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Paclitaxel and Carboplatin: A Relevant Combination in Uterine Carcinosarcoma
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Paclitaxel + carboplatin is a safe and effective combination therapy in patients with advanced primary or recurrent carcinosarcoma of the uterus. Further clinical development is warranted.
Source: Powel MA, et al. Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: A Gynecologic Oncology Group study. J Clin Oncol 2010;28:2727-2731.
Carcinosarcoma of the uterus is a rare condition accounting for less that 4% of all uterine neoplasms. Previous work has identified that the most active single agents are platinum, ifosfamide, paclitaxel, and doxorubicin. Ifosfamide combinations have proved to be more efficacious relative to ifosfamide alone, but substantially more toxic. Paclitaxel + carboplatin has been intimated from retrospective reviews to be active in this disease. In response, the Gynecologic Oncology Group (GOG) conducted a prospective, 2-stage, open label, multi-institutional study of combination paclitaxel (175 mg/m2) and carboplatin (AUC 6) in women with stage III/IV or recurrent carcinosarcoma. All patients had to have measurable disease and were treated until toxicity, progression, or complete clinical remission. The study design allowed for early study termination for inactivity. Fifty-five patients were accrued with 9 being excluded (5 wrong histology, 2 wrong primary site, 2 never treated). Of the 46 evaluable patients, response was documented and confirmed by second imaging study in 25 (6 complete and 19 partial responses; overall response rate: 54%). The regimen was well tolerated with expected hematological toxicity and minimal non-hematological grade 4 toxicity (1 cardiovascular, 2 pain); 59% received 6 or more cycles of therapy. Paclitaxel + carboplatin is active in this setting and met prespecified criteria for further clinical development. As such, the current chemotherapy backbone is the focus of a large prospective phase III non-inferiority trial against ifosfamide and paclitaxel.
Carcinosarcoma, also known as malignant mixed müllerian tumor (MMMT) is a rare uterine neoplasm associated with an aggressive phenotype, being frequently metastatic at primary diagnosis or recurring in short order after primary adjuvant therapy. The rarity of the tumor challenges the ability to expeditiously evaluate modalities and agents of therapy, which has limited our options for these patients. The disease has a unique signature wherein the primary site (uterus) is composed of malignant stroma and glands, but metastatic sites are nearly always of the epithelial component. Despite this, the biology of this disease may be different than high-grade endometrioid or non-endometrioid (serous or clear cell) cancer. Retrospective comparisons of carcinosarcoma to epithelial cancers demonstrate that the former is associated with a poorer prognosis independent of stage or histology. Nevertheless, risk for systemic spread in apparently localized cases and extrapelvic post-treatment failure have largely dictated systemic adjuvant chemotherapy in the management of these neoplasms.
Through a dedicated phase II queue in the GOG, several agents have been systematically studied for activity in patients with known metastatic or recurrent carcinosarcoma. From this long list, just 4 agents have emerged with sufficient promise (response rates from 10% to 42%) to be evaluated in the phase III setting: doxorubicin, ifosfamide, paclitaxel, and cisplatin. Phase III trials, heretofore, have most recently compared ifosfamide combinations (cisplatin or paclitaxel) to single agent ifosfamide. Both trials demonstrated superior response and progression-free survival (also overall survival in the ifosfamide + paclitaxel combination) for the doublet over the control arm. However, toxicity was substantial, frequently leading to dosing delays and use of marrow stimulants to maintain schedule.
The current trial evaluated a ubiquitous doublet in solid tumors with a well-known and comfortable toxicity profile in this rare tumor. The favorable activity and acceptable toxicity experience provided the rationale to examine the doublet in an ongoing phase III clinical trial in women with primary or recurrent carcinosarcoma against combination ifosfamide + paclitaxel. Results from this trial won't be available for some time; however, chemotherapy combinations with new biological agents (such as angiogenesis and PARP inhibitors) are continuing with the expectation of moving the therapeutic opportunities forward for these women.
In addition, microarray signatures suggest the histology of the tumor is more relevant than site of origin. As a result, at least one uterine carcinosarcoma trial (GOG 261) is being amended to accept ovarian carcinosarcomas, as well as those arising in the peritoneal cavity.