Category: Hem/Onc Updates

Anticoagulation Can be Safely Stopped for Invasive Procedures in Some Patient Groups

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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. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Clinicians are often confronted with the dilemma of using bridge therapy for patients with a history of VTE on Warfarin therapy, requiring invasive diagnostic or surgical procedures. Bridge therapy involves the use of rapid onset, short acting anticoagulant preparation such as Low Molecular Weight Heparin during the peri-procedural period (usually 5-10 days), to minimize the risk of subtherapeutic anticoagulation, during peri-procedure Warfarin withdrawal and reinitiation. Even though published studies have largely reviewed the risk of thrombotic events in patients with atrial fibrillation or mechanical heart valves, the risk for bleeding and VTE, associated with bridge therapy in patients receiving Warfarin for the secondary prevention of VTE, has remained unclear. Presently available guidelines that classify peri-procedural risk of recurrent VTE, off anticoagulant therapy, into high risk , medium risk and low risk, is based on indirect, low quality evidence and is not completely reliable. It is well established however, that anticoagulants stopped during the first four weeks of treatment, following diagnosis of VTE, predisposes an individual to increased risk of recurrent VTE.

To clarify the risk/benefits of bridge therapy, the authors conducted a retrospective cohort study, to assess the rates of clinically relevant bleeding and recurrent VTE, among patients in whom Warfarin therapy was interrupted for invasive procedures. They then compared the incidence of peri-procedure bleeding and recurrent VTE when a bridging strategy was used or not used. This study included 1178 patients and the most common indication for Warfarin therapy was DVT (56.3%). Majority of the patients (79%) were considered as low risk (acute VTE more than 12 months previously, with no other risk factors). The primary outcome of the study was clinically relevant bleeding resulting in hospitalization, ER visit or complicating the procedure in the first 30 days following the index procedure. Secondary outcomes included recurrent VTE, and all-cause mortality occurring in up to 30 days, following the index procedure.

It was noted that the 30-day rate of clinically relevant bleeding was significantly higher in the bridging group compared with the control group (2.7% versus 0.2%, HR=17.2; P=0.01). Further, there was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups. No deaths occurred in either treatment groups. The authors concluded that bridge therapy for invasive procedures in patients receiving Warfarin for secondary VTE prevention, is associated with a significant increase in the incidence of bleeding complications, without any decrease in the rate of recurrent VTE. Warfarin can be safely interrupted in this patient group without bridge therapy. Further research is needed to address the value of bridge therapy in the medium and high risk groups. Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. Clark NP, Witt DM, Davies LE, et al. JAMA Intern Med 2015;175:1163-1168.

Nicotinamide Reduces the Incidence of Non-Melanomatous Skin Cancers

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SUMMARY: Skin cancer is the most common of all cancers. Approximately, 3.5 million cases of Basal cell and Squamous cell skin cancer (Non-Melanomatous) are diagnosed in the US each year. Most Non-Melanomatous skin cancers develop on the sun-exposed areas of the skin and Basal cell cancers tend to be slow growing and rarely metastasize, whereas Squamous cell cancers are more likely to grow into deeper layers of skin and metastasize. There has been a 35% increase in the incidence of Non-Melanomatous skin cancers between 2006 and 2012 and there has been a 17% increase in the incidence of Basal cell carcinomas over the past 15 years. Patients with Non-Melanomatous skin cancer are at an increased risk of developing a new primary, including breast and lung cancer in woman and prostate cancer in men. A major risk factor for most skin cancers is exposure to UltraViolet (UV) radiation, which damages the DNA of skin cells and suppresses cutaneous immunity. The main source of UV rays are sunlight, tanning lamps and tanning beds. The 3 main types of UV rays include UVA rays, UVB rays that mainly cause sunburns and UVC rays that do not penetrate through our atmosphere and are not in sunlight. Most indoor tanning beds give off large amounts of UVA rays, which have been found to increase skin cancer risk. It appears that there are no safe UV rays. Nicotinamide is an amide form of Vitamin B3 and unlike Nicotinic acid does not cause vasodilatation and associated side effects. Severe Nicotinamide deficiency causes Pellagra, which is characterized by photosensitive dermatitis, dementia, diarrhea and death. Nicotinamide enhances DNA repair after UV exposure and reduces UV radiation induced immunosuppression and in previously published studies was shown to decrease the formation of Actinic keratoses.

The ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) trial is a double-blind, phase III Study, in which 386 patients were randomly assigned to receive either Nicotinamide 500 mg PO twice daily (N=193 patients) or placebo (N=193 patients), for a period of 12 months. Enrolled patients had 2 or more histologically confirmed Non-Melanomatous skin cancers during the previous 5 years. The mean age was 66 years and 63% of the enrollees were men. Skin evaluations were performed by Dermatologists every 3 months. The primary endpoint was the number of new Non-Melanomatous skin cancers at 12 months and secondary endpoints included number of Squamous cell carcinomas, Basal cell carcinomas, and Actinic keratoses over the same study period. Over the 12 month study period, it was noted that patients in the placebo group developed an average of 2.4 new Non-Melanomatous skin cancers compared with 1.8 in the Nicotinamide group. This meant a Relative Risk Reduction (RRR) of 0.23 (P= 0.02). With regards to the specific subtypes, there was an average of 1.7 new cases of Basal cell carcinoma for patients who received placebo compared to 1.3 new cases for patients who received Nicotinamide. The Relative Risk Reduction was 0.20 (P=0.1). For Squamous cell carcinomas, there was an average of 0.7 cases for patients in the placebo group compared with 0.5 in the Nicotinamide group. The Relative Risk Reduction was 0.30 (P= 0.05). With regards to Actinic keratosis, there was a Relative Risk Reduction of 11% at 3 months (P=0.01), 14% at 6 months (P<0.001), 20% at 9 months (P<0.0001) and 13% at 12 months (P<0.005).

Based on this data the authors concluded that Nicotinamide, an inexpensive, over-the-counter Vitamin supplement, significantly reduces the incidence of Non-Melanomatous skin cancers by 20-30%, in high risk patients and may be an effective chemopreventive agent for Non-Melanomatous skin cancers. Oral nicotinamide to reduce actinic cancer: A phase 3 double-blind randomized controlled trial. Martin AJ, Chen A, Choy B, et al. J Clin Oncol 33, 2015 (suppl; abstr 9000)

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)

Low Serum Vitamin D Levels are Associated with Inferior Survival in Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that about 71,850 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 19,800 individuals will die of this disease. Approximately 20% of all NHLs are Follicular Lymphomas. Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Advanced stage Follicular Lymphomas are not curable and as such prolonging Progression Free Survival (PFS) and Overall Survival (OS) while maintaining quality of life (QoL), has been the goals of treatment intervention. Asymptomatic patients with FL are generally considered candidates for “watch and wait” approach, whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy. Follicular Lymphoma International Prognostic Index (FLIPI) is of prognostic value and is used to help with treatment choices. Several studies have been underway evaluating the association between serum Vitamin D levels and cancer. Previously published studies have shown a relationship between Vitamin D deficiency and poor outcomes in patients with Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia. The beneficial effects of Vitamin D in malignancies has been attributed to its antiproliferative and antiangiogenic properties, as well as its effects on cell differentiation, promotion of apoptosis and its ability to decreases oxidative DNA damage. Further, macrophages play an important role in the human body’s response to therapy with monoclonal antibodies, an integral part of Follicular Lymphoma therapies and low serum Vitamin D levels may interfere with macrophage function and this may explain poor outcomes in some Follicular Lymphoma patients with low Vitamin D levels

XTANDI® After TAXOTERE® and ZYTIGA® Treatment in 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. Chemotherapy is usually considered for patients who progress on hormone therapy (Castrate Resistant Prostate Cancer-CRPC) and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on Androgen Deprivation Therapy. Tumors in patients with CRPC are not androgen independent and continue to rely on Androgen Receptor signaling and two oral agents are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). ZYTIGA® inhibits CYP 17A1 enzyme thus decreasing androgen biosynthesis and depletes adrenal and intratumoral androgens. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor (AR), thereby inhibiting AR signaling and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. There is presently very little guidance with regards to the sequencing of these two oral agents after progression on TAXOTERE®, in patients with metastatic CRPC. ZYTIGA® was approved initially by the FDA in April 2011, for use in combination with prednisone for the treatment of patients with metastatic CRPC, who had received prior chemotherapy containing TAXOTERE®. Treatment with ZYTIGA® resulted in a 35% reduction in the risk of death and a 36% increase in median Overall Survival (OS) compared with placebo. Subsequently, XTANDI® was approved by the FDA on August 31, 2012 for the treatment of patients with metastatic CRPC who had previously received TAXOTERE®. XTANDI® improved median OS and reduced the risk of death by 37% when compared to placebo. Even though these two anti-androgen therapies improved OS in metastatic CRPC patients previously treated with TAXOTERE®, the proper sequence of administration of these two agents after TAXOTERE® failure, has remained unclear. At least 2 published studies have shown that the use of ZYTIGA® as third line therapy after progression on TAXOTERE® and XTANDI® resulted in inferior outcomes.

The purpose of this study was to evaluate the role of XTANDI® as third line therapy, in patients with metastatic CRPC, following progression on TAXOTERE® and ZYTIGA®. The authors searched large, established medical databases and selected 10 publications out of 1264 articles, in which metastatic CRPC patients were treated with XTANDI® as third line therapy, following progression on TAXOTERE® and ZYTIGA®. The study included 536 patients. The primary outcomes were PSA Response Rate of more than 50%, activity of XTANDI® based on previous response to ZYTIGA® and median Progression Free Survival (PFS) or Time To Progression. The secondary outcomes included safety and the median Duration of Response. The pooled Response Rate in this patient population with XTANDI® was 22.9%. However, in patients previously sensitive to ZYTIGA®, the Response Rate with XTANDI® was higher at 35%. The median PFS was 3.1 months and the median OS was 8.3 months. This pooled analysis gives some perspective on the initial choice of anti-androgen therapy in metastatic CRPC patients who progress on TAXOTERE®, with XTANDI® benefitting the most, in patients who respond to second line treatment with ZYTIGA®. It remains to be seen if this sequencing strategy can be confirmed in prospective trials. Enzalutamide After Docetaxel and Abiraterone Acetate Treatment in Prostate Cancer: A Pooled Analysis of 10 Case Series. Petrelli F, Coinu A, Borgonovo K, et al. Clinical Genitourinary Cancer 2015;13:193-198

PRAXBIND® – An Antidote to Reverse the Anticoagulant Effects of PRADAXA®

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SUMMARY: There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent s

Intraperitoneal Chemotherapy Underused in Spite of Improved Survival in Advanced Ovarian Cancer

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SUMMARY: The American Cancer Society estimates that over 21,000 women will be diagnosed with ovarian cancer in the United States for 2015 and over 14,000 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Intraperitoneal (IP) delivery of antineoplatic drugs ("Belly Bath") for ovarian cancer dates back to the late 1970’s and 1980’s. This strategy for ovarian cancer was based on the fact that the peritoneal cavity is the primary site of spread and failure in most cases of advanced ovarian cancer. IP chemotherapy for ovarian cancer facilitates the exposure of tumors in the peritoneal cavity to 10-20 fold greater concentration of Cisplatin and Carboplatin and 1000 fold greater concentration of Paclitaxel, compared to IV administration, thus allowing continuous and prolonged exposure of the tumor to high drug concentrations, without systemic toxicities. Even though three Intergroup Phase III trials demonstrated the superiority of IP therapy over IV therapy, it has not been widely accepted in the US and abroad. Barriers to IP therapy have included inconvenience, IP catheter related complications, higher toxicities, lack of knowledge regarding patient selection for IP therapy as well as minimum number of cycles of IP therapy to administer and uncertain long term benefit.

The authors in this study retrospectively analyzed data from 876 patients in the two phase III, Gynecologic Oncology Group trials (GOG#114 and GOG#172). The purpose of this study was to determine the long-term survival and associated prognostic factors following IP chemotherapy, in patients with advanced ovarian cancer. In both studies, patients were randomly assigned to IP (combined N=440) or IV (combined N=436) chemotherapy. In GOG#114 trial, the two treatment groups were Paclitaxel at 135 mg/m2 IV followed by Cisplatin 75 mg/m2 IV for 6 cycles or Carboplatin IV for 2 courses followed by Paclitaxel 135 mg/m2 IV dose on day 1 and Cisplatin 100 mg/m2 IP on day 8, for 6 cycles. In GOG#172 trial, the two treatment groups (IV vs IP) were Paclitaxel at 135 mg/m2 IV followed by Cisplatin 75 mg/m2 IV on day 2 for 6 cycles or Cisplatin 100mg/m2 IP on day 2 and Paclitaxel 60 mg/m2 IP on day 8, for 6 cycles. Patients in the IP and IV groups were well balanced for baseline characteristics. At a median follow up of 10.7 years, the median Overall Survival with IP chemotherapy was 61.8 months compared with 51.4 months for IV chemotherapy and IP chemotherapy resulted in a 23% reduction in the risk of death (HR=0.77; P=0.002). IP chemotherapy was also associated with improved survival among those patients with gross residual disease ie.1 cm or less (HR = 0.75; P=0.006). The risk for death decreased by 12% for each cycle of IP chemotherapy that patients completed (HR=0.88; P<0.001). Factors significantly associated with poorer Overall Survival included clear/mucinous vs serous histology (HR=2.79; P <0 .001), gross residual vs no visible disease (HR=1.89; P< 0.001), and fewer vs more cycles of IP chemotherapy (HR=0.88; P<0.001). Younger patients were more likely to complete IP chemotherapy, with probability of completion decreasing by 5% with each additional year of age (P<0.001). The authors concluded that IP chemotherapy was associated with significantly prolonged Overall Survival in women with advanced ovarian cancer, including those with gross residual disease, when compared with IV chemotherapy. This benefit extends beyond 10 years and Overall Survival improved with increasing number of IP chemotherapy cycles administered. In a more recently published study by Wright, et al. (Wright AA, Cronin A, Milne DE, et al. Published online before print August 3, 2015, doi: 10.1200/JCO.2015.61.4776), even though the use of IP chemotherapy increased significantly at National Comprehensive Cancer Network centers between 2003 and 2012, this treatment schema was still significantly underutilized and fewer than 50% of eligible patients received it. IntraPeritoneal chemotherapy should be more often incorporated into clinical practice, to improve outcomes for patients with ovarian cancer. Long-Term Survival Advantage and Prognostic Factors Associated With Intraperitoneal Chemotherapy Treatment in Advanced Ovarian Cancer: A Gynecologic Oncology Group Study . Tewari D, Java J, Salani R, et al. JCO published online on March 23, 2015; DOI:10.1200/JCO.2014.55.9898.

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

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)