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) ≥ 80 (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.
Scherpereel
A
A
Dept of Pulmonary and Thoracic Oncology, CHRU de Lille and University of Lille II, Lille, France.
Berghmans
T
T
Lafitte
J J
JJ
Colinet
B
B
Richez
M
M
Bonduelle
Y
Y
Meert
A P
AP
Dhalluin
X
X
Leclercq
N
N
Paesmans
M
M
Willems
L
L
Sculier
J P
JP
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy*; D008875:Middle Aged; D020033:Protein Isoforms; D014635:Valproic Acid / Q000008:administration & dosage*
D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D014635:Valproic Acid; D004317:Doxorubicin