In this issue of Oncology, Dr. Maurie Markman has written an extremely thoughtful and useful review of the potential role of intraperitoneal chemotherapy for stage III epithelial ovarian carcinoma. I would like to add a further perspective on this topic, with a special emphasis on the activities of the Southwest Oncology Group’s (SWOG) Gynecologic Cancer Committee, especially regarding intraperitoneal therapy for this disease.
I would like to emphasize that there is, at this point, no standard treatment for stage III epithelial ovarian cancer. The paclitaxel(Drug information on paclitaxel) (Taxol)/carboplatin (Paraplatin) combination therapy that is most commonly used at this time should not be considered a standard treatment, since at least 70% of all treated patients with advanced disease will ultimately develop a recurrence and die of their disease.
As discussed by Dr. Markman, the intravenous (IV) paclitaxel/cisplatin (Platinol) control arm of the Gynecologic Oncology Group (GOG)-114/SWOG-9227 was associated with a progression-free interval of 22 months and a median survival of 52 months in patients with optimally resected stage III disease (ie, < 1 cm individually sized intraperitoneal tumor plaques following aggressive cytoreductive primary surgery). The combination of paclitaxel/carboplatin (ie, area under the concentration-time curve [AUC] = 7.5 mg · min/mL) would not be expected to be more active than the IV paclitaxel/IV cisplatin(Drug information on cisplatin) regimen in GOG-114/SWOG-9227. In fact, the initial data from GOG-158 documented a median progression-free interval of 22 months associated with the IV paclitaxel/IV carboplatin(Drug information on carboplatin) "experimental" treatment arm.
Intraperitoneal ChemotherapyIs It Ready for Prime Time?
Over the past 25 years, there has been considerable improvement in the technology used for intraperitoneal chemotherapy. These refinements have led to the significantly improved ease of intraperitoneal drug administration, a marked reduction in peritoneal catheter complications, and the ultimate efficacy of intraperitoneal therapy. Shown in Table 1 are specific guidelines for the efficaceous administration of intraperitoneal chemotherapy.
Clinically, however, intraperitoneal chemotherapy continues to be an experimental modality and thereby requires further study. In his article, Dr. Markman presents the final results of GOG-114/SWOG-9227, wherein the IV carboplatin/IV paclitaxel/intraperitoneal cisplatin/intraperitoneal paclitaxel experimental arm was associated with a median progression-free survival of 28 months and a median overall survival of 63 months, as compared to the previously discussed median progression-free survival of 22 months and median overall survival of 52 months observed with the standard IV paclitaxel/IV cisplatin treatment arm (P = .05 for survival comparison).
This is the first large, randomized trial in which the 5-year survival barrier has been broken by any treatment modality for patients with optimally resected stage III disease. Furthermore, the median progression-free survival of 28 months achieved in the experimental intraperitoneal therapy arm is considerably longer than the median 22 months achieved in GOG-158 with IV paclitaxel/IV carboplatin.
Thus, I agree with Dr. Markman that there is a definite role for intraperitoneal therapy in the management of ovarian cancer. However, we cannot designate any treatment for ovarian cancer as standard when far more than 50% of patients ultimately die of their disease!
Novel Intravenous/Intraperitoneal Drug Treatments
If we are to see major improvements in progression-free interval and overall survival in patients with stage III disease, we must continue to develop innovative treatment programs using novel cytotoxic and cytostatic agents. Furthermore, the use of these new agents must coincide with efforts to maximize the effectiveness of our standard treatments through the most efficacious administration routes.
Novel approaches to intravenous/intraperitoneal drug therapy for patients with optimally resected stage III disease are undergoing further phase II and phase III study by SWOG and GOG, as shown in Table 2. GOG-172 was designed on the basis of safety data obtained from SWOG-9619. Accrual to GOG-172 was completed in the fall of 2000, and it will take approximately 3 years for the study results to mature. In the meantime, SWOG-9912 has been constructed specifically to replicate the SWOG-9619 treatment regimen, with the addition of a promising third agent, IV liposomal doxorubicin(Drug information on doxorubicin) (Doxil)selected because of its well-documented activity in platinum-sensitive disease. It is possible that if the results of SWOG-9912 are promising (ie, showing prolonged progression-free and overall survival), then this new treatment combination may be taken into a definitive phase III trial.
Finally, SWOG-0009 was designed to add intraperitoneal therapy in patients who present with bulky intraperitoneal disease, provided they respond to an initial regimen of IV paclitaxel/IV carboplatin management. If these stage III patients do not undergo optimal resection, they will then be treated with a novel combination of IV paclitaxel, 135 mg/m2 (3 hours) on day 1, plus intraperitoneal carboplatin (AUC = 5 mg · min/mL on day 1), plus intraperitoneal paclitaxel 60 mg/m2 on day 8, every 21 days for six courses.
Hopefully, these novel treatment regimens will provide the basis for future phase III investigations in patients with optimally resected stage III disease. In addition, it is hoped that these new regimens will ultimately lead to significantly improved disease-free and overall survival durations in our patients.