Phase I and II clinical trial data have demonstrated the safety, pharmacokinetic advantage, and potential for enhanced cytotoxicity associated with the intraperitoneal administration of antineoplastic agents in the
In this issue of Oncology, Dr.Maurie Markman has written an extremely thoughtful and useful review of the potential role of intraperitonealchemotherapy for stage III epithelial ovarian carcinoma. I would like to add afurther perspective on this topic, with a special emphasis on the activities ofthe Southwest Oncology Group’s (SWOG) Gynecologic Cancer Committee, especiallyregarding intraperitoneal therapy for this disease.
I would like to emphasize that there is, at this point, nostandard treatment for stage III epithelial ovarian cancer. The paclitaxel(Taxol)/carboplatin (Paraplatin) combination therapy that is most commonly usedat this time should not be considered a standard treatment, since at least 70%of all treated patients with advanced disease will ultimately develop arecurrence 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 22months and a median survival of52 months in patients with optimally resected stage III disease (ie, < 1 cmindividually sized intraperitonealtumor plaques following aggressive cytoreductive primary surgery). Thecombination of paclitaxel/carboplatin (ie, area under the concentration-time curve [AUC] = 7.5 mg min/mL) would not be expected to be more activethan the IV paclitaxel/IV cisplatin regimen in GOG-114/SWOG-9227. In fact, theinitial data from GOG-158 documented a median progression-free interval of 22 monthsassociated with the IV paclitaxel/IVcarboplatin "experimental" treatment arm.
Intraperitoneal ChemotherapyIs It Ready for Prime Time?
Over the past 25 years, there has been considerable improvementin the technology used for intraperitoneal chemotherapy. These refinements haveled to the significantly improved ease of intraperitoneal drug administration, amarked reduction in peritoneal catheter complications, and the ultimate efficacyof intraperitoneal therapy. Shown in Table 1 are specific guidelines for theefficaceous administration of intraperitoneal chemotherapy.
Clinically, however, intraperitoneal chemotherapy continues tobe an experimental modality and thereby requires further study. In his article,Dr. Markman presents the final results of GOG-114/SWOG-9227, wherein the IVcarboplatin/IV paclitaxel/intraperitoneal cisplatin/intraperitoneal paclitaxelexperimental arm was associated with a median progression-free survival of 28months and a median overall survival of 63 months, as compared to the previouslydiscussed median progression-free survival of 22 months and median overallsurvival of 52 months observed with the standard IV paclitaxel/IV cisplatintreatment arm (P = .05 for survival comparison).
This is the first large, randomized trial in which the 5-yearsurvival barrier has been broken by any treatment modality for patients withoptimally resected stage III disease. Furthermore, the median progression-freesurvival of 28 months achieved in the experimental intraperitoneal therapy armis considerably longer than the median 22 months achieved in GOG-158 with IVpaclitaxel/IV carboplatin.
Thus, I agree with Dr. Markman that there is a definite role forintraperitoneal therapy in the management of ovarian cancer. However, we cannotdesignate any treatment for ovarian cancer as standard when far more than 50% ofpatients ultimately die of their disease!
Novel Intravenous/Intraperitoneal Drug Treatments
If we are to see major improvements in progression-free intervaland overall survival in patients with stage III disease, we must continue todevelop innovative treatment programs using novel cytotoxic and cytostaticagents. Furthermore, the use of these new agents must coincide with efforts tomaximize the effectiveness of our standard treatments through the mostefficacious administration routes.
Novel approaches to intravenous/intraperitoneal drug therapy forpatients with optimally resected stage III disease are undergoing further phaseII and phase III study by SWOG and GOG, as shown in Table2. GOG-172 wasdesigned on the basis of safety data obtained from SWOG-9619. Accrual to GOG-172was completed in the fall of 2000, and it will take approximately 3 years forthe study results to mature. In the meantime, SWOG-9912 has been constructedspecifically to replicate the SWOG-9619 treatment regimen, with the addition ofa promising third agent, IV liposomal doxorubicin (Doxil)selected because ofits well-documented activity in platinum-sensitive disease. It is possible thatif the results of SWOG-9912 are promising (ie, showing prolongedprogression-free and overall survival), then this new treatment combination maybe taken into a definitive phase III trial.
Finally, SWOG-0009 was designed to add intraperitoneal therapyin patients who present with bulky intraperitoneal disease, provided theyrespond to an initial regimen of IV paclitaxel/IV carboplatin management. Ifthese stage III patients do not undergo optimal resection, they will then betreated with a novel combination of IV paclitaxel, 135 mg/m2 (3 hours) onday 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 sixcourses.
Hopefully, these novel treatment regimens will provide the basisfor future phase III investigations in patients with optimally resectedstage III disease. In addition, it is hoped that these new regimens willultimately lead to significantly improved disease-free and overall survivaldurations in our patients.
1. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase IIIstudy of cisplatin (CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC inoptimal stage III epithelial ovarian cancer (OC): A Gynecologic Oncology GroupTrial (GOG 158) (abstract). Proc Am Soc Clin Oncol 18:356a, 1999.