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.
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 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.
The primary end point was Progression Free Survival (PFS) and secondary end points included Objective Response Rate (ORR), Overall Survival (OS), safety, and patient reported outcomes. The combination of AVASTIN® plus chemotherapy resulted in a 62% reduction in the risk of progression compared to those who received chemotherapy alone, with a median PFS of 6.8 months for the AVASTIN® plus chemotherapy group versus 3.4 months for the single agent chemotherapy group (HR=0.38, P<0.0001) and thus met the primary endpoint of this clinical trial. This PFS benefit was seen consistently across all subgroups including the subgroup of patients with ascites. The ORR was 27.3% with the AVASTIN® combination versus 11.8% with single agent chemotherapy (P =0.001). The median OS was 16.6 months for the AVASTIN® combination versus 13.3 months for the single agent chemotherapy group (HR=0.85; P < .17). The lack of statistical significance in the OS has been attributed to cross over of 40% of patients, initially randomized to the chemotherapy alone group, who upon progression received AVASTIN®. There was a 15% improvement in abdominal and GI symptoms as reported by patients, with the AVASTIN® combination, compared to chemotherapy alone. On exploratory analyses it was noted that the addition of AVASTIN® to TAXOL® resulted in the most benefit, with a 5.7 month improvement in median PFS (9.6 versus 3.9 months), a 23% improvement in the overall response rate (53% versus 30%) and a 9.2 month improvement in median OS (22.4 versus 13.2 months) compared to single agent TAXOL®. This benefit was seen in spite of the fact that 97% of the patients in the TAXOL® group had received this agent with previous chemotherapy regimens. These findings suggest that patients who have received prior treatment with TAXOL® may benefit from AVASTIN® plus weekly TAXOL®. The most common adverse reactions (greater than or equal to 15%) in patients treated with AVASTIN® plus chemotherapy were neutropenia, peripheral neuropathy, hypertension and GI perforation occurred in 1.7% of these patients. This low perforation rate has been attributed to the exclusion of patients with rectosigmoid involvement by pelvic examination or bowel involvement on CT scan as well as those with clinical symptoms of bowel obstruction. The authors concluded that AVASTIN® in combination with chemotherapy significantly improved Progression Free Survival and Objective Response Rates in patients with Platinum Resistant Recurrent Ovarian Cancer. Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol 2014;32:1302-1308
AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) is a multicenter, randomized, open-label, Phase III study in which 361 women with platinum resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer were enrolled. These patients had disease progression within six months of their platinum based chemotherapy (Platinum Resistant) and were randomly assigned to receive AVASTIN® (Bevacizumab) 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks in combination with investigators choice of single agent chemotherapy agent such as weekly TAXOL®, HYCAMTIN®, DOXIL® (N=179) or single agent chemotherapy alone (N=182). Patients with refractory disease, history of bowel obstruction, or those who had received two or more prior anticancer regimens were excluded. Treatment was given until disease progression. Patients who had progressed on single agent chemotherapy were allowed to cross over to single agent AVASTIN®. The primary end point was Progression Free Survival (PFS) and secondary end points included Objective Response Rate (ORR), Overall Survival (OS), safety, and patient reported outcomes. The combination of AVASTIN® plus chemotherapy resulted in a 52% reduction in the risk of progression compared to those who received chemotherapy alone, with a median PFS of 6.7 months for the AVASTIN® plus chemotherapy group vs 3.4 months for the single agent chemotherapy group (HR=0.48, P<0.001) and thus met the primary endpoint of this clinical trial. This PFS benefit was seen consistently across all subgroups including the subgroup of patients with ascites. The ORR was 27.3% with the AVASTIN® combination vs 11.8% with single agent chemotherapy (P =0.001). The median OS was 16.6 months for the AVASTIN® combination vs 13.3 months for the single agent chemotherapy group (HR=0.85; P < .17). The lack of statistical significance in the OS has been attributed to cross over of 40% of patients, initially randomized to the chemotherapy alone group, who upon progression, received single agent AVASTIN®. As expected, grade 2 or more hypertension and proteinuria were common in the AVASTIN® group and GI perforation occurred in 2.2% of these patients. There was a 15% improvement in abdominal and GI symptoms as reported by patients, with the AVASTIN® combination, compared to chemotherapy alone. The authors concluded that AVASTIN® in combination with chemotherapy significantly improved Progression Free Survival and Objective Response Rates in patients with Platinum Resistant recurrent Ovarian Cancer. Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol 2014;32:1302-1308