Ovarian cancer currently causes more deaths than any other cancer of the female reproductive system, and is the fourth leading cause of cancer death among women in the United States.[1] Postoperative treatment with an intravenous (IV) platinum/taxane doublet has been the standard of care for the past decade in these patients. Although most ovarian cancer patients will enter a clinical complete remission after surgery and chemotherapy, the majority will ultimately relapse and die of their disease. This indicates that small-volume, occult disease remains in most women after initial treatment. Changes in treatment that effectively address this small-volume residual have the potential for a significant impact on disease outcome. In this issue of ONCOLOGY, Drs. Hess and Alberts provide an informative, insightful, and timely discussion of one such treatment approach-intraperitoneal (IP) therapy—which has recently re-emerged as a viable first-line treatment alternative in this challenging patient population.

Historical Context and Rationale for IP Therapy

IP delivery of chemotherapy is particularly attractive in ovarian cancer, due to the tumor's unique pattern of spread. While lymphatic or hematogenous dissemination can occur, ovarian cancer most often disseminates via local shedding of tumor from the ovary into the surrounding peritoneal cavity. Hence, ovarian cancer is largely confined to the peritoneal cavity for much of its natural history. With IP therapy, disease within the peritoneal cavity is exposed to higher and more prolonged drug concentrations than can be achieved when drug is given via the IV route, and the site of disease predominance (the peritoneum) receives the majority of exposure to the chemotherapeutic agents. Patients with small-volume disease (ie, no tumors > 1 cm) following surgical debulking are expected to benefit most, based on data suggesting poor penetration into the center of bulky tumors.[2] Thus, clinical trials have largely targeted this patient population.

As early as 1955, researchers demonstrated the safety and efficacy of IP therapy in patients with ovarian cancer. Weisenberger et al administered IP nitrogen mustard to seven ovarian cancer patients with malignant ascites and effusions. This treatment was tolerable and associated with a significant decrease in ascites in six of the seven patients.[3] Further research was conducted in the 1960s and 1970s, led by scientists such as Dedrick and Speyers at the National Institutes of Health (NIH), who established the basic pharmacologic/pharmacokinetic principles and currently accepted guidelines for IP therapy. In subsequent years, Markman and Howell established the safety and efficacy of IP cisplatin(Drug information on cisplatin), a drug that rapidly became the backbone of therapy for ovarian cancer. This led directly to incorporation of cisplatin into phase II and III clinical trials of IP therapy in ovarian cancer.[4]

IP Therapy Brought to the Front Line

Despite the sound theoretical rationale for its use and cumulative clinical trial data spanning decades, it is only within the past year that IP therapy has seen more widespread acceptance for front-line treatment in optimally-debulked ovarian cancer. As discussed by Drs. Hess and Alberts, the Gynecologic Oncology Group (GOG)-172 trial, published in early 2006, is the third North American randomized phase III trial to demonstrate a survival advantage.[5] This study demonstrated a significant survival benefit of IP compared to IV therapy (65.6 vs 49.7 months, respectively).

In the decade before GOG-172, two other large, randomized studies (GOG-104 and GOG-114) also demonstrated improved survival for patients treated with IP therapy.[6,7] Why did these two studies not change the pattern of care? In the case of GOG-104, it was published the same year as the seminal trial documenting the efficacy of paclitaxel(Drug information on paclitaxel) in ovarian cancer.[8] It seems clear that oncologists chose the new drug (paclitaxel) over the new route (IP). GOG-114 was designed to chemically cytoreduce residual tumor with two carboplatin(Drug information on carboplatin) treatments before instituting IP therapy. The dose of carboplatin (area under the concentration-time curve [AUC] of 9) resulted in an unexpectedly high rate of toxicity that precluded continuing therapy in many patients. At the completion of that study, it was not clear whether the benefits seen in patients randomized to the IP arm were due to the two cycles of high-dose carboplatin, the IP therapy, or the eight cycles of treatment on the IP arm compared to six cycles in the IV arm. These questions precluded a widespread acceptance of the IP approach.

A recent Cochrane systematic review presented a meta-analysis of these three GOG studies as well as five smaller randomized trials of IP therapy. The review concluded that the average effect of IP therapy is to reduce the death rate of patients by approximately 20%.[9] As noted by Drs. Hess and Alberts, these cumulative findings also propelled the National Cancer Institute (NCI) to release a formal clinical announcement recommending that women with optimally debulked stage III ovarian cancer be considered for IP therapy.[10] As a result, the NCI and other organizations including the GOG, the Society for Gynecologic Oncologists. and Southwest Oncology Group have launched major educational campaigns including workshops and training videos, to assist health-care providers in the implementation of IP therapy.

Barriers and Controversies

There remains a reluctance among some oncologists to fully embrace this treatment alternative, which now has a solid record of clinical efficacy, and the authors provide a thoughtful discussion of multiple factors that underlie this issue. For one, IP therapy requires technical expertise in catheter placement and administration techniques that is not always available, particularly outside of a major academic setting. IP therapy may also be more costly. It requires increased staff time and training, and currently used billing procedures may not adequately capture the true cost of the therapy. Furthermore, the GOG-172 IP regimen includes a 24-hour IV infusion of paclitaxel that commonly requires an inpatient hospital stay. Modification of the regimen utilizing a 3-hour paclitaxel infusion is one way to decrease cost. As noted by the authors, this appears to be the most common modification of the GOG-172 IP regimen.