# First-Line Chemotherapy Regimens for Advanced and Metastatic Leiomyosarcoma: Doxorubicin vs. Gemcitabine—A Systematic Review

## TL;DR

This review compares doxorubicin and gemcitabine chemotherapy for advanced leiomyosarcoma, finding doxorubicin more effective but with higher toxicity.

## Contribution

The study provides a systematic review comparing first-line chemotherapy regimens for leiomyosarcoma without prior direct clinical trials.

## Key findings

- Doxorubicin-based regimens showed higher response rates and survival compared to gemcitabine–docetaxel.
- Doxorubicin plus trabectedin followed by maintenance therapy achieved a median survival of 33 months.
- Gemcitabine–docetaxel had limited and less durable benefits with lower toxicity.

## Abstract

Leiomyosarcoma (LMS) is a rare and aggressive cancer for which the optimal first-line chemotherapy remains uncertain, despite decades of clinical use. This systematic review summarizes the available evidence comparing two commonly used treatment approaches: doxorubicin-based regimens and gemcitabine–docetaxel. Although widely prescribed, these regimens have never been directly compared in first-line clinical trials. Overall, doxorubicin-based combinations—particularly doxorubicin–trabectedin followed by maintenance therapy, and when feasible, surgery—were associated with improved survival outcomes, but at the cost of higher toxicity. In contrast, gemcitabine–docetaxel showed more limited and less durable benefit. This review provides clinicians and researchers with a clear, up-to-date overview of treatment effectiveness, safety considerations, and remaining knowledge gaps, and highlights priorities for future clinical trials in advanced leiomyosarcoma.

Background: Leiomyosarcomas are an aggressive soft-tissue sarcoma that arise from smooth muscle, have a high metastatic potential and account for 10–20% of soft-tissue sarcomas. Despite decades of research, the first-line treatment remains unresolved due to the absence of direct comparative trials, heterogeneous study designs, and trade-offs between efficacy and toxicity. This systematic review evaluates the optimal therapeutic systemic chemotherapy regimens in the first-line setting, specifically gemcitabine- and doxorubicin-based regimens, including associated toxicities. Methods: A systematic search in MEDLINE (Ovid), Embase (Ovid), and Cochrane Library (Wiley) identified studies of first-line gemcitabine- or doxorubicin-based chemotherapy for leiomyosarcoma. The review protocol was registered in PROSPERO (CRD420261280028). Of the 3092 articles screened, 11 articles were eligible for inclusion, comprising results from 1225 patients. Eligible studies were in English and included ≥10 patients with advanced/metastatic leiomyosarcoma reporting on LMS-specific outcomes and no prior systemic therapy. This qualitative systematic review synthesizes prospective and retrospective evidence without quantitative meta-analysis. Results: The review included two phase 3 trials, six phase 2 trials, one phase 1b trial, and two retrospective studies. While there was no direct comparison in this setting, doxorubicin-based combinations consistently reported higher objective response rates, progression-free survival, and overall survival. The most favorable outcomes were observed in the LMS04 trial with doxorubicin plus trabectedin followed by surgery and trabectedin maintenance, yielding a median progression-free survival of 12 months, overall survival of 33 months, and objective response rate of 36%. This regimen also had the highest grade 3–4 toxicity. Conclusions: Doxorubicin-based regimens remain the most active first-line option for leiomyosarcoma, although treatment practices remain heterogeneous.