Valproate–Doxorubicin: Promising Therapy for Progressing Mesothelioma
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Eur Respir J 2011; 37: 129–135 DOI: 10.1183/09031936.00037310 CopyrightßERS 2011 Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study A. Scherpereel*,#,++, T. Berghmans",++, J.J. Lafitte*,#, B. Colinet+, M. Richez1, Y. Bonduellee, A.P. Meert", X. Dhalluin*, N. Leclercq", M. Paesmans**, L. Willems## and J.P. Sculier" for the European Lung Cancer Working Party (ELCWP) ABSTRACT: No treatment is recommended for patients with malignant mesothelioma (MM) failing AFFILIATIONS after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone *Dept of Pulmonary and Thoracic Oncology, CHRU de Lille and deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to University of Lille II, and induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined #INSERM U1019, Centre d’Infection valproic acid and doxorubicin in patients with unresectable MM failing after platinum-based et d’Immunite de Lille, Institut chemotherapy. Pasteur de Lille, Lille, France. "Dept of Intensive Care Unit and ? -2 Treatment consisted of doxorubicin (60 mg m ) plus valproic acid. An interim analysis for Thoracic Oncology, Institut Jules response rate was planned after the first 16 registered patients. All the cases were centrally Bordet, Centre des Tumeurs de reviewed. l’Universite´ Libre de Bruxelles (ULB), From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The **Data Centre, Institut Jules Bordet, Centre des Tumeurs de l’Universite´ majority of the patients were male (73%), had a performance status (PS) o80 (76%) and an Libre de Bruxelles ELCWP, Brussels, epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3– +Dept of Pneumology, Grand Hoˆpital 25%), all in patients with PS 80–100. The best disease control rate was 36% (95% CI 22–51%). Two de Charleroi, site Saint-Joseph, Gilly, 1 toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients Dept of Pneumology, CHR St Joseph, Warquignies with poor PS (60–70). eDept of Pneumology, CH Peltzer-La Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in Tourelle, Verviers, and good PS (80–100) patients with refractory or recurrent MM, for which no standard therapy was ##Gembloux Agro-Bio Tech and available. Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Lie`ge, Lie`ge, Belgium. KEYWORDS: Chemotherapy, doxorubicin, histone deacetylase inhibitors, mesothelioma, ++Both authors contributed equally to valproic acid this work ""A full list of the ELCWP Study Group members and their affiliations can be found in the alignant mesothelioma (MM) is a rare [7], pemetrexed plus carboplatine [7], vinorelbine Acknowledgements section. malignancy with increasing incidence, [8] or a combination of cisplatin, mitomycine and CORRESPONDENCE due to the large use of asbestos and a M irinotecan [9]. As seen from these results, new T. Berghmans, Institut Jules Bordet, poor prognosis. First-line chemotherapy combin- treatments, including drugs with original acti- Rue He´ger-Bordet, 1, 1000 Brussels, ing cisplatin and pemetrexed is currently the vity profile are needed. The 2008 European Belgium standard care [1] for inoperable patients, having Respiratory Society (ERS)/European Society of E-mail: thierry.berghmans@ demonstrated improved response rate and survi- Thoracic Surgeons (ESTS) Task Force on MM bordet.be val in comparison with cisplatin alone in a phase management recommended that patients demon- III trial [2]. A second randomised study confirmed strating prolonged symptomatic and objective Received: March 09 2010 the activity of the antifolate raltitrexed in MM response with first-line chemotherapy may be Accepted after revision: [3]. Currently, there is no standard second-line treated again with the same regimen in the event April 29 2010 therapy for MM [1]. In a phase III trial comparing of recurrence. In other cases, inclusion of the First published online: pemetrexed to palliative care alone, JASSEM et al. patients in clinical trials is encouraged [1]. June 07 2010 [4] demonstrated improved progression-free sur- vival and time to progression without impact on The purpose of the present phase II study was to overall survival. Few other studies assessed the evaluate the potentialities of a novel approach effectiveness of chemotherapy as a second-line based on the concept of gene activation therapy. European Respiratory Journal therapy. Response rates between 10% and 20% Our working hypothesis relied on the regulation Print ISSN 0903-1936 c were noted with doxorubicin [5, 6], pemetrexed of cell homeostasis, which is the result of a Online ISSN 1399-3003 EUROPEAN RESPIRATORY JOURNAL VOLUME 37 NUMBER 1 129 THORACIC ONCOLOGY A. SCHERPEREEL ET AL. clinical balance between cell proliferation and death. A Selection criteria resistance to apoptosis is among the key mechanisms To be eligible, patients had to present with histologically described in the pathogenesis of MM [10]. Our hypothesis confirmed unresectable or inoperable MM failing after at least was that the lack of apoptosis is the result of cell quiescence, one prior chemotherapy regimen including platinum deriva- correlating with an absence of gene expression of some tives (cisplatin or carboplatin), whatever the response to the apoptotic molecules. We proposed to relieve this silencing first-line treatment, and at least one evaluable or measurable block by using a histone deacetylase inhibitor (HDACi). lesion. Other eligibility criteria included Karnofsky perfor- HDACi have a potential role in the regulation of gene mance status (PS) o60, and good renal (serum creatinine level -1 -1 expression, induction of cell death, apoptosis, cell cycle arrest f1.5 mg?dL ), hepatic (serum bilirubin level f1.5 mg?dL of cancer cells, and inhibition of angiogenesis, motility and and aspartate aminotransferase/alanine aminotransferase less invasion of tumour cells by altering the acetylation status of than twice the normal range) and haematological (neutrophil chromatin and other non-histone proteins [11, 12]. HDACi count o2,000 per mL and platelet count o100,000 per mL) exert profound modifications of the cell biology and some of functions. Coagulation tests (activated partial thromboplastin these molecules have been proposed as potential anticancer time, partial thromboplastin time and prothrombin time) and agents [13]. fibrinogen had to be in the normal ranges. Patients had to be accessible for participating in the detailed follow-up of the HDACi include a variety of compounds belonging to several protocol and to have provided written informed consent. structural classes: hydroxamic acids (trichostatin A, suberoy- lanilide hydroxamic acid or vorinostat); cyclic peptides Ineligibility criteria were the following: recent (,3 months) (trapoxin and depsipeptide), benzamides (MS-27-275) and myocardial infarction, congestive heart failure (ejection frac- , short-chain fatty acids (butyric acid and valproic acid). tion of the left ventricle 50%) or cardiac arrhythmia requiring Presently, the molecular basis of response to HDACi is not medical treatment; uncontrolled infectious disease or other fully understood. Valproic acid, an old anti-convulsant drug serious medical or psychiatric illness precluding adherence to the study protocol; prior history of malignancy except non- widely used in patients with epilepsy, exhibited HDACi melanoma skin cancer or in situ carcinoma of the cervix and properties at therapeutic blood concentrations [14] without ‘‘cured’’ malignant tumour (.5-yr disease-free interval); active documented negative interactions with doxorubicin [15]. epilepsy needing a specific treatment; concomitant treatment Valproic acid has demonstrated interesting inhibiting activity with monoamine-oxidase inhibitor, carbamazepine, meflo- on different cell lines and tumour xenografts in mice. Growth quine, phenobarbital, primidone, phenytoı¨n, lamotrigine, inhibition and apoptosis were reported in haematological and zidovudine; history of prior HIV infection; pregnancy or solid tumours [16–22]. We showed that valproic acid increases refusal to use active contraception; known allergy to valproic the apoptosis induced by a combination of cisplatin and acid and/or doxorubicin; previous treatment with anthracyclin pemetrexed in MM cell lines and in tumour cells from patient’s derivatives. biopsies [23]. More recently, VANDERMEERS et al. also found that valproic acid synergised with doxorubicin to induce apoptosis Investigations in MM cells (F. Vandermeers, Gembloux Agro-Bio Tech and Initial work-up included clinical evaluation completed by Interdisciplinary Cluster for Applied Genoproteomics (GIGA), weight, height, surface area and record of Karnofsky PS, University of Lie`ge, Lie`ge, Belgium; personal communication). complete blood sampling, electrocardiogram, chest radiograph Valproic acid was tested in a few phase I-II studies in acute and computed tomography scan, isotopic or echographic left leukaemia and myelodysplastic syndrome, in combination ventricular fraction assessment. Blood counts were performed with chemotherapeutic agents [12]. Several studies were weekly. Blood chemistries including valproic acid measure- performed in solid tumours in a limited number of patients, ment, chest radiograph and clinical examination were repeated either alone or in combination with chemotherapy [24–27].