L Lang-Lazdunski, A Bille, S Marshall, R Lal, D Landau, J Spicer

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1 Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine and systemic chemotherapy in malignant pleural mesothelioma. A 10-year experience. L Lang-Lazdunski, A Bille, S Marshall, R Lal, D Landau, J Spicer Department of Thoracic Surgery, Guy s & St Thomas hospital, London, United Kingdom Division of Cancer Studies, King s College London

2 Disclosure AATS Annual Meeting 2014, Toronto, ON, Canada No conflict of interest to declare

3 The legacy of asbestos: malignant mesothelioma The asbestos-related cancer malignant mesothelioma remains a major health problem worldwide, 50 years after Wagner recognised the link between asbestos and mesothelioma in South-African miners (1960). The epidemic is expected to reach its peak within 10 years, eventually > mesothelioma deaths expected in Europe. More than 1.8m people exposed to asbestos every year in Britain (source: Health and Safety Executive, 2011). In Britain, more than 2200 mesothelioma deaths registered yearly, highest incidence worldwide. By 2015, >2500 deaths per year expected in Britain, due to asbestos (HSE). Majority of malignant pleural mesotheliomas > peritoneal mesotheliomas.

4 Objectives: Evaluate the long-term results of a multi-modality regimen involving total P/D, hyperthermic pleural lavage with povidone-iodine and adjuvant systemic chemotherapy in patients with malignant pleural mesothelioma. Feasibility and safety, mortality, complications, overall survival

5 Diagnostic investigations / Staging Biopsy to prove diagnosis of malignant pleural mesothelioma: CT-guided biopsy, VATS or open pleural biopsy (cytology not reliable) Chest CT, MRI rarely (diaphragm/great vessels?) 18 FDG-PET and PET-CT (SUVmax prognostic value, TGV) Laparoscopy (rarely) Bronchoscopy

6 Methods: Prospective study of all patients receiving this multi-modality regimen from January 2004 on All patients discussed in a thoracic oncology MDM Several meetings with the team and informed consent given Procedure approved by hospital committee on new procedures Surgery followed by prophylactic radiotherapy at 4-5 weeks (21 Gy in 3 fractions), followed by systemic chemotherapy at 6-8 weeks (pemetrexed and cisplatin, 6 cycles) Follow up at 4 weeks, 6 months and 6-monthly thereafter with PET-CT Second and third-line therapies offered: systemic chemotherapy, or targeted therapy when disease progression (clinical trials) Survival curves computed using Kaplan-Meier method. Survival comparison: log-rank test. Factors affecting survival tested in univariate analysis. When p<0.10, tested in multivariate analysis using Cox proportional hazards model

7 Total P/D and hyperthermic pleural lavage with povidone-iodine

8 Results: 102 patient from January 2004 to December 2013, 4 excluded due to active empyema at the time of surgery. 98 patients entered prospectively into our database, none lost a follow-up 77 males and 21 females. Median age 64 (range 32-81), 22 patients > 70 years 60 patients had right-sided mesothelioma 71 patients with epithelioid histology, 25 biphasic, 2 sarcomatoid. Final IMIG stage: 1, n=7, 2, n=23, 3, n=57, 4, n=11 No 90-day mortality. 19 patients underwent extended resections. 28 patients had complications: 16 persistent air leak, 4 chylothorax, 3 pneumonia, 2 empyema, 2 fast AF, 1 ARDS, 1 TIA 97% of patients started chemotherapy within 6-8 weeks of surgery and received 4-6 cycles of adjuvant chemotherapy At last follow-up (April 2014), 49 patients alive and 49 dead. Relapses mainly local. Age > 70 years, sex M vs F, nodal status N0 vs N+, previous chemotherapy, had no significant impact on survival in multivariate analysis

9 Results: overall survival Median overall survival 32 months (95% CI ), 5-year survival 24.1%

10 Results: impact of histology on survival Epithelioid type versus non-epithelioid Median survival 35.3 versus 14.9 months, 5-year survival 32.7% versus 7.2%

11 Results: impact of complete macroscopic resection on survival Median survival 46.4 months versus 15 months. 5-year survival 35.6% versus 0%

12 Effect of povidone-iodine on mesothelioma cells Diluted povidone-iodine inhibits tumor growth in a dose-dependent manner through different mechanisms: induction of apoptosis, necrosis, suppression of SOD activity (colon, breast, hepatoma) Sun P et al., Onc Rep 2012 Povidone-iodine induces mesothelioma cell death in vitro and in vivo Opitz I, et al. Lung Cancer 2007, Opitz I et al., Eur J cardiothorac Surg 2007 Povidone-iodine induces necrosis in all mesothelioma cell lines in vitro with increasing concentration (0.1 to 1%) and time (>10 min) Fiorelli A, et al. Eur J Cardiothorac Surg 2014

13 Conclusion Total P/D with hyperthermic pleural lavage with povidone-iodine followed by systemic chemotherapy is a safe multi-modality regimen in patients with malignant pleural mesothelioma. It is well-tolerated and associated with good long-term results. We should now focus our efforts on tackling residual microscopic disease and preventing local recurrence.

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