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Objectives: There is little evidence regarding the use of chemotherapy as part of multimodality treatment of malignant pleural mesothelioma (MPM). We aimed to determine whether, in those patients fit for chemotherapy, a delay in this treatment affected survival., Materials and Methods: We analysed postoperative variables of 229 patients undergoing either extrapleural pneumonectomy (EPP) (81 patients) or extended pleurectomy-decortication (EPD) (197 patients) for MPM at a single centre. There was no standard protocol for additional chemotherapy and varied with referral centre. Outcome was compared between 4 chemotherapy strategies: true adjuvant therapy, neo-adjuvant therapy, therapy reserved until evidence of disease progression in those otherwise fit in the post-operative setting, and those unfit for chemotherapy., Results: There was no effect of the timing of chemotherapy on overall or progression free survival in patients fit enough for treatment (p=0.39 and p=0.33 respectively). However delaying chemotherapy until evidence of disease progression in patients with non-epithelioid disease had a detrimental effect on overall survival (OS), and on progression free survival (PFS) in lymph node positive patients (15.6 vs. 8.2 months p=0.001, and 14.9 vs. 6.0 months p=0.016). Further analysis of 169 patients receiving platinum/pemetrexed as first line treatment, showed similar results; there was no effect of the timing of chemotherapy on OS or PFS (p=0.80 and p=0.53 respectively) and an improved OS in patients with non-epithelioid disease, and improved PFS in those with lymph node metastases, if chemotherapy was given in the immediate adjuvant setting (p=0.001 and 0.038) when therapy was not delayed until disease progression., Conclusion: Our results suggest that the timing of additional chemotherapy may be important in those with a poorer prognosis on the basis of cell type and nodal stage. In these patients additional postoperative chemotherapy should not be delayed., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Malignant pleural mesothelioma (MPM) is a highly chemoresistant cancer with a poor prognosis. Hypoxia is a specific property of solid tumours, contributes to low apoptotic potential, and can be selectively targeted by bioreductive drugs. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a subunit of a heterodimeric transcription complex that regulates several genes associated with tumour progression and anti-apoptosis. In this study, we measured for the first time the expression of HIF-1alpha in MPM. Our results show that HIF-1alpha is commonly expressed in MPM but not in normal mesothelium, consistent with the presence of hypoxia. HIF-1alpha does not appear to predict survival; however, this study suggests that bioreductive drugs should be investigated in clinical trials of MPM.

Prognostic factors can help clinicians and patients when deciding a treatment plan. Patients in the best prognostic groups can be considered for more intensive or experimental therapy. Alternatively, patients in the best prognostic groups might prefer a period of observation prior to commencement of therapy. For patients with mesothelioma prognostic factors are potentially especially important because of the lack of a widely applicable anatomical staging system. Both the International Mesothelioma Interest Group (IMIG) and Brigham staging systems are of limited relevance to patients not undergoing radical debulking surgery. Radiological prediction of IMIG or Brigham stage is of little value. Review of the best-known prognostic scoring systems from the EORTC and CALGB has shown that the most important predictors of poor prognosis are: poor performance status; non-epithelioid histology; male gender; low hemoglobin; high platelet count; high white blood cell count; and high lactate dehydrogenase (LDH). The EORTC model was validated at St Bartholomew's Hospital in a group of 145 patients treated in sequential phase II chemotherapy trials. For 70 patients treated with vinorelbine, those having the best EORTC prognosis had a median survival of 19.2 months [95% C.I.=14.7-23.7] compared to 9.9 months [95% C.I.=8.5-11.3] for those in the worst group. The suggestion is that all clinical and biological factors relevant to prognosis should be recorded prospectively in mesothelioma patients selected for clinical trials.

Unlabelled: The incidence of malignant pleural mesothelioma (MPM) is increasing. Treatment options are limited, although recently published data have offered cause for optimism. We reported a response rate of 24% with low toxicity for single agent vinorelbine. Here we report a phase II trial of vinorelbine with oxaliplatin (VO) in patients with untreated MPM. Chemotherapy consisted of vinorelbine 30 mg/m(2), days 1 and 8 of a 21-day-cycle, and oxaliplatin 130 mg/m(2), day 1. Treatment continued up to six cycles. The primary endpoint was objective response. Secondary endpoints were toxicity, progression-free and overall survival. Responses were assessed by modified RECIST criteria. Twenty-six patients were enrolled. There were six partial remissions, 17 patients with stable disease, and three patients with PD. Response rate was 23% (95% confidence interval 9-44%). Median number of cycles delivered was four. Progression-free survival from first treatment was 4.7 months, and overall survival was 8.8 months. One-year-survival was 27%. Toxicity (% of patients with at least one episode of grade 3 or 4 toxicity): neutropenia 18%, phlebitis 12%, malaise 12%, anorexia 12%, nausea and vomiting 12%, constipation 6%. Quality of life assessed by Rotterdam symptom checklist was associated with stabilization or improvement of psychological well-being and lung symptoms in the majority of patients, but deterioration in physical symptoms., Conclusion: VO has activity in MPM with most patients responding or having stable disease, although this doublet is associated with significant toxicity.