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  MTE14 - Second Line Chemotherapy in Mesothelioma - What is the Best Evidence? (ID 58)

  • Event: WCLC 2013
  • Type: Meet the Expert (ticketed session)
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:N. n/a
  • Coordinates: 10/29/2013, 07:00 - 08:00, Bayside 106, Level 1

  • 11432

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    MTE14.1 - Second Line Chemotherapy in Mesothelioma - What is the Best Evidence? (ID 607)

    07:00 - 08:00  |  Author(s): G.L. Ceresoli
    • Abstract
    • Presentation
    • Slides

    Abstract
    Most patients affected by malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of the disease, as single modality treatment or within the context of a multimodality approach. Following the results of a large phase III trial, the combination of cisplatin and pemetrexed has become the preferred first-line chemotherapy, although there is also evidence for the activity of the combination with carboplatin. Unfortunately, nearly all MPM patients progress during or after first-line treatment. Second-line therapies are being increasingly used in the clinical practice because patients are frequently still in good clinical conditions at the time of disease progression. However, the role of these treatments in MPM is unproven, and the optimal regimens still remain to be defined. In pemetrexed-naïve patients, data from a randomized trial vs. best supportive care suggest the use of single-agent pemetrexed as a standard second-line treatment. This evidence is supported also by the results of the Expanded Access Programs. To date, there is no standard approach for pemetrexed-pre-treated patients. Several phase II and a few phase III trials have been performed or are ongoing, and this remains a field of active research. Unfortunately, studies available until now have frequently severe limitations, due to the small number and to the heterogeneity of patients included, and often to the design of the studies themselves. In selected cases with a prolonged response to first-line pemetrexed-containing chemotherapy (less than 25% of the whole population of MPM patients treated in first-line), re-treatment with a pemetrexed-based regimen should be considered, based on preliminary evidence reported in small case series. Clinicians should be aware of the risk of hypersensitivity reactions when carboplatin is used in combination with pemetrexed in the re-treatment setting. For the remaining patients the evidence is still limited. Targeted therapies with agents such as EGFR and PDGFR inhibitors, anti-angiogenic compounds, and histone-deacetylase inhibitors have so far achieved disappointing results. Trials with small molecules or monoclonal antibodies that target different molecular pathways are ongoing. Patients should be encouraged to participate in these trials. When a trial is not available or patients are not eligible for an experimental approach, second-line chemotherapy can be a reasonable option for palliation. Gemcitabine and vinorelbine are the most commonly administered agents. However, prospective studies in this setting are sparse, and most evidence comes from retrospective reports. Gemcitabine has been studied mainly in combination with other compounds in small studies. Overall, all these studies showed a modest activity, with a response rate of 10% or less and a disease control (including also stable disease) in about half of patients. The incidence of severe toxicity was low, and mainly related to hematological adverse events. Vinorelbine has been studied in the second-line setting mainly as a single agent. There are at least 4 studies available, 2 of them with a retrospective design. These studies are difficult to compare, because of different patient selection and drug schedules. In the largest study patients were pretreated with various chemotherapy regimens, including pemetrexed-based regimens, while in the other studies all patients were pemetrexed-pretreated. Two studies included also patients treated beyond second line, while the others were pure second-line trials. Treatment schedules were different, and this was reflected by the higher hematological toxicity in studies with the higher vinorelbine dose-intensity. Overall, response rate ranged from 0 to 15%, with disease control rates variable according to patient selection. When gemcitabine and vinorelbine were used in combination, no survival benefit was observed as compared to single-agent chemotherapy, with a higher (mainly hematological) toxicity. In conclusion, evidence for a benefit of second-line chemotherapy in MPM patients is weak, and should be confirmed in prospective studies. A few trials with new chemotherapeutic compounds (e.g. trabectedin) are ongoing. Ideally, future second-line trials in MPM should be designed as at least randomized phase II trial and according to strict eligibility criteria, mainly as far as pre-treatment is concerned (prior regimens and numbers of treatment lines). Patients should be stratified according to the outcome of first-line therapy and to known prognostic factors (like EORTC prognostic score). Time-related events (median PFS or 3-month PFS) should be the primary endpoints. Finally, second-line setting is the ideal field for high-quality correlative studies aimed to identify the patients who will benefit from treatment, and to improve the knowledge of MPM biology.

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