Elsevier

Gynecologic Oncology

Volume 109, Issue 3, June 2008, Pages 329-334
Gynecologic Oncology

Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: A Gynecologic Oncology Group phase II trial

https://doi.org/10.1016/j.ygyno.2008.03.010Get rights and content

Abstract

Objectives

Fixed-dose rate gemcitabine plus docetaxel is active as second-line therapy for metastatic uterine leiomyosarcoma. We sought to determine the activity of this regimen as first-line treatment.

Methods

Eligible women with advanced uterine leiomyosarcoma were treated with gemcitabine 900 mg/m2 over 90 min, on days one and eight, plus docetaxel 100 mg/m2 on day eight, with granulocyte growth factor support on day nine of a 21-day cycle. Patients with prior pelvic radiation received lower doses. Patients were treated until progression or unacceptable toxicity. Response was assessed every other cycle by RECIST.

Results

Forty-two women enrolled, with 39 evaluable for response. Objective responses were observed in 15 of 42 patients (35.8% overall; complete response 4.8%, partial response 31%, 90% confidence interval 23.5 to 49.6%), with an additional 11 (26.2%) having stable disease. Nineteen of 38 (50%) received six or more cycles of study treatment. Myelosuppression was the major toxicity: neutropenia grade 3 in 5%, grade 4 in 12%; anemia grade 3 in 24%; thrombocytopenia grade 3 in 9.5%, grade 4 in 5%. One patient had a grade 3 allergic reaction, 17% had grade 3 fatigue. One possibly-related grade 4 pulmonary toxicity was observed. The median progression-free survival (PFS) was 4.4 months (range 0.4 to 37.2+ months). Among 15 women with objective response, median response duration was 6 months (range 2.1 to 33.4+ months). Median overall survival was 16+ months (range:.4–41.3 months).

Conclusion

Fixed-dose rate gemcitabine plus docetaxel achieves high objective response rates as first-line therapy in metastatic uterine leiomyosarcoma.

Introduction

Doxorubicin-based therapy has been the mainstay of first-line therapy for metastatic, unresectable soft tissue sarcomas, including uterine leiomyosarcomas, for decades. Single-agent doxorubicin remains standard first-line therapy in many treatment settings, with first-line response rates of approximately 25% [1], [2]. The combination of doxorubicin plus ifosfamide (response rate 28–30%) has not been shown to improve outcomes among patients with soft tissue sarcoma compared with doxorubicin alone [3], [4]. Other single agents with moderate activity in leiomyosarcoma include ifosfamide (response rate 17.2%), gemcitabine (bolus infusion achieved a 20% response rate among women with uterine leiomyosarcoma), ecteinascidin-743 (response rate of 8% among patients with prior treatment, and 17% as first-line therapy) and temozolomide (15.5% objective response with daily oral treatment) [5], [6], [7], [8], [9]. Multiple chemotherapy agents, including cisplatin, mitoxantrone, amonafide, oral etoposide, diaziquone (AZQ), intravenous etoposide, topotecan, paclitaxel, thalidomide, and trimetrexate have been tested in the first and second-line setting with negligible activity demonstrated [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20].

Fixed-dose rate infusion of gemcitabine is a term that refers to infusing the gemcitabine at a rate that maintains the gemcitabine concentration at a level that optimizes the incorporation of the active gemcitabine metabolite, gemcitabine triphosphate, into deoxyribonucleic acid (DNA). Pre-clinical data have shown that maintaining the gemcitabine triphosphate concentration at 20 μmol/l, optimizes in vivo cell kill [21], [22]. Pharmacokinetic analyses in a single-institution phase II study showed that fixed-dose rate gemcitabine at 10 mg/m2/min increased the duration of time that the gemcitabine metabolite remained above the threshold for incorporation into deoxyribonucleic acid (DNA) compared with bolus gemcitabine infusion in patients with leiomyosarcoma [23].

The single-institution study of fixed-dose rate gemcitabine plus docetaxel yielded high objective response rates among patients with advanced leiomyosarcoma in both the second-line, and first-line setting [23]. More recently, fixed-dose rate gemcitabine plus docetaxel has been shown to yield higher response rates, progression-free, and overall survival (OS) than fixed-dose rate single-agent gemcitabine in a randomized trial for patients with soft tissue sarcoma who had received up to three prior regimens [24]. In a Gynecologic Oncology Group (GOG) phase II trial for women with advanced leiomyosarcoma who had received one prior cytotoxic regimen, fixed-dose rate gemcitabine plus docetaxel achieved objective response in 28% of patients, with an additional 50% having stable disease [25].

Given the evidence for efficacy in the second-or-greater-line setting, the GOG sought to determine the objective response rate of fixed-dose rate gemcitabine plus docetaxel among women with advanced, unresectable uterine leiomyosarcoma who had received no prior cytotoxic therapy.

Section snippets

Patients

Women with advanced, unresectable uterine leiomyosarcoma, with measurable disease and no prior cytotoxic therapy were eligible. All tumors were histologically confirmed by central review of the GOG Pathology Committee. Prior therapy with gemcitabine or docetaxel was not permitted. Patients were permitted to have had prior pelvic radiotherapy. Patients were required to have GOG performance status of 0–2, and adequate bone marrow function (absolute neutrophil count (ANC) greater than or equal to

Results

Between December 2003 and June 2006, 42 women were enrolled in this phase II study from 24 GOG participating institutions. Three patients were considered inevaluable for objective response (one patient declined further treatment or follow-up imaging after day one treatment with gemcitabine alone; one patient had an immediate hypersensitivity reaction to docetaxel on cycle one day eight and declined further treatment or imaging after cycle 1; one patient received gemcitabine on cycle 1, day one

Discussion

Doxorubicin has been the backbone of first-line therapy for unresectable soft tissue sarcoma for decades, and continues to be recommended by sarcoma treatment guidelines [27]. High objective response rates in phase II trials of fixed-dose rate gemcitabine plus docetaxel as second-or-greater-line therapy in leiomyosarcoma led to this cooperative group, multi-institution study testing the activity of this regimen as first-line therapy for unresectable uterine leiomyosarcoma [25], [28]. Objective

Authors disclosure of potential conflicts of interest

MLH has received research support for other clinical trials from Lilly Oncology and Sanofi-Aventis. PGR has received honoraria from Lilly Oncology. JAB and RM have no conflicts of interest to declare.

Acknowledgments

This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, University of Washington, University of Cincinnati, University of North Carolina School of Medicine, University of

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