Elsevier

Lung Cancer

Volume 75, Issue 3, March 2012, Pages 360-367
Lung Cancer

Second-line chemotherapy in malignant pleural mesothelioma: Results of a retrospective multicenter survey

https://doi.org/10.1016/j.lungcan.2011.08.011Get rights and content

Abstract

The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients’ characteristics: median-age 64 years (range: 36–85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression  12 months (TTP  12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p = 0.017) and FL-TTP  12 (OR: 3.50; p = 0.006). PFS was related to younger age (<65 years) (HR: 0.70; p = 0.045), ECOG-PS0 (HR: 0.67; p = 0.022), and FL-TTP  12 (HR: 0.45; p < 0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p < 0.001) and to FL-TTP  12 (HR: 0.54; p = 0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p < 0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting.

Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.

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.

References (37)

  • M. Schemper et al.

    A note on quantifying follow-up in studies of failure time

    Control Clin Trials

    (1996)
  • P. Taylor et al.

    Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program

    J Thorac Oncol

    (2008)
  • A.R. Razak et al.

    Re-treatment with pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM): a second line treatment option

    Lung Cancer

    (2008)
  • J. Steer et al.

    Life after first-line chemotherapy in malignant pleural mesothelioma: a North-East England experience

    Clin Oncol

    (2010)
  • J. Peto et al.

    The European mesothelioma epidemic

    Br J Cancer

    (1999)
  • J.B. Sorensen et al.

    Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma

    Br J Cancer

    (2008)
  • M.J. Byrne et al.

    Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study

    J Clin Oncol

    (1999)
  • A.K. Novak et al.

    A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

    Br J Cancer

    (2002)
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