1. In patients with advanced leiomyosarcoma, a regimen of doxorubicin-trabectedin was superior to doxorubicin alone in improving progression-free and overall survival.
2. Trabectedin was associated with higher incidence and severity of adverse events, most notably hematologic toxicity.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Leiomyosarcomas are a group of rare soft-tissue malignancies with poor prognosis in advanced stages. These sarcomas are highly heterogeneous in their clinical courses and genetic underpinnings. Nevertheless, the standard first-line therapy has remained the same: doxorubicin monotherapy. Combination therapies with various agents have shown survival benefits in metastatic disease, including trials of their use as first-line treatments. This was a phase three trial comparing a six-cycle regimen of doxorubicin alone against doxorubicin-trabectedin followed by maintenance trabectedin in patients with metastatic or unresectable leiomyosarcoma who had not been treated with chemotherapy. By a median follow-up of 55 months, the median overall survival and progress-free survival were longer in the doxorubicin-trabectedin group than in the doxorubicin-alone group, with the corresponding lowered risk of progression or death. The doxorubicin-trabectedin combination was associated with higher incidence and severity of adverse events, including neutropenia, anemia, and thrombocytopenia, requiring dose reduction. This study differed from the previous phase three trials, which focused on leiomyosarcoma. Its results demonstrated the potential benefits of utilizing first-line doxorubicin-trabectedin and continued trabectedin maintenance in treating advanced leiomyosarcoma.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: This was a phase three, open-label, multicenter randomized controlled trial comparing two chemotherapy approaches in treating advanced leiomyosarcoma. Patients were eligible for inclusion if they had unresectable locally advanced or metastatic leiomyosarcoma with at least one measurable lesion and had not received chemotherapy. Exclusion criteria included other types of sarcomas or malignancies, cerebral metastasis, contraindication to trial drugs, and participation in another investigational trial. In total, 150 patients were randomized 1:1 to receive either doxorubicin alone with lenograstim once every three weeks for six cycles or doxorubicin followed by trabectedin with pegfilgrastim once every three weeks. In the doxorubicin-trabectedin group, maintenance trabectedin alone was continued for up to 17 cycles in patients without disease progression. In contrast, trabectedin could be started as subsequent lines of treatment following disease progression in the doxorubicin group (59% of these patients). Surgery for residual disease was permissible after six cycles of therapy. The primary outcome was progression-free survival, defined as the time from randomization to progression or death from any cause. Progression-free survival was longer in the doxorubicin-trabectedin group (12 months, 95% confidence interval [CI] 10-16) than the doxorubicin group (six months, 95% CI 4-7), with the adjusted hazard ratio for progression or death of 0.37 (95% CI 0.26-0.53). The median overall survival was 33 months in the doxorubicin-trabectedin group (95% CI 26-48) and 24 months in the doxorubicin group (95% CI 19-31), resulting in the adjusted hazard ratio for death of 0.64 (95% CI 0.44-0.95). Surgery was performed in 15 patients (20%) in the doxorubicin-trabectedin group and 6 (8%) in the doxorubicin group. Doxorubicin-trabectedin was associated with a higher incidence of adverse events. This study demonstrated the benefit of a doxorubicin-trabectedin combination for first-line treatment with immediate trabectedin maintenance over doxorubicin monotherapy in treating advanced leiomyosarcoma.
Image: PD
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