Is There Room for Second-Line Treatment of Pleural Malignant Mesothelioma?

Malignant pleural mesothelioma (MPM) is characterized by a bad prognosis and modest activity of systemic treatment. Currently, there is no clear agreement on the clinical role of second-line chemotherapy in patients with MPM; nevertheless, early case study reports including some pretreated patients had provided evidence that additional responses are possible with the use of further chemotherapy1 after the failure of firstline treatment. Unfortunately, the evidence supporting the efficacy of second-line treatment in this setting is globally weak. A randomized phase 3 trial, enrolling 243 patients, compared pemetrexed plus best supportive care vs best supportive care alone in patients previously treated with a first-line regimen not including pemetrexed. When this study was published, however, the use of pemetrexed in combination with cisplatin had been already accepted as standard first-line treatment. The study showed a statistically significant increase in objective response rate, disease control rate, and time to progression for pemetrexed, but without significant benefit in overall survival.2 Whether the benefit in other end points, in the absence of difference in survival, could be considered sufficient to recommend second-line pemetrexed for clinical practice is debatable. In any case, the trial recruited patients who were pemetrexed naive, which greatly reduces the current applicability of these results, with pemetrexed being part of first-line treatment in the majority of patients now. Can we consider the external validity of these results useful for clinical practice? Probably not. Even when we consider the shift from pemetrexed to other chemotherapy drugs, like vinorelbine, their use as second-line treatment is based on small, nonrandomized series. Following previous experience in the firstline setting,3 weekly vinorelbine was tested within a single-center phase 2 open-label study in 63 patients with previous exposure to chemotherapy. Like all the single-arm trials, the results obtained in this series of patients are at strong risk of being conditioned by selection bias: median interval between the end of the firstline chemotherapy and the start of the weekly secondline vinorelbine was 6 months, most patients had a good performance status, all were classified as low risk according to the European Organization for Research and Treatment of Cancer prognostic score, and median age of this highly selected population was 59 years. A total of 10 partial responses (16%) were observed, and a further 43 patients (68%) had stable disease defined as no evidence of progression for 6 months. Median overall survival was 9.6 months. However, can we trust in the reproducibility of these results in unselected patients, with a shorter treatment-free interval, older age, and worse performance status? Probably not. Similarly, rechallenge with platinum-pemetrexed chemotherapy is sometimes considered in patients who have obtained a long progression-free interval, but the evidence supporting this strategy is again weak. This strategy is probably more supported by the analogy with the rechallenge in other solid tumors where platinumbased therapy is used, rather than by data specifically produced in patients with MPM. In this specific setting, the rechallenge has been explored by Ceresoli et al,4 describing the outcome of patients who had obtained prolonged progression-free survival (PFS) (greater than 3 months) with the previous first-line treatment. Thirtyone patients were included in the study, but there was heterogeneity in the treatment adopted: 15 patients had a rechallenge with single-agent pemetrexed alone, while 16 had a real rechallenge with both drugs. One patient experienced a complete response, whereas a partial response was achieved in 5 patients, producing a modest overall objective response rate of 19%, and an overall disease control rate of 48%. Is this evidence sufficient to consider rechallenge with pemetrexed-based chemotherapy as a second-line treatment option in patients with MPM? Probably not. Considering this absence of robust evidence supporting the use of second-line treatment in clinical practice, what is the position of existing guidelines? National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines seem to support the use of secondline treatment. In fact, although specifying that limited data are available to guide the choice, NCCN guidelines state that “second-line chemotherapy options include pemetrexed (if not administered as first-line therapy), vinorelbine, or gemcitabine, and data suggest that rechallenging with pemetrexed is effective if patients had a good response to first-line pemetrexed.”5 Moving from the United States to Europe, current guidelines of the European Society of Medical Oncology, published in 2015, state that, given the absence of standard secondline or further-line therapy, it is recommended that patients who are in good clinical condition at disease progression after first-line treatment should be enrolled into clinical trials.6 There is no explicit recommendation for patients outside the opportunity of clinical trials, although the statement that “single agent vinorelbine has shown useful activity in phase II trials” implies that, although not standard, second-line treatment can be considered in clinical practice. Italian experts participating in the Third Italian Consensus Conference for MPM stated that, in patients progressing after a first-line pemetrexedbased regimen, there is no standard second-line therapy, and patients should be encouraged to participate in cliniVIEWPOINT