The Legacy of Intraperitoneal Therapy in Ovarian Cancer: Why Are We Never Satisfied With the Answer

The evidence is overwhelming. The completion of four phase III randomized trials by the Gynecologic Oncology Group (GOG), the reporting of three of these trials in prominent high-impact journals, and the release of the 2006 National Cancer Institute consensus statement all support the use of intraperitoneal (IP) therapy.[1] Articles in the “pro-IP” publications-New England Journal of Medicine and Journal of Clinical Oncology-are always followed by waves of enthusiasm for this approach, but sadly not by a paradigm shift. The evidence suggests that few centers offer IP therapy routinely. Why? The answer may be that oncologists simply don’t know what to do. There have been three completely distinct regimens, none of which has been used in the outpatient setting. As outlined in the article by Drs. Oseledchyk and Zivanovic,[2] most centers providing IP therapy do not use GOG-approved dose-reduced regimens.[3,4] Very little research has been done on how to administer cytotoxics to the peritoneum, an important issue for the community oncologist in an outpatient center. The fact is, the drugs are old and the approach is old. The emphasis in oncology is always, as it should be, on the next breakthrough: paclitaxel in the 1990s, bevacizumab in 2000s, and perhaps immunotherapy in the next decade.

But healthcare reform may place a new emphasis on outcomes rather than new, exciting (and expensive) targeted drugs. With the push for Medicare to bundle payments for cancer care, less expensive approaches will certainly get more attention. In addition, pay-for-performance incentives will likely drive cancer treatment more toward purely evidence-based treatment pathways. This could be the right time to develop IP therapy for our community oncology networks. In the meantime, is there a new kid on the IP therapy block?

A small group of surgical oncologists in the 1990s began to explore the use of heated cytotoxic therapy administered as a single infusion intraoperatively. The outcomes and toxicities have been mixed at high-grade cancers. However, retrospective data and a few randomized trials seem to suggest that hyperthermic IP chemotherapy (HIPEC) is efficacious for well-differentiated gastrointestinal malignancies with very small–to–microscopic-volume disease. In ovarian cancer, HIPEC has been prospectively studied by groups in Italy and France; in addition, a few US centers, including Memorial Sloan Kettering and the University of California Irvine Chao Center, have undertaken prospective trials to define the role of HIPEC in ovarian cancer. There is much to be done before the level of evidence supporting HIPEC can approach the sizable body of existing data for ovarian cancer IP therapy in an evidence-based paradigm.

Still, Oseledchyk and Zivanovic provide valuable insight as to the possible role of HIPEC as an “alternative” IP therapy in ovarian cancer. Their article explores eloquently and thoroughly the issues that prevent the adoption of HIPEC as a replacement for traditional IP therapy. As the authors state, little support for the approach can be gained without a published prospective randomized trial in an ovarian cancer population. It is likely that the added complexity of HIPEC and the training required to manage HIPEC in ovarian cancer centers are preventing further exploration by more centers until there is evidence to support such efforts. Among the obstacles impeding wider use of HIPEC in ovarian cancer is the requirement for extremely small disease volume. Residual disease of a few millimeters or less is currently accepted as a requirement for HIPEC to be effective. It is hard to know exactly how many ovarian cancer patients have such small-volume residual disease following cytoreduction. However, most ovarian cancer surgeons have accepted 1 cm as “optimal” for treatment, a disease volume far too large for HIPEC to be effective. For this reason, we feel HIPEC may be better studied in consolidation or at interval cytoreductions where small-volume residual disease is common and hard to treat effectively.[5]

Now that the fourth GOG phase III study has closed and its data are maturing, we hopefully will soon have a fourth new, dose-reduced outpatient IP regimen. The results of GOG 252 may or may not validate the IP approach to the satisfaction of the modern community-based oncologist, but we hope they will achieve this goal. Pending the results of GOG 252, more exploration of the HIPEC approach in ovarian cancer should be encouraged, perhaps as a replacement for IP therapy, but more likely as an additional option for consolidation of primary or recurrent disease.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Trimble EL, Alvarez RD. Intraperitoneal chemotherapy and the NCI clinical announcement. Gynecol Oncol. 2006;103(2 suppl 1):S18-S19.

2. Oseledchyk A, Zivanovic O. Intraoperative hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer. Oncology (Williston Park). 2015;29:695-701, 706.

3. Naumann RW, Sukumvanich P, Edwards RP. Practice patterns of intraperitoneal chemotherapy in women with ovarian cancer. Gynecol Oncol. 2009;114:37-41.

4. Lesnock JL, Richard SD, Zorn KK, et al. Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications. Gynecol Oncol. 2010;116:345-50.

5. Edwards RP. Is hyperthermic intraoperative peritoneal chemotherapy and systemic chemotherapy as effective as standard intraperitoneal chemotherapy: time for a prospective trial? Gynecol Oncol. 2011;122:207-8.