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Should intraperitoneal chemotherapy become the standard of care for ovarian cancer?
IP should be standard
Several large randomized phase-3 clinical trials have compared intraperitoneal with intravenous chemotherapy and have demonstrated improved outcomes for patients with advanced, optimally debulked ovarian cancer. The first two were reported in 1996 and 2001, with the first showing a significant survival advantage in the pre-paclitaxel era and the second showing improved progression-free survival, but only borderline improvement in overall survival. Despite these results, a number of factors prevented the widespread acceptance of intraperitoneal chemotherapy as standard treatment: increased toxicity of the regimen, catheter-related complications, as well as lack of experience with intraperitoneal chemotherapy administration.
However, with the report of the results of GOG-172 in 2006, little doubt remains that the current standard regimen for adjuvant treatment of optimally debulked advanced ovarian cancer should be the combination of intraperitoneal and intravenous cisplatin and paclitaxel. Over 400 patients were treated on this clinical trial, and those receiving intraperitoneal treatment experienced a statistically significant 16-month improvement in overall survival.
It must be noted that toxicities were greater on the intraperitoneal arm (mostly hematologic, gastrointestinal, and neurologic). Though only 42% of patients could complete the prescribed six cycles of intraperitoneal therapy with the remainder of treatments being given intravenously, survival was analyzed on an intent-to-treat basis, with patients still experiencing a significant survival advantage. Although quality of life was worse during and immediately after treatment for those receiving intraperitoneal chemotherapy, by one year after treatment, there was no appreciable difference.
Outside of a clinical trial, patients with advanced, optimally cytoreduced ovarian cancer should be carefully counseled regarding the benefits and toxicities of intraperitoneal therapy. Those in good physical condition who are better able to tolerate the increased toxicity should be treated with intraperitoneal chemotherapy. Even those who cannot tolerate a full six courses of treatment may reap the benefits of the initial doses.
Christina Chu, MD, is an Assistant Professor, Gynecologic Oncology at the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
IP efficacy not yet proven
The preferred adjuvant therapy regimens for patients with optimally debulked, locally advanced ovarian cancer are still debated today. Following the 2006 report of phase-3 trial comparing experimental IP chemotherapy with control IV only chemotherapy, which showed a significant advantage in progression free survival and overall survival, the National Cancer Institute issued a clinical announcement recommending that IP cisplatin plus a taxane be considered for these patients.
The debates revolve around four issues: toxicity, incomplete treatment, improper controls, and gynecologic consensus conference recommendations.
IP chemotherapy was significantly more toxic than IV treatment, including excess drug toxicity and significant catheter-associated morbidity. There was a reduced quality of life experienced by the IP patients that equalized by one year after treatment.
Only 42% of patients assigned to the IP treatment arm completed the assigned treatment. Patients who experienced excessive toxicity had their treatments reduced, changed to IV, or changed to the less toxic drug, thus challenging the validity of the pharmacologic principles. Weekly paclitaxel administration has been shown to be superior to every three-week administration of paclitaxel in patients with breast cancer. The use of weekly paclitaxel in patients on the IP arm may have accounted for part of the therapeutic benefit reported.
The use of a technically more complicated, more toxic, more costly IP regimen in the community where patients with less rigorous eligibility criteria will be treated is not appealing.
Although several phase-3 randomized trials have shown statistically and consistently superior results for IP chemotherapy compared with IV controls with regard to both progression-free survival and overall survival in optimally debulked stage III epithelial ovarian cancer, patients in the control arms in each of these studies are not those that would be the standard of care today. They are inferior to the carboplatinum paclitaxel every three weeks standard, which has been shown to produce progression-free survival and overall survival results approximately equal to those reported for the IP treatment arm and at significantly less toxicity.
A gynecologic consensus conference recommended the every three week carboplatinum, paclitaxel regimen be used as the community standard. Until IP chemotherapy is compared to an optimally effective control, it is difficult to subject patients not on experimental protocols to IP chemotherapy with its attended excessive toxicity and morbidity.
Daniel Lehane, MD, is an oncologist at Methodist Hospital, Houston, Texas.