Author: RR

Superior Outcomes with GAZYVA® and TREANDA® Combo in Indolent Non Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2015, 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. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, 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). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL 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 indolent NHL 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.

GAZYVA® (Obinutuzumab) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells such as natural killer cells, macrophages and neutrophils, Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis is significantly enhanced, whereas it induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® (Rituximab), which is a first generation type I, chimeric anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GADOLIN is a pivotal multicenter, open-label phase III, study in which TREANDA® (Bendamustine) alone was compared with TREANDA® plus GAZYVA® followed by GAZYVA®, in patients with indolent NHL (iNHL), refractory to RITUXAN®. Four hundred and thirteen (N=413) RITUXAN® refractory iNHL were randomized and patients in the control arm received TREANDA® 120 mg/m2 IV on days 1 and 2 every 28 days for a total of 6 cycles. Patients in the experimental arm received TREANDA® 90 mg/m2 IV on days 1 and 2 every 28 days for 6 cycles and GAZYVA® 1000mg IV days 1,8 and 15 every 28 days of cycle 1 and on day 1 of cycles 2-6. In patients with non-progressive disease in the experimental arm, GAZYVA® was continued (maintenance) every 2 months for up to 2 years. Both treatment groups were well balanced and the median age was 63 years, with a median of two prior lines of therapy. More than 90% of patients in each treatment group were refractory to their previous therapy and between 76% and 81% were double-refractory to both RITUXAN® and an alkylating agent. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival and Response Rate.

The study was unblinded at the time of planned interim analysis and had to be halted early, upon recommendations from the Independent Data Monitoring Committee, as the primary end point was reached. The median Progression Free Survival was 29 months with GAZYVA®/ TREANDA® plus maintenance GAZYVA® versus 14 months with TREANDA® monotherapy and no maintenance (HR=0.52; P<0.001). This meant a 45% reduction in the rate of disease progression. There was however no difference in the Response Rates between the treatment groups and the best Overall Response Rate up to 12 months from start of treatment was, 76.6% in the TREANDA® alone group and 78.6% in the TREANDA® plus GAZYVA® group. Median Overall Survival has not yet been reached in either arm and longer follow up is needed. The combination experimental group experienced more grade 3 adverse events such as infusion related reactions and neutropenia whereas the TREANDA® alone group experienced more thrombocytopenia, anemia and pneumonia. The authors concluded that GAZYVA® in combination with TREANDA® is superior to TREANDA® alone, in patients with RITUXAN® refractory indolent Non Hodgkin Lymphoma, with a significant improvement in Progression Free survival. The lack of difference in the Response Rate begs the question, if the improvement in PFS was predominantly contributed by the continuous maintenance treatment with GAZYVA®. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Sehn LH, Chua NS, Mayer J, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA8502)

Stereotactic Body Radiation Therapy (SBRT) Instead of Surgery for Patients with Early Stage Inoperable or Advanced Oligometastatic NSCLC

RR

SUMMARY: Stereotactic RadioSurgery (SRS) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional radiation therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SRS include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Stereotactic Body Radiation Therapy (SBRT) refers to stereotactically guided radiation therapy delivered over several days. Because SBRT is fractionated and is offered in three precise treatments, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

SBRT is a viable option for elderly and frail patients and those with comorbidities or those who decline surgery. Two studies presented at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO) have provided convincing evidence in favor of SBRT in patients with inoperable early-stage lung cancer and for patients with oligometastatic stage IV Non Small Cell Lung Cancer (NSCLC). RTOG 0236 is a phase II trial in which 59 frail, elderly patients with early stage, medically inoperable Stage I Non Small Cell Lung Cancer received SBRT in three fractions of 18 Gy (total of 54 Gy) over a period of 10 days to 2 weeks. The median age was 72 years and these patients had multiple comorbidities that precluded them from curative surgery. The primary end point was 2-year actuarial primary tumor control. Secondary end points included Disease Free Survival (i.e., primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity and Overall Survival. At 5 years, the Disease Free Survival and Overall Survival were 26% and 40%, respectively and the median Overall Survival was 4 years. The 5-year primary tumor and involved lobe (local) failure rate was 20%, local-regional failure rate was 38% and disseminated failure rate was 31%. In a second study, Ashworth and colleagues reported the individual patient data meta-analysis, which included 757 patients diagnosed with stage IV NSCLC at 20 cancer centers worldwide. All patients had 1-5 synchronous or metachronous metastases treated with surgical metastectomy, SBRT, or radical external beam radiation therapy and the primary tumor was treated aggressively with a curative intent. The 1-year Overall Survival (OS) was 70.2% and 5-year Overall Survival was 29.4%. The authors were able to develop a risk stratification model for survival, to help identify which patients would be the best candidates for SBRT or surgery. They noted that patients with metachronous metastases had a 5-year Overall Survival of 48% and were considered low risk, those with synchronous metastases and negative nodes had a 5-year OS of 36% and were considered intermediate risk and patients with synchronous metastases and positive nodes were considered high risk and had a 5-year overall survival of 14%.

Taken together, these two studies have demonstrated that SBRT improves Overall Survival in elderly frail patients with medically inoperable early stage Lung Cancer and SBRT also improves Overall survival in patients Stage IV Non Small Cell Lung Cancer, with metachronous metastases without nodal involvement. A multidisciplinary team approach is strongly recommended, as treatment decisions are made for the latter group.

1)Long-term Results of RTOG 0236: A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Medically Inoperable Stage I Non-Small Cell Lung Cancer. Timmerman RD, Hu C, Michalski J, et al. DOI:http://dx.doi.org/10.1016/j.ijrobp.2014.05.135

2)An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors After Treatment of Oligometastatic Non-Small Cell Lung Cancer. Ashworth A, Senan S, Palma DA, et al. DOI: http://dx.doi.org/10.1016/j.ijrobp.2014.08.028

Late Breaking Abstract – ASCO 2015 Elective Neck Dissection Improves Overall Survival and Disease Free Survival in Early Oral Cavity Cancers

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SUMMARY: The American Cancer Society estimates that approximately 39,500 individuals will be diagnosed with oral cavity and oropharyngeal cancer in the United States in 2015 and about 7,500 will die of the disease. These cancers are more than twice as common in men as in women and tobacco and alcohol use are among the strongest risk factors. Routinely screening for oral mucosal lesions can improve survival in this patient group. The primary treatment of oral cavity squamous cell carcinoma is complete surgical resection with tumor free margins. Surgical management of the neck in patients with early stage oral cancers has remained unclear, with regards to the benefit of ipsilateral Elective Neck Dissection (END) at the time of primary surgery following diagnosis versus Therapeutic Neck Dissection (TND) after nodal relapse in the neck. To address this question, the authors conducted a prospective, randomized, controlled trial between 2004 and 2014, in which 596 treatment naïve patients with invasive squamous cell carcinoma of the oral cavity (tongue-85%, buccal mucosa-14%, floor of the mouth-1%) were enrolled and randomized to 1:1 to Elective Neck Dissection (END) or Therapeutic Neck Dissection (TND) following primary oral surgery. Patients had T1 (2 cm or less) or T2 (more than 2 cm and less than 4 cm) tumors that was lateralized to one side of the midline and were amenable to oral excision with adequate margins. Elective Neck Dissection (END) consisted of removal of submandibular (level 1), upper jugular (level 2)and midjugular (level 3) lymph nodes, with lower jugular (level 4) and posterior triangle (level 5) lymph nodes removed only if any of the lymph nodes in the first three levels showed intraoperative metastatic disease. Therapeutic Neck Dissection (TND) consisted of modified neck dissection (level 1-5) at the time of nodal relapse. All patients with high risk disease received adjuvant radiotherapy. The Primary end point was Overall Survival and Secondary end point was Disease Free Survival.

This publication summarizes the outcomes for the first 500 patients (245 in the END group and 255 in the TND group), following a median follow-up of 39 months. The 3 year Overall Survival was significantly higher in the Elective Neck Dissection group compared with the Therapeutic Neck Dissection group (80.0% vs. 67.5%, HR=0.63; P=0.01). The three year Disease Free Survival was also significantly higher in the END arm compared with TND (69.5% vs 45.9%, HR=0.45; P<0.001). The authors concluded that Elective Neck Dissection in patients with early stage oral squamous cell carcinoma resulted in 37% reduction in mortality risk as well as significantly high Disease Free Survival rates with a 55% reduction in the risk of disease recurrence. END should therefore be considered a standard treatment option. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. D’Cruz AK, Vaish R, Kapre N, et al. N Engl J Med 2015; 373:521-529

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

RR

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

RR

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.