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
]. Objective responses were observed in 35.8% of all patients enrolled on study, with an additional 26.2% having minor responses or stable disease. This first-line response rate compares favorably with response rates seen with doxorubicin, gemcitabine, and other single-agent and combination-agent regimens tested in phase II trials [4
]. While the objective response rate of 35.8% is somewhat lower than the 50% response rate reported from the single-institution phase II study of this regimen, a discrepancy of this magnitude is not unexpected when regimens are tested in the cooperative group, multi-institution setting.
The toxicity of fixed-dose rate gemcitabine plus docetaxel is primarily myelosuppression. Seventeen percent of patients had grade 3 or 4 neutropenia, however, there were no episodes of neutropenic fever. One-quarter of patients had grade 3 anemia, and 10% had grade 3 or 4 thrombocytopenia, but there were no significant bleeding events. While the frequencies of neutropenia and anemia are similar to those seen in the GOG study of fixed-dose gemcitabine plus docetaxel as second-line therapy, the frequency of thrombocytopenia was much lower in this study of the regimen as first-line treatment, most likely reflecting the effects of prior chemotherapy on bone marrow reserves among patients in the second-line study [25
]. In addition, the percent of patients who had prior pelvic radiation was somewhat higher in the second-line study (35%) than in this first-line study (29%), which may have also influenced the frequency of myelosuppression. One patient experienced grade 4 pulmonary toxicity. She was treated for pneumocystis carinii pneumonia and improved. However, the clinical picture is also potentially consistent with the pneumonitis-type pulmonary toxicity described with both gemcitabine and docetaxel, thus we considered this event possibly treatment-related. [7
Fixed-dose rate gemcitabine as a single agent was compared to fixed-dose rate gemcitabine plus docetaxel in a randomized trial for patients with soft tissue sarcoma and 0−3 prior regimens [24
]. In that study, gemcitabine plus docetaxel treatment was associated with higher rates of response, and longer progression-free survival (6.2 months) and OS (18 months) compared to gemcitabine alone. The response rates, PFS and OS in this GOG phase II study of gemcitabine plus docetaxel for uterine leiomyosarcoma compare favorably with those results. The percentage of patients remaining progression-free at 12 weeks and 24 weeks may be regarded as a reasonable indicator of treatment activity [34
]. Treatment regimens associated with 39% of patients progression-free at 12 weeks, and 14% progression-free at 24 weeks are considered to be active in soft tissue sarcoma [34
]. First-line treatment of uterine leiomyosarcoma with fixed-dose rate gemcitabine plus docetaxel exceeded these criteria, with 60% of patients progression-free at 12 weeks and 40% of patients progression-free at 12 weeks.
It has been suggested that patients with leiomyosarcoma may have a higher chance of responding to cytotoxic chemotherapy than do patients with other soft tissue sarcoma histologies. A retrospective study evaluated responses to gemcitabine plus docetaxel among patients with soft tissue sarcoma treated outside of a clinical trial setting. In that study, the overall response rate was 18.3% among 133 patients [35
]. The response rate among the subset of patients with leiomyosarcoma was 24% compared with 10% for patients with non-leiomyosarcoma histology (p=0.06). This response rate among leiomyosarcoma patients is comparable to the response rates seen among uterine leiomyosarcoma patients treated in the GOG study of second-line gemcitabine-docetaxel (objective response 27%), and in this GOG study of first-line therapy (objective response 35.8%) [25
As first line treatment for unresectable uterine leiomyosarcoma, fixed-dose rate gemcitabine achieves objective response in more than one-third of patients. The median duration of objective response was six months. Fixed-dose rate gemcitabine plus docetaxel is a reasonable option for first line treatment of uterine leiomyosarcoma.