationship between plasma 25(OH)D level and patient outcomes, which included Overall Survival and Progression Free Survival (PFS). CALGB 80405 is a phase III trial in which patients with newly diagnosed, advanced colorectal cancer were initially randomized to three groups- 1) Chemotherapy (FOLFIRI or mFOLFOX6) with ERBITUX® (Cetuximab) 2) Chemotherapy with AVASTIN® (Bevacizumab) 3) Chemotherapy with ERBITUX® and AVASTIN®. The protocol was later amended to only include patients with KRAS Wild Type tumors and the chemotherapy with ERBITUX® and AVASTIN® group was deleted. This trial was not designed to compare chemotherapy regimens. The Overall Survival (OS) in both the treatment groups were similar at 29+ months.
In the present study, plasma 25(OH)D level were measured at baseline in 1,043 patients at the time of their enrollment in CALGB 80405, and dietary and lifestyle behaviors were collected from self-administered questionnaires. The median plasma 25(OH)D level was 17.2 ng/mL, with the range varying from 2.2 to 72.7 ng/mL (recommended range is 20-30 ng/mL). Factors associated with lower 25(OH)D level included older age, black race, lower dietary and supplemental vitamin D intake, higher Body Mass Index (BMI), ECOG performance status of 1 versus 0 and lower physical activity. Additionally, patients whose blood specimens were drawn in the winter and spring months had significantly lower 25(OH)D level, as did patients who were from the Northern and Northeastern parts of the United States. Vitamin D supplement use was uncommon in this patient population. After adjusting for pathologic and clinical prognostic factors, patients in the group with the highest level of 25(OH)D had significantly improved median OS compared to those in the group with the lowest level (32.6 vs 24.5 months; HR=0.67, P trend 0.002). Higher level of 25(OH)D was also associated with improved PFS (median 12.2 vs 10.1 months; HR 0.80, P trend = 0.02). These results were consistent across all subgroups of patients. The authors concluded that higher plasma level of 25(OH)D was associated with significantly improved survival in metastatic CRC patients treated with a combination of chemotherapy and biologic agents. With 30-35% of the malignancies attributed to dietary habits, the onus is therefore on the treating physicians to provide nutrition counseling during and after cancer treatment. Recommending vitamin D supplements for those patients with colon cancer with low vitamin D levels, may therefore not be unreasonable. Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance). Ng K, Venook AP, Sato K, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 507)
Long Term Survival with YERVOY® in Advanced Malignant Melanoma
SUMMARY: The American Cancer Society’s estimates that for 2015, approximately 74,000 new melanomas will be diagnosed in the United States and about 10,000 people are expected to die of the disease. The incidence of melanoma has been on the rise for the past 30 years. The US Food and Drug Administration approved YERVOY® (Ipilimumab) for the treatment of unresectable or metastatic melanoma in March 2011. This therapy was the first, to improve Overall Survival in a phase III trial. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody, that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), and this is the first Immune checkpoint protein that was clinically targeted.
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, 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 response. CA184-024 is a phase III trial in which treatment naïve patients with stage IIIc, N3 (unresectable), or stage IV melanoma were randomly assigned to receive YERVOY® 10 mg/kg IV given along with Dacarbazine 850 mg/m2 IV (N=250) or placebo plus Dacarbazine 850 mg/m2 IV (N=252) administered every 3 weeks for 4 doses followed by Dacarbazine given alone every 3 weeks through week 22. Responders and those with stable disease from week 12 through week 24 were then allowed to receive YERVOY® or placebo as maintenance therapy given every 12 weeks beginning at week 24, until disease progression or unacceptable toxicity. Dacarbazine was not given during the maintenance phase. The median Overall Survival was significantly longer in the group treated with YERVOY® plus Dacarbazine than in patients treated with placebo plus Dacarbazine (11.2 vs 9.1 months, HR=0.72; P< 0.001). This Overall Survival benefit was maintained after 3 years of follow up and toxicities were manageable.
The authors in this publication conducted a milestone survival analysis with a minimum follow-up of 5 years and they noted that the 5-year survival rate doubled and was 18.2% for patients treated with YERVOY® plus Dacarbazine versus 8.8% for patients treated with placebo plus Dacarbazine (P=0.002). The plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued maintenance YERVOY®, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. Based on these findings, it was concluded that patients treated with YERVOY® for advanced melanoma, continue to respond following a period of stable disease and these ongoing and durable responses may contribute to long term survival in some patients. Five-Year Survival Rates for Treatment-Naive Patients With Advanced Melanoma Who Received Ipilimumab Plus Dacarbazine in a Phase III Trial. Maio M, Grob J, Aamdal S, et al. J Clin Oncol 2015;33: 1191-1196
Oral Bisphosphonates May Decrease the Risk of Postmenopausal Endometrial Cancer
SUMMARY: Cancer of the endometrium is the most common cancer of the female reproductive organs in the United States. The American Cancer Society estimates that for 2015, about 54,870 new cases of cancer of the body of the uterus will be diagnosed and 10,170 women will die of the disease. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, family history, diet and exercise, drugs such as Tamoxifen, etc.
Bisphosphonates such as DIDRONEL® (Etidronate) have been available in the US since the late 1970’s. Bisphosphonates inhibit bone resorption (loss of bone mass) and are indicated for the treatment of osteoporosis and related diseases. The risk of fractures in postmenopausal women with osteoporosis is significantly reduced with the use of bisphosphonates. Several bisphosphonate derivatives have been developed for the treatment of osteoporosis. Aminobisphosphonates such as AREDIA® (Pamidronate) and ZOMETA® (Zoledronic acid) are an integral part of patient management in oncology practice, when bone metastases are initially diagnosed and may have cytostatic, proapoptotic, and antimetastatic properties. An estimated 14.7 million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2012. Previously published studies have shown an inverse relationship between bisphosphonate use and breast cancer risk. Endometrial cancers which are hormone mediated, share risk factors with breast cancer and women with a history of fractures have a lower risk of endometrial cancers.
The association between bisphosphonate use and endometrial cancer has remained unclear except for a few, small retrospective studies, which have shown an inverse relationship. To further explore this observation, the authors conducted a large prospective study which included 89,918 postmenopausal women participating in the Women’s Health Initiative (WHI). Following a health information interview conducted at baseline, the use of bisphosphonate was ascertained at baseline and over the follow up period. All women had an intact uterus at the time of enrollment and the most common type of bisphosphonate used was FOSAMAX® (Alendronate). During the study median follow up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was inversely associated with age-adjusted endometrial cancer risk (HR=0.76; P=0.01). There was no evidence of statistically significant interactions with age at baseline, BMI (Body Mass Index), or hip fracture probability score. In this large prospective cohort of postmenopausal women, the authors concluded that bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk, in postmenopausal women. Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer. Newcomb PA, Passarelli MN, Phipps AI, et al. J Clin Oncol 2015; 33: 1186-1190