Intraperitoneal Therapy for Ovarian Cancer.

Twenty-four years ago, David Alberts and I wrote a letter to the Journal of Clinical Oncology to speak in favor of studying intraperitoneal (IP) therapy. Now, the editorial by Bookman and Brady on the article by Tewari et al merits comments on this longrunning debate. The joint analysis of long-term survival of two Gynecologic Oncology Group (GOG) phase III studies, GOG-0114 and GOG-0172, is an informative tour de force given that the two studies shared identical intravenous (IV) comparator arms and patient entry criteria. Doubters of the survival impact of first-line, cisplatin-based IP therapy on ovarian cancer often readily dismiss GOG-0114 as being a negative study because of its overall survival difference of IP over IV reaching only borderline statistical significance (one-tailed P 5 .51). As a footnote, Tewari et al erroneously describe the IP regimen as giving IP cisplatin on day 8—it should be day 2. The editorial by Bookman and Brady covers three take home messages from such joint analyses: extended survival at 10 years was deemed true as, indeed, it is clearly shown; sustained impact of IP therapy on small volume tumors (from only microscopic to 1 cm or less) was deemed of interest and largely unexplained; and six IP cycles demonstrated an advantage vis-a-vis three to five, less than three, and IV therapy (from Fig 4 by Tewari et al), which was deemed to be subject to interpretation, that is, it should be taken it with a grain of salt. The critiques by Bookman and Brady elicit these thoughts: good points are made, with full agreement that the analysis by Tewari et al showing favorable outcomes for those women who complete six cycles is subject to selection bias. However, their overarching conclusion that new approaches are needed does not take us very far. Is the greater than 10-fold pharmacologic advantage for IP cisplatin really trumped by the discredited experience with IV dose intensity? Their informative analysis seems ready to dismiss future efforts in IP therapy for ovarian cancer “. in spite of demonstrated improvement in [overall survival] ([hazard ratio], 0.76). ” Why should one not consider it a priority to follow leads that identify those most likely to benefit from IP interventions? In fact, patients with high-grade serous cancers associated with BRCA mutations or other forms of homologous recombination deficiency have been reported to have superior outcomes following IP platinum-based regimens. The toxicities, complications, and expense of IP therapy differ among the GOG trials. GOG-0172 excessive sensory neuropathy is a direct result of adding more paclitaxel to the well-characterized, dose-related toxicities of cisplatin. A dose of cisplatin 100 mg/m that was dismissed from IV regimens after clear documentation of its adverse therapeutic index should, by now, be discarded from IP regimens as an historical footnote. Studying IP carboplatin or more modest doses of cisplatin that nonetheless confer considerably greater IP over IV drug exposures for tumor cells within the peritoneal cavity are steps in the right direction. In fact, the rapid accrual to the GOG-0252 trial is tangible proof that well-trained gynecologic oncologists can safely study new IP drug delivery concepts in the appropriate patients.