Elsevier

Lung Cancer

Volume 38, Issue 2, November 2002, Pages 111-121
Lung Cancer

Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis

https://doi.org/10.1016/S0169-5002(02)00180-0Get rights and content

Abstract

The role of chemotherapy for unresectable malignant mesothelioma is unclear. The aims of the present study were to evaluate the methodological quality of published papers relative to chemotherapy or immunotherapy in malignant mesothelioma and to aggregate, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens. The literature relative to this topic, published between 1965 and June 2001 was reviewed. A methodological qualitative evaluation was performed according to the European Lung Cancer Working Party scale, specifically designed for phase II trials. A study was considered as potentially positive if the upper limit of the 95% confidence interval (CI) of the response rate was greater than 20% and positive if the lower limit of the 95% CI was >20%. Eighty-three studies (88 treatment arms) were eligible for the systematic review. Fifty-three arms were considered as positive or potentially positive. No statistically significant difference in the methodological quality was observed between negative and positive studies. Studies were aggregated in four groups according to the presence of cisplatin and/or doxorubicin in the treatment regimen. The combination of cisplatin and doxorubicin had the highest response rate (28.5%; P<0.001). Cisplatin was the most active single-agent regimen. Our systematic qualitative and quantitative overview of the literature suggests that the most active chemotherapeutic regimen, in term of objective response rate, is the combination of cisplatin and doxorubicin and the best single-agent is cisplatin. The combination of these two drugs can be recommended as control arm for future randomised phase III trials.

Introduction

Malignant mesothelioma is an infrequent tumor but its incidence is rising. It accounts for around 1500 deaths per year in the United States [1]. Wagner et al. [2] observed the relationship between exposure to asbestos and development of this type of cancer in 1960 and its incidence is expected to increase in the future due to the widespread use of this carcinogen, as observed in Australia [3]. The latency period between asbestos exposure and development of malignant mesothelioma can be as high as 30 years or more [1]. Malignant mesothelioma progresses generally locally, causing death by progressive respiratory failure or intestinal obstruction in the majority of the cases [4].

Long-term survivors are unfrequent [5]. Surgical pleurectomy or extrapleural pneumonectomy are rarely curative. Only a minority of the patients are eligible for these treatments [6], whose mortality and morbidity can be considerable. The efficacy of radiotherapy is not proven [1]. Several chemotherapeutic agents have been tested. Numerous studies are made of case-reports or are retrospective and their significance is weak. The majority of the published prospective trials are non-randomised phase II studies. Recent reviews [1], [7] have pointed out some potentially useful agents: platinum compounds, anthracyclins, high dose methotrexate, alkylating agents and mitomycin C. The response rate to single-agent chemotherapy rarely exceeds 20%. The superiority of polychemotherapy over single-agent therapy is not proven [7]. Some favorable effects have been reported with intrapleural administration of biological response modifiers [7].

The aims of the present study were to assess the methodological quality of publications relative to chemotherapy or immunotherapy in malignant mesothelioma and to aggregate, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens, which could be selected for future randomised trials. For this purpose, we have used the methodological evaluation scale of the European Lung Cancer Working Party (ELCWP) previously published [8] but adapted to the specific design of phase II studies [9].

Section snippets

Material and methods

The search for prospective published trials relative to the treatment of malignant mesothelioma of pleural or peritoneal origin was performed by consulting the Medline, Health Star and National Cancer Institutes electronic data bases and completed by references found in the papers, in textbooks, in reviews and those known by the investigators.

The criteria of eligibility of the articles were the following: to focus only on patients with malignant mesothelioma; to be related to the study of

Trials characteristics

Eighty-three articles, published between 1983 and June 2001, met our selection criteria and were eligible for the analysis. Out of these 83 eligible studies, 80 were single arm phase II trials and three were randomised phase II trials. For the purpose of this review, each arm of the randomised studies was assessed as an independent trial. In two papers, two separate phase II trials were reported in the same publication. Thus, 88 ‘arms’, each considered as an independent study, were analysed.

Discussion

The systematic review that we performed on the medical treatment of malignant mesothelioma and in which we incorporated a quality assessment of the trials suggests that, in term of tumoral activity, the best regimen is the combination of cisplatin and doxorubicin with an overall objective response rate of 28%. Cisplatin containing regimen without doxorubicin, with a 23% objective response rate, is less active than the combination of the two drugs but remains significantly more active than the

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