What role, if any, should intraperitoneal chemotherapy play in the management of ovarian cancer? It is rather remarkable that this question must be asked after more than 2 decades of clinical investigation.[1,2] Perhaps we should first inquire as to why it has taken so long to answer this question.
In the earliest days of the modern chemotherapeutic era (1950s), it was recognized that the direct delivery of cytotoxic agents into the peritoneal cavity had the potential to be a clinically useful approach in the treatment of malignancies principally confined to this body compartment.[3,4] However, it was only with the publication of a pharmacokinetic modeling study by Dedrick et al in the late 1970s that a sound theoretical rationale for this approach in the management of ovarian cancer was presented.
Simply stated, this model predicted that for certain cytotoxic agents, higher concentrations and longer durations of tumor exposure could be achieved with the intraperitoneal, rather than systemic, delivery of the same drug. This article stimulated considerable interest in the concept of regional therapy with antineoplastic drugs in the treatment of ovarian cancer, and subsequently, numerous phase I and II trials of single-agent and combination intraperitoneal chemotherapies were conducted.[2,5-7]
These studies, conducted during the 1980s and early 1990s, revealed a major pharmacokinetic advantage associated with the regional delivery of selected antineoplastic agents (Table 1),[2,5-7] and established the feasibility and safety of this approach. These studies also demonstrated that surgically defined complete responses and long-term survival could be observed following cisplatin(Drug information on cisplatin) (Platinol)-based intraperitoneal therapy delivered in the second-line setting in patients with ovarian cancer (Table 2).[8-16]
Unfortunately, these studies failed to provide a definitive answer to the question asked in the title of this article: Is there a role for intraperitoneal chemotherapy in the management of ovarian cancer? In fact, this question could only be answered directly through well-designed randomized phase III studies, the results of which were not available until relatively recently.
Table 3 lists the regimens studied in the few phase III trials of intraperitoneal therapy in the initial management of ovarian cancer.
Cisplatin Plus Cyclophosphamide(Drug information on cyclophosphamide)
In 1996, investigators from the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) published the results of the first large randomized phase III trial comparing intraperitoneal chemotherapy to standard intravenous (IV) chemotherapy in the treatment of advanced ovarian cancer. In this landmark study, more than 600 patients, whose largest residual intraperitoneal tumor mass was < 2 cm in maximum diameter, were randomized to receive either IV or intraperitoneal cisplatin (100 mg/m2). All patients were also treated with IV cyclophosphamide (Cytoxan, Neosar) 600 mg/m2.
Toxicity: As anticipated, there was more abdominal discomfort in the patient population receiving the intraperitoneal program than the IV approach. However, in the majority of treated individuals, this discomfort was temporary and patients were able to continue with the planned treatment program.
Of some surprise, the study revealed a statistically significant reduction in both neutropenia and ototoxicity associated with the regional treatment regimen. Overall, however, there were no major differences between the two treatment arms in terms of severe toxicity, including treatment-related deaths or removal from the study due to side effects. The toxicity data generated in this study were of interest, particularly considering the "learning curve" required by both surgeons and medical oncologists participating in this trial (many of whom had never previously administered intraperitoneal chemotherapy).
Survival: The study was most notable for the overall survival results of the two treatment arms. There was a statistically significant improvement in overall survival associated with the intraperitoneal cisplatin arm49 months for the intraperitoneal arm vs 41 months for the IV arm (P = .02). This outcome translated into approximately a 22% reduction of relative risk of death. To place these results into perspective with other currently accepted standard-of-care interventions, the relative risk reduction observed in this important intraperitoneal trial is comparable to that observed with the use of adjuvant tamoxifen(Drug information on tamoxifen) (Nolvadex) for women with node-positive breast cancer.
Thus, it is now appropriate to ask: If the results of this randomized trial were so favorable, why did the oncology community not embrace them and begin using intraperitoneal therapy as a standard treatment approach in small-volume residual advanced ovarian cancer? While several possible answers might be provided, perhaps the most likely is the fact that this study did not include the use of paclitaxel(Drug information on paclitaxel) (Taxol) in either the control or experimental treatment arm.
Cisplatin, Paclitaxel, and Carboplatin(Drug information on carboplatin)
The role of paclitaxel in the standard initial management of ovarian cancer had not been demonstrated at the time the aforementioned randomized intraperitoneal study was initiated. Thus, investigators questioned whether the favorable results associated with the use of intraperitoneal cisplatin would still be achievable in a regimen that included paclitaxel (rather than cyclophosphamide). Therefore, researchers from SWOG, GOG, and the Eastern Cooperative Oncology Group (ECOG) conducted a second randomized, controlled trial examining the clinical utility of intraperitoneal vs intravenous cisplatin in patients with small-volume residual advanced ovarian cancer, but this time also administered IV paclitaxel to all patients as a component of the treatment program.
Before discussing the results of this trial, several additional features of this study should be noted. First, the maximum tumor diameter permitted for entry into this trial was only 1 cm, compared to 2 cm for the previously discussed study. Presumably, this clinical feature would improve the survival outcome for both treatment arms. Second, the investigators attempted to optimize the chances that the high local concentrations of cisplatin present within the peritoneal cavity following regional delivery could be translated into a favorable outcome by administering two courses of moderately high-dose IV carboplatin (Paraplatin) prior to the initiation of the regional program. It was hypothesized that this IV therapy could "chemically debulk" the tumor, thereby decreasing the size of any residual tumor masses before the administration of intraperitoneal cisplatin.
Results: To date, the outcomes associated with this randomized trial have been presented only in abstract form. However, the preliminary results provide additional data regarding a potential role of intraperitoneal drug delivery in the management of small-volume residual advanced ovarian cancer.
Unfortunately, the two courses of moderately high-dose carboplatin were associated with severe bone marrow suppression, particularly thrombocytopenia, which resulted in 19% of patients in the experimental arm receiving two or fewer courses of intraperitoneal therapy. In addition, gastrointestinal toxicity was significantly greater in the experimental treatment arm. Consequently, the experimental regimen could not be delivered as initially planned in a substantial percentage of individuals, thereby potentially reducing the impact of regional drug delivery on the ultimate outcome.
Nevertheless, use of the intraperitoneal program was found to be associated with a statistically significant improvement in progression-free survival (28 vs 22 months, P = .01) and a borderline improvement in overall survival (63 vs 52 months, P = .05). The relative risk reduction for death (19%) was remarkably similar to that seen in the previously discussed randomized intraperitoneal chemotherapy studya finding that provides strong support for the general conclusions regarding the effectiveness of regional therapy observed in the individual trials.
Investigators of this second randomized intraperitoneal study appropriately concluded that the survival advantage associated with this regimen could not justify the level of toxicity. Consequently, they recommended that this specific program not be employed in standard clinical practice or considered for further clinical development. However, despite the observed toxicity, the results of this study continued to stimulate interest with regard to defining a role for intraperitoneal drug delivery in ovarian cancer.
Cisplatin Plus Intraperitoneal Paclitaxel
To further explore this potential, GOG investigators subsequently initiated a third randomized intraperitoneal trial, this time examining an experimental regimen containing intraperitoneal cisplatin and both intravenous and intraperitoneal paclitaxel. The study arm of this trial was again compared to a control arm of IV cisplatin and IV paclitaxel.
The use of intraperitoneal paclitaxel in this trial was based on the impressive pharmacokinetic advantage (> 1,000-fold increased exposure of the peritoneal cavity vs the systemic compartment) noted with the regional delivery of the agent.[22,23] In addition, previously reported phase II data had revealed that the intraperitoneal administration of paclitaxel, employed as second-line therapy for ovarian cancer, was associated with a high surgically documented complete response rate in patients with microscopic disease only at the initiation of the regional treatment program.
Results: Preliminary results of this ongoing randomized intraperitoneal chemotherapy trial are anticipated within the next 2 years. These results should help define a role for regional treatment in the front-line management of small-volume residual advanced ovarian cancer. This study is particularly relevant because it utilizes the intraperitoneal route to administer both the most active drug in ovarian cancer (a platinum agent) and the drug with the most profound pharmacokinetic advantage for cavity exposure (paclitaxel) following regional delivery.