Deleterious effect of ifosfamide in leiomyosarcoma: Convergence of weak signals.

Abstract

D’Ambrosio et al1 report the results of a large retrospective study assessing the activity of doxorubicin-based chemotherapy in patients with advanced leiomyosarcoma. This work is outstanding because of the large number of cases (303 patients), the well-known quality of the European Organisation for Research and Treatment of Cancer database, and the use of propensity score–matched analysis.1 Seventy-one of these 303 patients received a combination of ifosfamide and doxorubicin, and 41 of these 71 patients were included in the propensity score–matched subanalysis. This study allows an analysis of the activity of 3 commonly used regimens: doxorubicin alone, doxorubicin and dacarbazine, and ifosfamide and doxorubicin. It is striking to see that the combination of ifosfamide and doxorubicin is systematically associated with poor outcomes. In the matched population, the objective response rate was 25.6% with doxorubicin, 19.5% with ifosfamide and doxorubicin, and 30.9% with doxorubicin and dacarbazine. Progression-free survival was 4.8 months with doxorubicin, 8.2 months with ifosfamide and doxorubicin, and 9.2 months with doxorubicin and dacarbazine. Overall survival was 30.3 months with doxorubicin, 36.8 months with ifosfamide and doxorubicin, and 21.9 months with doxorubicin and dacarbazine. The outcome differences between doxorubicin and the combination of ifosfamide and doxorubicin did not reach the level of significance.1 Nevertheless, 10 years earlier, the French Sarcoma Group conducted a retrospective study of 147 patients with advanced leiomyosarcoma. We also found that the addition of ifosfamide was associated with poor overall survival (hazard ratio, 1.42; P = .028).2 We know that retrospective data or merged data coming from different trials must be interpreted with caution, but these findings are a matter of concern. Despite its inconvenient administration, which requires hyperhydration and the use of uromitexan, since the 2002 Van Oosterom trial demonstrating the activity of ifosfamide in advanced soft-tissue sarcoma, ifosfamide has been largely used in curative-intent and palliative settings.3 Ifosfamide is part of common first-line combination regimens used in soft-tissue sarcoma management (doxorubicin with ifosfamide, epirubicin with ifosfamide, doxorubicin and dacarbazine with ifosfamide, and so forth).4 Because of recent large randomized clinical trials, there is debate regarding the use of the anthracycline-ifosfamide combination for the neoadjuvant treatment of localized soft-tissue sarcoma.4 Regarding the results of both studies, the key question is whether we have to avoid ifosfamide administration in patients with localized leiomyosarcoma receiving perioperative chemotherapy. This has to be properly investigated because the benefit of neoadjuvant chemotherapy in sarcoma is highly debated. Furthermore, the term leiomyosarcoma encompasses different clinicopathological entities, including uterine leiomyosarcoma, soft-tissue leiomyosarcoma, and great vessel leiomyosarcoma, that could respond differently to ifosfamide. Furthermore, recent extensive molecular analysis has stressed the extraordinary molecular heterogeneity of leiomyosarcoma.5, 6 As a result, the sensitivity of leiomyosarcoma to ifosfamide is likely a more complex issue. From our point of view, this is the second time that a deleterious effect of ifosfamide in leiomyosarcoma management has been demonstrated, and this fact should not be ignored by medical oncologists. No specific funding was disclosed. The authors made no disclosures.