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

Our plain-English summary of Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study, by A. Scherpereel, T. Berghmans, J.J. Lafitte, et al (The European Respiratory Journal, 2011).

The study

• Authors: A. Scherpereel, T. Berghmans, J.J. Lafitte, B. Colinet, M. Richez, Y. Bonduelle, A.P. Meert, X. Dhalluin, N. Leclercq, M. Paesmans, L. Willems, J.P. Sculier, European Lung Cancer Working Party (ELCWP)
• Journal: The European Respiratory Journal
• Published: 2011;37(1):129-35
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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) ≥ 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.

In plain English

This was a phase II trial run by the European Lung Cancer Working Party. It tested valproic acid (an epilepsy medicine) together with the chemotherapy drug doxorubicin. Patients had mesothelioma that could not be removed surgically and had progressed after platinum-based chemotherapy. Between July 2006 and March 2009, 46 patients were registered; 45 were eligible, and all had pleural mesothelioma. Patients took valproic acid by mouth, then received doxorubicin into a vein. Seven of the 45 patients (16%; 95% CI 3 to 25%) had a partial response. All seven were in good general condition (performance status 80 to 100), though statistical tests found no factor that significantly predicted response. The best disease control rate (partial response plus stable disease) was 36% (95% CI 22 to 51%), and median survival was 6.7 months (95% CI 4.9 to 8.5 months). The main side effects were low white blood cell counts. Two patients in poorer condition died of treatment toxicity. The authors concluded the combination appeared effective in patients in good condition, but said results need confirmation in a randomised trial.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-arm phase II clinical treatment trial (academic trial using a two-stage design), run by the European Lung Cancer Working Party
• Who was studied: 46 consecutive patients were registered between July 2006 and March 2009. One was ineligible because of wrong histology, leaving 45 eligible patients. All had pleural malignant mesothelioma that was unresectable or inoperable and had failed after at least one platinum-based chemotherapy regimen. 73% were male, and 80% had the epithelioid subtype.
• Exposure: This was a treatment study, not a study of asbestos exposure. Patients took oral valproic acid (20 to 30 mg per kg per day) to reach the blood levels used for treating epilepsy. They then received doxorubicin at 60 mg per square metre as a short intravenous infusion every 3 weeks, with valproic acid continued throughout.
• Main results:
  • Best response: 7 of the 45 eligible patients (16%; 95% CI 3 to 25%) had a partial response.
  • All seven responders had good performance status (80 to 100), but univariate analyses found no statistically significant factor predicting response.
  • Best disease control rate (partial response plus stable disease) was 36% (95% CI 22 to 51%).
  • In all patients, median progression-free survival was 2.5 months (95% CI 2.0 to 3.0 months) and median survival was 6.7 months (95% CI 4.9 to 8.5 months).
  • In univariate analysis, performance status was the only statistically significant prognostic factor for survival. Median survival was 1.5 months for the 11 patients with performance status 60 to 70 and 8.8 months for the 34 patients with 80 to 100.
  • Using a landmark at 3.88 months, median survival after the landmark was 16.7 months for responding patients and 4.5 months for the 24 nonresponders alive at the landmark. The difference was reported as statistically significant (p = 0.03).
  • The main toxicities were leukopenia and neutropenia. Two toxic deaths occurred, both in patients with poor performance status: one from febrile neutropenia and one from a cerebral thrombotic event. One patient developed grade IV cardiac failure.
• The authors' conclusion: The authors concluded that doxorubicin plus valproic acid appears to be an effective chemotherapy regimen in patients with good performance status (80 to 100) whose mesothelioma was refractory or recurrent after first-line cisplatin-based chemotherapy. They added that the results need confirmation in a randomised trial.
• Limitations the authors state:
  • The authors stated that the results need confirmation in a randomised trial to validate the regimen's effectiveness.
  • The authors acknowledged they did not detect a statistically significant association between performance status and response.
  • The authors noted that toxicities other than neurological ones are difficult to compare with previous studies because the chemotherapy and populations differ.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Doxorubicin, Mesothelioma, Malignant Mesothelioma, Cisplatin, Chemotherapy, Apoptosis, Unresectable, Performance Status.

Related studies

• A 5-aza-2'-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma — S. Leclercq, F. Gueugnon, et al. (2011)
• Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study — G. Hillerdal, J.B. Sorensen, et al. (2008)
• Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma — D. Bensaid, T. Blondy, et al. (2018)
• High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with (99m)Tc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin — O. Arrieta, L.A. Medina, et al. (2014)
• A phase II trial of dose-escalated doxorubicin and ifosfamide/mesna in patients with malignant mesothelioma — L.Y. Dirix, J. van Meerbeeck, et al. (1994)
• Phase-II study with the combination of cisplatin and doxorubicin in advanced malignant mesothelioma of the pleura — H. Henss, H.H. Fiebig, et al. (1988)

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