Tag: Ovarian Cancer

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. The FDA in 2014 approved AVASTIN® (Bevacizumab) in combination with Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan, for the treatment of patients with Platinum-resistant, recurrent epithelial Ovarian, Fallopian tube, or Primary Peritoneal cancer. The approval was based on the AURELIA Open-Label Randomized Phase III Trial which concluded that AVASTIN® in combination with chemotherapy significantly improved Progression Free Survival and Objective Response Rates, in patients with Platinum Resistant, Recurrent Ovarian Cancer.

ICON7 is an open-label, randomized, phase III trial, in which the safety and efficacy of combining AVASTIN® with standard chemotherapy was evaluated, in patients with Newly Diagnosed Ovarian Cancer. One thousand five hundred and twenty eight (n=1528) patients were enrolled and eligible women with newly diagnosed Ovarian cancer had either early stage disease (FIGO Stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO Stage IIb–IV) disease. Patients had undergone debulking, cytoreductive surgery, or in those with advanced disease, had a biopsy for tissue diagnosis, with no further surgery planned. High risk disease in this study was defined as Stage IV disease, inoperable Stage III disease, or suboptimally debulked (more than 1 cm) Stage III disease. Patients were randomly assigned in a 1:1 ratio to receive either 6 cycles of combination chemotherapy with PARAPLATIN® (Carboplatin) AUC of 5 or 6 and TAXOL® (Paclitaxel) 175mg/m2 IV, given every 3 weeks or the same chemotherapy regimen given concurrently with AVASTIN® (Bevacizumab) 7.5mg/kg IV, every 3 weeks for 6 cycles followed maintenance AVASTIN® given IV every 3 weeks for 12 additional cycles or until disease progression, which ever was the earlier. The median age was 57 years. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival and Safety outcomes of adverse events. The median follow up was 48•9 months.

The Primary endpoint of Progression Free Survival (PFS) has been previously reported and was 21•8 months with the addition of AVASTIN® to chemotherapy compared with 20•3 months with chemotherapy alone, in the entire study population (HR=0•81; P=0•004). However, in the predefined high risk population of patients with suboptimally cytoreduced stage III or stage IV disease, the PFS with the addition of AVASTIN® to chemotherapy was 18•1 months versus 14•5 months (HR=0•73; P=0•002).

In this publication, the authors reported the final Overall Survival results of the ICON7 trial. They noted no difference in the Overall Survival between AVASTIN® plus chemotherapy versus chemotherapy alone groups. (45.5 months vs 44.6 months, P=0.85). However, in the predefined group of high risk patients with inoperable or suboptimally cytoreduced stage III or stage IV disease, there was an Overall Survival benefit, with a mean Overall survival of 39•3 months in the AVASTIN® plus chemotherapy group versus 34•5 months in the chemotherapy alone group (P=0•03). This survival benefit was not seen in clear cell, early stage high grade, or low grade serous tumors. It is hypothesized that the effect of AVASTIN® on the tumor microenvironment is dependent on residual tumor burden, which is presumably producing VEGF (Vascular Endothelial Growth Factor). The authors concluded that the Overall Survival benefit with a combination of AVASTIN® and chemotherapy is best accomplished in newly diagnosed Ovarian cancer patients, with poor prognostic factors. Oza AM, Cook AD, Pfisterer J, et al. Lancet Oncol 2015;16:928-936. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial

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.

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. 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.

SUMMARY:The FDA on December 19, 2014 approved LYNPARZA® (Olaparib) as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) advanced ovarian cancer who had been treated with three or more prior lines of chemotherapy. It is estimated that in the United States, approximately 22,000 women will be diagnosed with ovarian cancer in 2014 and a little over 14,000 women will die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. They also account 15 percent of ovarian cancers in addition to other cancers such as colon and prostate. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal. The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. LYNPARZA® is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The approval of LYNPARZA® was based on a single arm phase II trial in which 137 platinum resistant ovarian cancer patients with measurable germline BRCA mutations were enrolled. The BRCA mutation status was verified retrospectively in 97% of the patients with available blood samples from the phase II study, using the BRACAnalysis CDx® test. These patients had received three or more lines of prior chemotherapy. Treatment consisted of LYNPARZA® administered orally twice a day and was continued until disease progression or unacceptable toxicity. The primary endpoint was Objective Response Rate (ORR). The Overall Response Rate was 34% and the median response duration was 7.9 months. In a larger cohort of patients reported by the authors (ovarian cancer cohort, N=193) the median Progression Free Survival was 7 months, 55% of patients were progression free at 6 months, the median Overall Survival was 16.6 months and 64.4% of patients were alive at 12 months. The most common adverse reactions associated with LYNPARZA® were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort. This ground breaking therapy with LYNPARZA® is first of a new class of drugs, for treating ovarian cancer and along with the BRACAnalysis CDx® companion diagnostic test, is a significant milestone for patients with difficult-to-treat advanced ovarian cancer, with germline BRCA mutations. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. [published online November 3, 2014]. J Clin Oncol. doi:10.1200/JCO.2014.56.2728.