Second-line chemotherapy in malignant pleural mesothelioma: Results of a retrospective multicenter survey
Introduction
Malignant pleural mesothelioma (MPM) is a rare tumor with a poor prognosis, whose incidence is increasing worldwide [1]. Most of MPMs patients are not amenable to radical surgery and, for them, systemic therapy is the standard treatment option. Several new cytotoxic agents with definite activity in mesothelioma have been evaluated in the last years, including vinorelbine, gemcitabine, and the antifolates pemetrexed and raltitrexed [2], [3], [4], [5], [6]. Recently, the combination of cisplatin and pemetrexed has become the standard of care in the first-line (FL) MPM treatment [5]. However, considering that many MPM patients are unfit to receive a cisplatin-based chemotherapy, schedules containing carboplatin have been tested in an attempt to reduce toxicity maintaining the same survival outcomes [7], [8], [9].
Unfortunately, nearly all MPM patients progress after FL treatment, and second-line (SL) therapies are being increasingly used in the clinical practice. Patients who experience clinical benefit from FL chemotherapy have frequently a good performance status (PS) when radiological progression of MPM is documented. However, the role of SL chemotherapy in MPM is not yet proven. In a retrospective analysis of patients treated in the phase III cisplatin-pemetrexed trial, a significantly prolonged survival in the groups treated with post-study chemotherapy (PSC) was reported [10]. Anyway, because receipt of PSC was not randomized, it was impossible to know whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. As a matter of fact, the crucial point is to distinguish the clinical/radiological stability due to the treatment effect from the natural history of disease. Despite these limitations, there is increasing evidence from single-arm studies that chemotherapy in the SL setting is feasible and active [11], [12], [13], [14], [15], [16], [17], [18], but at this time no regimen has been widely approved [19]. Pemetrexed, both alone and combined with carboplatin, was reported to be active as SL treatment following prior platinum-based chemotherapy [20]. In a phase III trial comparing SL pemetrexed with best supportive care, improved tumor response and progression-free survival were reported (3.8 months versus 1.5 months), whereas the use of pemetrexed did not significantly increase OS, possibly due to the significant imbalance in PSC between the arms [21].
However, most patients are treated with pemetrexed-based regimens in the FL setting, and SL chemotherapy must therefore focus on other compounds. At now, very few prospective studies of SL chemotherapy in pemetrexed-pretreated MPM patients have been published, and it is unclear whether a SL chemotherapy might improve the outcome and which are the best agents and schedules to be used. The European Respiratory Society/European Society of Thoracic Surgeons Task Force (ERS/ESTS) stated in the 2009 guidelines that selected patients demonstrating a prolonged symptomatic and objective response with first line chemotherapy may be treated again with the same regimen in the event of recurrence [22]. Several trials are ongoing [19].
With this in mind, we performed a retrospective survey of SL treatments administered to MPM patients out of the context of clinical trials in eight Italian Institutions, focusing on the delivered therapy regimens and on their potential impact on clinical outcomes.
Section snippets
Patient selection and assessment
Data of all MPM patients who received SL chemotherapy from 1996 to 2008 in 8 Italian Institutions were retrospectively reviewed. Only patients with sufficient data to evaluate clinical outcomes of FL and SL chemotherapies and patient characteristics were considered for the analysis. For each patient, age and gender, Eastern Cooperative Oncology Group (ECOG) PS, European Organization for Research and Treatment of Cancer (EORTC) score, histology and FL outcomes (response evaluation and time to FL
Whole population
Out of a group of 423 MPM patients treated with SL chemotherapy at the eight participating centers between 1996 and 2008, 181 cases (43%) with full clinical data were identified. Patient characteristics, SL therapy characteristics, and the outcomes according to the clinical variables are listed in Table 1, Table 2, Table 3, respectively.
Overall DCR was 52.6%, with 1 CR (0.7%), 20 PR (11.1%), and 74 SD (40.8%). With a median follow-up of 43.3 months (range 0.2–136.3 months), median PFS was 4.3
Discussion
This retrospective survey was performed to identify the characteristics of MPM patients who in clinical practice receive SL treatment, and to analyze the delivered chemotherapy regimens and their potential impact on clinical outcomes. SL regimens had been empirically chosen in the participating centers according to the local experiences, and outside the context of clinical trials.
The study has important limitations, due to its retrospective nature. In particular, results should be considered
Conclusions
SL therapy in MPM remains an ideal field in which to test new chemotherapeutic agents as well as new therapeutic strategies. In our population, even if considering the limitations of this study due to retrospective nature and the possible selection bias, younger patients with a good PS and a prolonged TTP after first-line therapy were more likely to benefit from SL treatment. In pemetrexed-pretreated patients, a good PS, epithelial histology, and a prolonged TTP after FL were predictive of a
Conflict of interest statement
None declared.
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