A New Standard for Uterine Leiomyosarcoma
Abstract & Commentary
By Robert L. Coleman, MD, Associate 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: Fixed-dose rate gemcitabine and docetaxel demonstrates impressive response rates and survival characteristics in women with metastatic/recurrent previously untreated uterine leiomyosarcoma.
Source: Hensley M, et al. Gynecol Oncol. 2008;109:329-334.
Doxorubicin-based chemotherapy has remained a standard for the treatment of soft tissue sarcoma for decades. Recently, combination gemcitabine and docetaxel demonstrated significant clinical activity in a single-institution mixed population study of women with uterine leiomyosarcoma. The current report addresses the histologic diagnosis in women previously untreated for recurrent disease in a multi-institutional setting. Utilizing a two stage design, the authors designed a trial of women with measurable disease infusing gemcitabine on day 1 and both gemcitabine and docetaxel on day 8 of a 21-day cycle. The gemcitabine was administered at a fixed-dose rate of 10 mg/m2/minute. Bone marrow support was administered in all patients starting on day 9 or 10. Forty-two patients were accrued, meeting the 2-stage design requirements in 24 months of enrollment. Overall the treatment was well tolerated with infrequent grade 3 or 4 hematological toxicity. Blood transfusions were administered to 43% of the patients. No neutropenic fevers were recorded. Similarly, non-hematological toxicity, predominately fatigue, was infrequent and not dose-limiting. All patients were considered in the response despite 3 patients not completing the first cycle of protocol therapy. Nonetheless, objective response was recorded in 15 patients (36%) including 2 complete responders. The progression-free survival at 12- and 24-weeks was 60% and 40% respectively. Responders had a progression-free survival of 6 months on the median; overall PFS was 4.4 months (range 0.4 - 37.2+ months). The data are favorable to other phase II studies of alterative agents, including doxorubicin and represent a major milestone in the treatment for this disease.
Commentary
Uterine leiomyosarcoma (LMS) is a tumor with some very discouraging natural history statistics. Like advanced ovarian cancer patients entering into clinical remission following primary therapy, the risk for recurrence is high, unpredictable, usually fatal when documented and is unaccompanied by an effective mechanism to prevent it. Unlike ovarian cancer, however, this disease is so uncommon that large randomized clinical trials are generally infeasible and unlikely to be nimble enough to clearly evaluate the impact of new and novel therapeutic approaches in a timely manner. However, serial evaluation of phase II studies can be instructive when the treatment population is stable. Such is the case in the current report, which is one of several conducted over the last 2 decades by the Gynecologic Oncology Group in patients with essentially the same eligibility criteria. The clinical efficacy of the regimen is remarkable and surpasses any previous single agent or combination studied to date; the oncological community has already largely embraced it. Several important issues are relevant to consider with the strategy and are highlighted in more detail in an accompanying editorial: first, the dose of docetaxel used was significant and required bone marrow support for repetitive use; could this be reduced? Second, an accompanying article in the same issue of the journal reported a 27% response rate in patients with recurrent, previously treated LMS with this same regimen. The results from that GOG study compare favorably to doxorubicin (a current front-line standard) when administered in that setting (13%); should this active combination be administered first- or second-line? Third, fixed-dose rate gemcitabine was used in this study based on preclinical (pharmacological) and clinical (PFS and OS) data supporting its use; could bolus infusion meet the same conclusion while adding convenience? And last, could this strategy be given adjuvantly to help reduce the nearly 50% recurrence rate observed at 2 years in completely resected stage I/II disease? All good questions, but unlikely to be addressed further in randomized clinical trials. However, the Group has embarked upon a randomized study evaluating the potential value-added impact of the anti-angiogenesis agent bevacizumab to this promising combination. Although the trial is expected to take more than 4 years to accrue, the results may move the benchmark further, imparting more therapeutic benefit to our patients.
Suggested Reading
- Edmonson JH, et al. Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2002;85:507-510.
- Hensley ML, et al. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study. Gynecol Oncol. 2008;109:323-328.
- Fleming G. Gemcitabine/docetaxel—welcome to a new standard. Gynecol Oncol. 2008;109:313-315.
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