Original ResearchProgression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: An individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation☆
Introduction
The occurrence of malignant pleural mesothelioma (MPM) parallels the exploitation and use of asbestos, with a mean latency period of approximately 40 years [1]. Thus, the incidence of MPM was expected to peak in the United States of America around 2010 [2], but continues to rise during the next 10 years in Europe [3]. Although the incidence of MPM should then decrease in developed countries, it will increase in developing countries, where the use of asbestos is poorly regulated, if at all [4]. Consequently, MPM will remain a major health problem worldwide for many decades.
While MPM was considered as refractory to treatments, two randomised phase III trials have demonstrated that first-line chemotherapy combining cisplatin and an antifolate (either pemetrexed [5] or raltitrexed [6]) significantly increased overall survival in patients with MPM compared to cisplatin alone. However, median overall survival does not exceed 12 months with these treatments and no standard of care is defined after failure of the latter. Research efforts must continue in the field of MPM to improve the efficacy of first-line therapy and identify effective second-line treatments. In phase II cancer clinical trials, the biological antitumour activity of drugs is generally assessed by measuring tumour shrinkage and the primary end-point is classically the response rate (response rate (RR), i.e. the proportion of complete and partial responses). However, this end-point has some disadvantages in the particular case of MPM. Due to its unique pattern of growth, response criteria have always been difficult to apply to MPM and for that reason a modified version of Response Evaluation Criteria in Solid Tumours (RECIST) has been developed [7]. Moreover, new drugs and notably targeted therapies are often more likely to work as cytostatic than cytotoxic agents. Thus, more relevant end-points should be considered in future MPM trials. From this perspective, one could propose to integrate disease stabilisation in the definition of drug activity.
The use of progression free/disease control as a primary end-point in phase II clinical trials has been previously explored. Lara et al. [8] showed that progression free rate was a stronger predictor of survival than tumour response rate in advanced non small cell lung cancer (NSCLC). Francart et al. [9] suggested that progression free rate at 18 weeks can be used as the primary end-point of phase II clinical trials in mesothelioma. In addition, Blayney et al. [10] explored the association of response with overall survival in patients with MPM.
We hypothesised that progression free survival rate (PFSR) could be a better predictor of survival than RR in MPM patients treated with first-line chemotherapy.
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Patients and methods
The European Organisation for Research and Treatment of Cancer Lung Cancer group conducted between 1984 and 2001 a large screening programme to identify any active drug for first-line treatment of patients with MPM. A total of nine phase II trials were conducted. Later, one randomised phase III trial was implemented to compare a chemotherapy doublet to a monotherapy. Details concerning the chemotherapy regimens assessed in these 10 trials are summarised in Table 1.
The inclusion criteria were
Patient characteristics
Table 3 summarises the baseline characteristics of 523 patients from 10 EORTC studies where the model was developed and those of 82 patients from EORTC-08052 validation study. The majority of patients were male (83% versus 67%) with a median (range) age of 58 versus 55 (19–80 versus 22–77) years, had a performance status of 0/1 (86% versus 100%), epithelial histology (59%, versus 59%) and had stage III/IV disease (23/39% versus 23/43%) for all versus validation study, respectively. The baseline
Discussion and conclusions
This landmark survival analysis of 10 EORTC studies in patients with mesothelioma attempts to describe a reliable end-point which is simple to measure for early phase (phase II) clinical trials in mesothelioma, where traditional response measurement is challenging.
The data showed that PFSR status and response at 9 and 18 weeks strongly predict positive survival outcome. These findings hold up even after adjusting for known prognostic factors.
Although the models have been developed in
Conflict of interest statement
None declared.
Acknowledgement
This publication was supported by Fonds Cancer (FOCA) of Belgium.
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Effects of Reduction in Tumor Burden on Survival in Epithelioid Malignant Pleural Mesothelioma
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2015, Annals of OncologyCitation Excerpt :A study to evaluate ADI-PEG20, in combination with chemotherapy, in AS-negative mesothelioma [NCT02029690] is underway. Mutation of NF2 occurs in around 50% of mesotheliomas, sensitising inhibition of FAK [34–36]. Accordingly, this trial is stratifying patients by Merlin expression.Unlabelled Text
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Presented as abstracts at ASCO Meetings in Chicago, June 2011 and June 2013.