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

Abstract

Objective

Doxorubicin-based treatment is standard therapy for metastatic uterine leiomyosarcoma. There is no standard second-line therapy. We determined activity of fixed-dose rate gemcitabine plus docetaxel as second-line treatment for metastatic uterine leiomyosarcoma.

Methods

Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy were treated with gemcitabine 900 mg/m² days one and eight over 90 min, plus docetaxel 100 mg/m² on day 8 of a 21-day cycle with granulocyte growth factor. Patients with prior pelvic radiation received lower doses. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT).

Results

Forty-eight of 51 women were evaluable for response (one wrong histology, two never treated). Prior therapy was doxorubicin-based in 90%, and ifosfamide-based in 6%. The overall objective response rate is 27%, with complete response in 6.3% (3/48), and partial response in 20.8% (10/48). An additional 50% (24/48) had stable disease (median duration 5.4 months). The median number of cycles per patient was 5.5 (range 1–22); 73% of patients remained progression-free at 12 weeks and 52% at 24 weeks. The predominant toxicity was uncomplicated myelosuppression: thrombocytopenia grade 3 (29%), grade 4 (10.4%); neutropenia grade 3 (12.5%), grade 4 (8.3%) anemia grade 3 (20.8%), grade 4 (4.2%). While pulmonary toxicity was reported, no patient had drug-related pneumonitis/hypoxia-type toxicity. Median progression-free survival (PFS) was 5.6+ months (range 0.7–27+ months). The median duration of objective response was 9+ months (range 3.9–24.5+ months).

Conclusion

Fixed-dose rate gemcitabine plus docetaxel is active second-line therapy for uterine leiomyosarcoma.

Introduction

Uterine leiomyosarcoma accounts for approximately 1% of all uterine malignancies and thus is diagnosed in only a few thousand women each year [1]. Women who present with advanced disease, and women whose disease recurs after initial surgical resection have a poor prognosis; and, except for rare, highly-selected cases with resectable, isolated pulmonary metastases, are not curable [2]. Median survival among women with advanced disease is less than one year.

Current treatment options for recurrent or advanced uterine leiomyosarcoma are limited. Negligible activity was observed in phase II trials testing the following drugs as single agents: cisplatin, mitoxantrone, amonifide, oral etoposide, diazoquone (AZQ), intravenous etoposide, topotecan, paclitaxel, thalidomide, and trimetrexate [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Single agents that show moderate activity in leiomyosarcoma include ifosfamide (response rate 17.2%), doxorubicin (response rate 25%), and gemcitabine (bolus infusion achieved a 20% response rate among women with uterine leiomyosarcoma who had received 0–1 prior cytotoxic regimen) [15], [16], [17]. Trabectedin achieved a response rate of 8% among patients with prior treatment, and 17% as first-line therapy, in patients with soft tissue sarcoma [18], [19].

Combination chemotherapy regimens with activity in previously untreated patients include hydroxyurea, dacarbazine and etoposide (overall response rate 18.4%) and doxorubicin plus ifosfamide (response rate 30.3%) [20], [21]. Doxorubicin with or without ifosfamide is frequently employed as first-line therapy for women with advanced or recurrent leiomyosarcoma. Standard second-line therapy for uterine leiomyosarcoma has not been established.

In a single-institution study, the combination of fixed-dose-rate gemcitabine plus docetaxel achieved objective response rates of 53% among patients with unresectable leiomyosarcoma who had received up to two prior cytotoxic regimens. Nearly all patients had uterine-primary leiomyosarcoma [22]. This high response rate was observed even among the subgroup of patients previously treated with doxorubicin-based chemotherapy. The rationale for using the fixed-dose rate infusion of gemcitabine was based on pre-clinical data which showed that a gemcitabine concentration of 20 μmol/l was optimal for the formation of the active gemcitabine metabolite, and for its subsequent incorporation of into deoxyribonucleic acid (DNA). Delivering gemcitabine at a rate of 10 mg/m²/min was determined to be the best rate for maintaining the gemcitabine concentration at 20 μmol/l, and thus optimizing in vivo cell kill [23], [24]. Pharmacokinetic analyses in the single-institution phase II study [22] 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. Furthermore, in a randomized phase II trial in pancreatic cancer, fixed-dose-rate gemcitabine (1500 mg/m² over 150 min) achieved longer time-to-treatment-failure and longer median survival than bolus gemcitabine therapy at a higher dose (2200 mg/m² over 30 min) [25].

The Gynecologic Oncology Group (GOG) conducted this phase II trial of fixed-dose-rate gemcitabine plus docetaxel to determine the activity of this regimen as second-line therapy among women with advanced or recurrent uterine leiomyosarcoma.