Survival advantage of intraperitoneal chemo persists beyond a decade

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IP therapy adds complexity, toxicity, and cost

The role of intraperitoneal chemotherapy is one of the longest-running controversies in gynecologic oncology. One reason is that the chief rationale for intraperitoneal chemotherapy – that direct contact between tumor implants and peritoneal fluid containing high concentrations of cytotoxic agents is more effective than systemic intravenous therapy – has never been established. One might question why understanding the mechanism is important when the overall survival (OS) data are positive. However, IP therapy adds complexity, toxicity, and cost, particularly with the original GOG-0172 regimen, which includes cisplatin at 100 mg/m2 and paclitaxel over a 24-hour period. This has triggered several ad hoc modifications. None of these reasonable alternatives has been prospectively compared with the original regimen, and without a clear understanding of the underlying mechanism, it is difficult to predict which changes might be detrimental to OS. Our cumulative experience with intraperitoneal (IP) therapy has demonstrated sustained improvement in median OS (HR, 0.76) without an impact on long-term disease-specific mortality at the expense of increased complexity, toxicity, and cost. Similar gains in OS have been observed with other approaches, including intravenous therapy that incorporates dose-dense weekly paclitaxel, especially in high-risk patients with larger-volume residual disease. Important questions remain regarding patient selection (in terms of the extent of residual disease), mechanism of action, treatment modifications, timing, optimal number of IP cycles, and integration with targeted agents. Some of these questions will be addressed in the context of GOG-0252, and it remains to be seen whether better intravenous chemotherapy might match the outcomes previously associated with IP chemotherapy.

Dr. Michael A. Bookman is at U.S. Oncology Research in the Woodlands, Tex., and at Arizona Oncology in Tucson. He reported serving as a consultant or adviser to AstraZeneca, AbbVie, Sanofi, Boehringer Ingelheim, Genentech, Roche, Novartis, Immunogen, Endocyte, Gradalis, and NRG Oncology. Dr. Mark F. Brady is at the NRG Oncology Statistical and Data Center, Buffalo, N.Y. He reported ties to Endocyte, Genentech/Roche, and Advaxis. Dr. Bookman and Dr. Brady made these remarks in an editorial accompanying Dr. Tewari’s report (J. Clin. Oncol. 2015 March 23 [doi:10.1200/JCO.2014.60.2797]).



The survival advantage conferred by intraperitoneal chemotherapy over intravenous chemotherapy in advanced ovarian cancer persists beyond 10 years, according to a report published online March 23 in the Journal of Clinical Oncology.

Several clinical trials have demonstrated that compared with standard intravenous chemotherapy, intraperitoneal chemotherapy yields longer short-term survival. This benefit has been attributed to the much higher concentrations of active drug delivered into the peritoneal cavity with the latter approach, although this purported mechanism of action has never been proven. One previous study showed a 20-fold higher level of cisplatin in the peritoneal space with intraperitoneal than with intravenous administration, and another demonstrated a 1,000-fold higher concentration of paclitaxel in the peritoneal space with intraperitoneal than with intravenous administration, said Dr. Devansu Tewari of Kaiser Permanente Irvine (Calif.) Medical Center and his associates.

Nevertheless, intraperitoneal chemotherapy has not been widely adopted in the United States and is used only rarely in Europe. Clinicians’ hesitancy to use this approach has been attributed to its higher toxicity, inconvenience, and catheter-related complications, as well as to a lack of evidence regarding its long-term benefits.

To assess any long-term survival benefit, Dr. Tewari and his colleagues performed an exploratory, post hoc analysis of data pooled from two clinical trials first reported in 1996 and 2001 (Gynecologic Oncology Group protocols 114 and 172), which involved 876 women who had stage III epithelial ovarian or peritoneal carcinoma with no residual disease greater than 1 cm in diameter after surgery. The study participants were randomly assigned to receive either six cycles of intravenous paclitaxel plus intravenous cisplatin, or intravenous carboplatin plus intravenous paclitaxel plus intraperitoneal cisplatin in trial 114; those in trial 172 were randomly assigned to receive either intravenous paclitaxel plus intravenous cisplatin, or intraperitoneal cisplatin plus intraperitoneal paclitaxel for six cycles.

After a median follow-up of 10.7 years, the overall median survival was 61.8 months with intraperitoneal chemotherapy and 51.4 months with intravenous chemotherapy, a significant difference. Thus, intraperitoneal delivery was associated with a 23% decreased risk of death, with a hazard ratio of 0.77 after adjustment for patient age and performance status, tumor cell type and grade, and the presence or absence of residual disease, the investigators reported (J. Clin. Oncol. 2015 March 23 [doi:10.1200/JCO.2014.55.9898]).

Patients who completed all six cycles of intraperitoneal chemotherapy had longer survival than did those who completed only three. The risk of death decreased by 12% for each cycle of intraperitoneal chemotherapy completed, with an adjusted HR of 0.88. This indicates that clinicians should support patients through the entire intraperitoneal regimen, particularly if toxicities are not excessive, Dr. Tewari and his associates said.

In addition, the intraperitoneal approach conveyed a survival advantage in patients who had residual disease of 1 cm or less, as well as in those who had no visible residual disease.

If these findings are confirmed in future studies, more patients might be candidates for intraperitoneal chemotherapy, and more clinicians might adopt this approach in their practices, the researchers said.

This analysis, like the two Gynecologic Oncology Group trials on which it was based, was supported by the National Cancer Institute. Dr. Tewari reported having no financial disclosures; one of his associates reported receiving honoraria from Johnson & Johnson, Genentech, and AstraZeneca. 

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