Abstract
The primary site of spread and failure in most cases of advanced epithelial ovarian carcinoma (EOC) is the peritoneum. Even in relapses, the disease is typically confined to the peritoneal cavity. Previous studies have found a 20-fold higher concentration of cisplatin in the peritoneum after intraperitoneal (IP) administration compared with that in plasma after intravenous (IV) administration. In 3 intergroup trials, cisplatin delivered via the IP route in patients with advanced, low-volume EOC showed a clear survival benefit over that administered intravenously. Prolonged drug exposure resulting from slow absorption from the peritoneum may also contribute to an IP advantage. Despite these positive findings and a subsequent National Cancer Institute alert, IP therapy has not been widely accepted as the standard of care in the United States. Reluctance of clinicians to use IP therapy is likely due to higher toxicity, inconvenience, catheter complications, and uncertain long-term benefits. The majority of patients in the most recent trial did not complete the IP regimen because of toxicity and other related complications. Thus, the therapeutic advantage of increasing the number of IP cycles is unclear, as is whether the benefit of IP therapy persists over an extended period. The aim of this study was to investigate long-term survival and associated prognostic factors after IP chemotherapy in patients with advanced EOC. Exploratory analysis of 2 Gynecologic Oncology Group (GOG) randomized phase 3 clinical trials compared the 10-year survival outcomes of those who underwent IP versus IV chemotherapy. In addition, factors associated with survival after IP therapyincluding the extent of residual disease and number of cycles of IP therapywere evaluated. Data from GOG protocols 114 and 172 were retrospectively analyzed. Cox proportional hazards regression models were used to assess the relationship of treatment modality and survival outcomes, adjusting for baseline demographic and clinicopathologic factors. A total of 876 patients were included in the study. Median follow-up was 10.7 years. Median overall survival was longer with IP therapy compared with IV therapy: 61.8 months for IP (95% confidence interval [CI], 55.5-69.5) compared with 51.4 months for IV therapy (95% CI, 46-58.2; P < 0.042). Compared with IV therapy, there was a 23% decreased risk of death with IP therapy; the adjusted hazard ratio (aHR) was 0.77, with a 95% CI of 0.65 to 0.90, P < 0.002. Intraperitoneal therapy also improved survival of those with gross residual (1 cm) disease (aHR, 0.75; 95% CI, 0.62-0.92; P < 0.006). For each cycle of IP chemotherapy completed, risk of death decreased by 12% (aHR, 0.88; 95% CI, 0.83-0.94; P < 0.001). Prognostic factors associated with poorer long-term survival after IP therapy included clear cell/mucinous versus serous histology (aHR, 2.79; 95% CI, 1.83-4.24; P < 0.001), gross residual versus no visible disease (aHR, 1.89; 95% CI, 1.48-2.43; P < 0.001), and fewer versus more cycles of IP chemotherapy (aHR, 0.88; 95% CI, 0.83-0.94; P < 0.001). Younger patients were more likely to complete 6 cycles of the IP regimen. There was a 5% decrease in probability of completing therapy with each increasing year at enrollment; the odds ratio was 0.95, with a 95% CI of 0.93 to 0.96, P < 0.001. This study provides the first updated results of GOG IP chemotherapy trials, showing long-term survival benefit extending beyond 10 years. Intraperitoneal therapy has a survival advantage over IV therapy in patients with gross residual disease.
Younger age is associated with increased likelihood of completing 6 cycles of IP therapy. Survival improves in those who completed more cycles of IP therapy.