The ability to better select patients who are more likely to complete [intraperitoneal] therapy with better outcomes and less toxicity warrants further investigation as we move toward individualizing therapies.
—Devansu Tewari, MD, and colleagues
In an analysis of Gynecologic Oncology Group (GOG) studies reported in the Journal of Clinical Oncology, Devansu Tewari, MD, of Kaiser Permanente Irvine Medical Center, and colleagues found that intraperitoneal chemotherapy was associated with a survival advantage compared with intravenous chemotherapy over long-term follow-up in women with advanced ovarian cancer.1 The findings of long-term benefit may raise issues regarding wider incorporation of intraperitoneal treatment into clinical practice in this setting.
The retrospective analysis involved data from 876 patients in the phase III GOG studies 114 (N = 462) and 172 (N = 414), both of which randomly assigned patients to intraperitoneal (combined n = 440) or intravenous (combined n = 436) chemotherapy. All patients had stage III epithelial ovarian or peritoneal carcinoma with no residual disease more than 1 cm in diameter after surgery.
In GOG 114, patients were randomly assigned to receive either intravenous paclitaxel at 135 mg/m2 followed by intravenous cisplatin at 75 mg/m2 for six courses or intravenous carboplatin for two courses followed by intravenous paclitaxel at 135 mg/m2 on day 1 and intraperitoneal cisplatin at 100 mg/m2 on day 8 for six courses. Intravenous cisplatin was substituted for intraperitoneal cisplatin in patients with catheter-related problems.
In GOG 172, patients received 135 mg/m2 of intravenous paclitaxel followed by either 75 mg/m2 of intravenous cisplatin on day 2 or 100 mg/m2 of intraperitoneal cisplatin on day 2 and 60 mg/m2 of intraperitoneal paclitaxel on day 8 for six cycles. Substitution with intravenous carboplatin was permitted if administration of intraperitoneal cisplatin was prevented by toxicity or catheter-related problems.
Patients in the intraperitoneal and intravenous groups were generally balanced for baseline characteristics. Overall, patients had a median age of 47 years (55% aged ≥ 55 years); 90% were white; GOG performance status was 0 for 44% and 1 for 48%; tumor grade was 1 in 11%, 2 in 38%, and 3 in 50%; histology was serous in 72% and endometrioid in 9%; and 64% had gross residual disease. Overall, 94 patients in the intraperitoneal group (21%) crossed over to intravenous treatment.
Improved Overall Survival
Median follow-up was 10.7 years. Median progression-free survival was 25 months in the intraperitoneal group vs 20 months in the intravenous group (P = .019). Median overall survival with intraperitoneal therapy was 61.8 months (95% confidence interval [CI] = 55.5–69.5 months) vs 51.4 months (95% CI = 46.0–58.2 months) for intravenous therapy (P = .042).
After adjustment for age, performance status, cell type, tumor grade, and residual disease, hazard ratios (HRs) were 0.79 (P = .003) for progression and 0.77 (P = .002) for death among those receiving intraperitoneal therapy. Overall, there was a significant association of reduced risk of death with each cycle of intraperitoneal treatment completed (adjusted HR = 0.88, P < .001, for each cycle).
Subgroup Analysis and Predictive Factors
In subgroup analysis, intraperitoneal treatment was associated with significantly improved overall survival among patients with gross residual (≥ 1 cm) disease vs no visible disease (adjusted HR = 0.75, P = .006), with this improvement observed in the context of the significantly increased risk of mortality associated with gross residual disease (adjusted HR = 1.89, P < .001). Factors significantly associated with poorer overall survival included clear/mucinous vs serous histology (adjusted HR = 2.79, P < .001), gross residual vs no visible disease (adjusted HR = 1.89, P < .001), and fewer cycles of intraperitoneal chemotherapy with crossover to intravenous therapy (adjusted HR = 1.43, P = .041).
Overall, only 50% of patients completed the protocol-stipulated six cycles of intraperitoneal treatment. Younger patients were more likely to complete intraperitoneal regimens, with the probability of completion decreasing by 5% with each additional year of age (odds ratio = 0.95, P < .001). Other demographic and clinicopathologic factors, including performance status, were not predictive of completing intraperitoneal therapy.
The investigators concluded: “The advantage of [intraperitoneal] over intravenous chemotherapy extends beyond 10 years. [Intraperitoneal] therapy enhanced survival of those with gross residual disease. Survival improved with increasing number of [intraperitoneal] cycles.”
The long-term survival benefits described in this report may encourage more clinicians to adopt [intraperitoneal] chemotherapy in the community. In addition, [intraperitoneal] therapy may be implemented as a quality measure at institutions with the expertise and support teams necessary to administer [intraperitoneal] treatment. Clinicians should support patients through the [intraperitoneal] regimen, particularly if there are no significant or excessive toxicities. Lastly, the ability to better select patients who are more likely to complete [intraperitoneal] therapy with better outcomes and less toxicity warrants further investigation as we move toward individualizing therapies.
John K. Chan, MD, of California Pacific/Palo Alto Medical Foundation/Sutter Research Institute, San Francisco, is the corresponding author for the Journal of Clinical Oncology article. ■
Disclosure: The study was supported by National Cancer Institute grants, a Gynecologic Oncology Group Young Investigator Award, and the John A. Kerner Denise & Prentis Cobb Hale Research Award. For full disclosures of the study authors, visit jco.ascopubs.org.
1. Tewari D, Java JJ, Salani R, et al: Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer. J Clin Oncol 33:1460-1466, 2015.
Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center, offers his thoughts on the future of intraperitoneal treatment in advanced ovarian cancer.