Phase II Evaluation of Paclitaxel and Carboplatin in the Treatment of Carcinosarcoma of the Uterus: A Gynecologic Oncology Group Study

Carcinosarcomas (CSs) of the uterus, also known as malignant mixed Mullerian tumors, represent < 4% of uterine neoplasms with an estimated annual incidence of less than two per 100,000 women. Uterine CSs are aggressive uterine cancers with poor survival rates, even when presenting at an apparent early stage. Five-year disease-free survival by stage is poor (stage I, 56%; stage II, 31%; stage III, 13%; stage IV, 0%) with most patients developing extrapelvic disease.

 Advanced or recurrent disease portends a grim prognosis. The Gynecologic Oncology Group (GOG) has developed a series of phase II trials to identify potentially active cytotoxic agents for the treatment of advanced or recurrent uterine CS. Active single-agent therapies include ifosfamide (response rate [RR]: 29% to 36%), cisplatin (28% to 42%), paclitaxel (18%), and doxorubicin (10% to 25%).Ifosfamide combinations have been compared with single-agent ifosfamide in two large phase III GOG trials. Sutton  reported on the cisplatin-ifosfamide combination, which resulted in a statistically significant increase in RR (54% v 36%; median progression-free survival [PFS]; 6 v 4 months), but the difference in overall survival (OS) was not statistically different.  Ifosfamide-paclitaxel-filgrastim demonstrated statistically significant improvements in RR (45% v 29%), PFS (6 v 4 months), and OS (14 v 8 months) over ifosfamide alone.

At the time this study was initiated, the only published data with the combination of carboplatin and paclitaxel for uterine CS was a small retrospective study with response noted in four of five evaluable patients. Given these factors, our objective in this prospective multi-institutional study was to estimate the antitumor activity and nature and degree of toxicity of carboplatin plus paclitaxel in patients with recurrent or advanced uterine CS with measurable disease.

Paclitaxel is the regimen with established superiority based on a randomized phase III trial conducted through the Gynecologic Oncology Group. However, the toxicity, multiday schedule, and limited activity of this regimen support further development of novel regimens. Our primary objective was to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas.

Patients and Methods Eligible patients had advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. Patients received paclitaxel at 175 mg/m² intravenously (IV) over 3 hours plus carboplatin (area under the serum concentration-time curve = 6) IV over 30 minutes every 3 weeks until disease progression or until adverse effects occurred. Common Terminology Criteria for Adverse Events v3.0 was used to grade adverse events.

Results Fifty-five patients were entered onto the study with nine being excluded from analysis, leaving 46 evaluable for analysis. Treatment was well tolerated with expected hematologic toxicity and minimal nonhematologic grade 4 toxicity (one cardiovascular and two pain) with 59% of patients completing six or more cycles of chemotherapy. The proportions of patients with confirmed complete and partial responses were 13% and 41%, respectively, resulting in a total overall response rate of 54% (95% CI, 37% to 67%).

Conclusion Paclitaxel plus carboplatin demonstrates antitumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials.