Intraperitoneal (IP) chemotherapy is a preferred treatment option that should be offered to all women for front-line treatment of stage III optimally debulked ovarian cancer. Patients should be provided with information on the survival and toxicity for both IP and intravenous (IV) therapies, as well as practical information about the administration of each regimen, so that they may play an active role in the decision-making process. When making a decision between IP and IV therapeutic options, the experience and preference of the oncologist are critical factors in determining appropriate therapy for each woman.
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. 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) therapywhich 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. 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. 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, 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.
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. 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 in ovarian cancer. 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 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%. 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. 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.
In addition to these practical considerations, increased short-term toxicities were seen in the IP arm of GOG-172 including myelosuppression, fatigue, neuropathy, abdominal discomfort, and emesis, although there was no difference in treatment-related deaths or quality of life at 1 year. IP therapy, like most intensive therapies, may thus be less well tolerated and less desirable in patients with a borderline performance status or significant comborbidities. It is possible that toxicities can be lessened, at least in part, with the use of more aggressive and contemporary supportive care measures. A recent analysis of the GOG-172 regimen using aprepitant (Emend) and pegfilgrastim (Neulasta) prophylaxis showed a substantially greater completion rate for the IP therapy and a significant decrease in toxicity.
Further study is needed to address whether adjustments in the GOG-172 IP regimen to decrease toxicity will preserve the survival benefits seen in this trial. Perhaps the most intriguing consideration for modulating the toxicity of IP therapy is the use of IP carboplatin in place of IP cisplatin. However, as Drs. Hess and Alberts indicate, the kinetics of IP carboplatin differ from those of IP cisplatin. Thus, regimens utilizing IP carboplatin will require rigorous testing in randomized phase III trials before they can be routinely recommended.
In addition to refining the GOG-172 regimen of IP cisplatin/paclitaxel as discussed above, we are faced with numerous other questions and research challenges as we strive to maximize the clinical potential of IP therapy in ovarian cancer. The incorporation of novel agents into IP clinical studies is an obvious and compelling area requiring further investigation. Promising chemotherapeutic agents include carboplatin, docetaxel, gemcitabine (Gemzar), and topotecan (Hycamtin). These agents have a well established track record in the treatment of ovarian cancer and have properties that favor their use as IP agents and/or via IV but as part of an IP regimen.
Other potential avenues of investigation include the adjunctive use of agents that modulate IP absorption and alter the systemic pharmacokinetics of drugs administered IP. Finally, molecularly targeted agents such as bevacizumab (Avastin) have been shown to improve the efficacy of chemotherapy in diseases such as colorectal, lung, and breast cancer. When these agents are tested in ovarian cancer, they should be tested with the best regimens we have, and today that includes IP therapy.
Studies are also needed to address the use of IP therapy in other patient populations. For example, patients with larger-volume (> 1 cm) tumors following surgery might benefit from IP therapy as a consolidation treatment after neoadjuvant therapy. Other potential scenarios for IP studies include early-stage disease, recurrent disease, or in the palliation of end-stage symptoms such as refractory ascites. Finally, prospective, randomized trials are also needed to more rigorously assess whether the measures noted in the preceding section, such as educational programs for health-care providers, standardization of IP equipment and techniques, and more aggressive supportive care, can decrease toxicities and complications associated with IP therapy.
IP therapy is not a new concept, but it is only now emerging as a standard front-line treatment for advanced ovarian cancer. Integration of this therapy into standard oncologic practice has been slow to materialize, and we concur with the authors' central statement that "physicians have the obligation to offer IP therapy as a viable treatment choice and to allow patients to make informed decisions about their care." This laudable aim is greatly aided by the thorough and comprehensive review presented by Drs. Hess and Alberts.
Julie Jaffe, MD
Deborah Armstrong, MD
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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