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

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.