Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study

Abstract

No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined valproic acid and doxorubicin in patients with unresectable MM failing after platinum-based chemotherapy.Treatment consisted of doxorubicin (60 mg?m -2 ) plus valproic acid. An interim analysis for response rate was planned after the first 16 registered patients. All the cases were centrally reviewed.From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The majority of the patients were male (73%), had a performance status (PS) o80 (76%) and an epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3-25%), all in patients with PS 80-100. The best disease control rate was 36% (95% CI 22-51%). Two toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients with poor PS (60-70).Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in good PS (80-100) patients with refractory or recurrent MM, for which no standard therapy was available.

Histone deacetylase inhibitors in cancer therapy. A review

“…90 ). VPA with doxorubicin appeared to be an effective chemotherapy regimen (16% response rate) in patients with refractory or recurrent mesothelioma 91 . Vorinostat .…”

Thoracic oncology in Europe: the ERS action plan by the Thoracic Oncology Assembly

“…We encourage all our members who are active in research on thoracic oncology to submit their results in the ERJ, thus contributing crucially to the development of thoracic oncology in the ERS; recent ERJ publications on mesothelioma treatment should serve as an encouraging example for this serious call [6,7]. For continuous medical education, we plan a European course entitled ''An Update for Management of Pleural Malignancies'' in November 2011 in Lille, France, in collaboration with the European School of Oncology.…”

Second line therapy in malignant pleural mesothelioma: A systematic review

“…In a phase II trial, 45 patients pre-treated with at least one chemotherapy regimen including platinum derivatives, regardless response, received the combination of valproic acid and doxorubicin [25]. The RR was 16%.…”