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    MS 06 - Combined Modality Treatment for Thymic and Pleural Malignancy (ID 528)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      MS 06.03 - PD vs. EPP in the Treatment of MPM (ID 7665)

      15:45 - 17:30  |  Presenting Author(s): David Rice

      • Abstract
      • Presentation
      • Slides

      The argument for cytoreduction The argument in favor of cytoreduction is supported by several observations: First, several randomized trials support this procedure for other disease sites including advanced ovarian, colorectal and renal cell cancer. Second, most long-term survivors of MPM have had surgery as a component of their therapy, whereas there are very few long-term survivors who have been treated with non-operative strategies. Analyses of both the Surveillance Epidemiology and End Results (SEER) and the National Cancer Database have show longer survival of patients who have had ‘cancer-directed’ surgery compared to those whose treatment did not include surgery. Third, the median survival of patients in most recent phase III trials of chemotherapy is between 10 to 13 months, whereas in three multicenter trimodality phase II surgical studies median survival is significantly longer ranging 17 to 20 months. Nevertheless, the quality of evidence supporting a role for cytoreductive surgery for mesothelioma is low, and the only randomized study to performed date, the small, underpowered and highly controversial MARS 1 trial, failed to show benefit of extrapleural pneumonectomy compared to chemotherapy and supportive care. Cytoreductive surgical options There are two approaches to cytoreductive surgery for pleural mesothelioma: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). The pendulum has swung back and forth over the last 40 years regarding the best operative approach and decisions are influenced by factors including tumor biology, patient physiology, surgical philosophy and availability of adjuvant therapies. A goal common to both EPP and extended PD/PD is macroscopic complete resection (MCR) of tumor, which is generally interpreted as <1cm residual tumor remaining after resection. The argument for EPP Extrapleural pneumonectomy (EPP) involves the en-bloc resection of the parietal and visceral pleura, lung, ipsilateral pericardium and diaphragm. The latter structures are usually reconstructed with prosthetic mesh, often polytetrafluoroethylene (Goretex), though use of polyglycolic acid (Vicryl), polypropylene and various biologic meshes has also been described. The procedure is associated with an operative mortality of 2 to 8% in experienced centers, however, a recent review of the Society of Thoracic Surgeon’s database reported a 30-day mortality rate of nearly 11%. 90-day mortality as high as 17% has been reported. Postoperative morbidity ranges from 30% to 80%, and major complications include bronchopleural fistula, empyema, hemorrhage, pulmonary embolus and ARDS/pneumonia. The potential value of EPP over PD is that it may offer a more complete cytoreduction in that tumor cells involving the lung and visceral pleura are completely removed. Indeed, most retrospective series show much lower rates of local failure after EPP (13%-35%) than PD (36%-100%). However, distant recurrence (most commonly in the contralateral chest or abdomen) are frequent (~50%). Median survival reported in 3 phase II trials that included EPP in the setting of neoadjuvant chemotherapy ranged between 17 to 20 months from initiation of treatment. Use of intrapleural adjuncts including photodynamic therapy (PDT), heated chemotherapy and other cytotoxic agents is controversial and has yielded varying results. Adjuvant radiation therapy is relatively easy to administer as there is no risk of ipsilateral lung toxicity (lung is removed) and though excellent local control has been reported in several phase II single arm studies, a recent randomized phase III trial showed no benefit to either disease free or overall survival. The argument for PD Pleurectomy decortication involves the resection of parietal and visceral pleura, and localized resection of any tumor involving the lung, diaphragm or pericardium. If the latter two structures are resected the term ‘extended’ PD (EPD) is applied. Several retrospective series have shown improved DFS and OS in patients undergoing either PD or EPD compared to partial pleurectomy (PP) although selection bias is likely to have influenced outcomes to some extent. Perioperative mortality rates following PD averages 3% and major morbidity ranges between 13% to 60%. A common complication after the procedure is prolonged air leak (14% - 58%). Rates of local recurrence after PD are higher than EPP most likely related to the larger surface area at risk for harboring residual microscopic tumor, however this does not appear to influence overall survival. Analysis of retrospective series reveals a median survival of approximately 20 months, similar to EPP, thought there have been notable recent reports of median survival as high as 36 months in patients who have received EPD with intrapleural therapies. Compared to EPP, adjuvant radiation therapy is more difficult to safely administer after PD, and though technically feasible, the benefit in terms of effect on local control (48% - 64%) is questionable. Comparisons of EPP and PD PD/EPD is associated with lower mortality and fewer and less severe postoperative complications than EPP. Additionally, retrospective comparisons of quality of life metrics tend to favor PD/EPD regarding global health, physical and social function and dyspnea[9]. Analysis of 9 retrospective series that have compared cancer related outcomes of EPP and PD/EPD reveals similar or improved survival in most cases with PD/EPD (Table). Differences in patient selection and prognostic factors such as tumor stage, volume and epithelioid histology make direct comparisons difficult, however. Nonetheless, there does not appear to be a survival benefit to performing EPP, and since the procedure is associated with greater risk of operative mortality, morbidity and functional deficit, it seems justified to recommend PD/EPD as the cytoreductive procedure of choice, where technically feasible[10]. The ongoing prospective, randomized MARS-2 trial currently accruing in the United Kingdom will better define the true role of cytoreductive surgery (PD) in the treatment of malignant pleural mesothelioma.

      Author Group n Epithelioid (%) Node +ve (%) T3 or T4 (%) Stage III or IV (%) Median survival (mo) Median follow-up (mo) Local failure (%) Distant failure (%)
      Flores, 2008 EPP 385 70% nr 75% 75% 12 17 (all) 19% 38%
      PD 278 64% nr 65% 65% 16* 31% 17%
      Lang-Lazdunski, 2012 EPP 22 64% 46% nr 87% 13 13 52% 56%
      PD 61 67% 30% nr 63% 23* 16 nr nr
      Rena,2012 EPP 40 86% 0% 0% 0% 20 nr 47% 53%
      PD 37 84% 0% 0% 0% 25 nr 100% 44%
      Nakas, 2012 EPP 98 78% (all) nr 100% 100% 15 21 60% 40%
      PD 67 nr 100% 100% 13 16 56% 18%
      Batirel, 2016 EPP 42 75% (all) 49% (all) 52% (all) nr 18 23 68% (all) 21% (all)
      PD 66 nr 15 16
      Infante, 2016 EPP 91 89% 44% nr 80% 19 17 45% 50%
      PD 47 98% 30% nr 62% 30 11 26% 24%
      Sharkey, 2016 EPP 229 72% 53% 76% 86% 13 nr 43% 57%
      PD 133 76% 56%* 69% 80%* 12 nr 53% 41%
      Korston, 2017 EPP 52 94% nr nr 65% 23 nr nr nr
      PD 26 94% nr nr 65% 32* nr nr nr
      Verma, 2017 EPP 271 34% 27% 43% 51% 19 15 (all) nr nr
      PD 1036 26% 20% 37% 47% 16 nr nr
      Table: Comparative studies of EPP and PD References 1. Nelson DB, Rice DC, Niu J, et al. Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. J Clin Oncol. 2017:JCO2017738401. 2. Flores RM, Riedel E, Donington JS, et al. Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population. J Thorac Oncol. 2010;5(10):1649-1654. 3. Burt BM, Cameron RB, Mollberg NM, et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg. 2014;148(1):30-35. 4. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015;16(16):1651-1658. 5. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg. 2015;149(2):558-565; discussion 565-556. 6. Marulli G, Breda C, Fontana P, et al. Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre studydagger. Eur J Cardiothorac Surg. 2017. 7. Friedberg JS, Simone CB, 2nd, Culligan MJ, et al. Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg. 2017;103(3):912-919. 8. Rimner A, Zauderer MG, Gomez DR, et al. Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol. 2016;34(23):2761-2768. 9. Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer. 2012;77(1):151-155. 10. Waller DA, Tenconi S. Surgery as part of radical treatment for malignant pleural mesothelioma. Curr Opin Pulm Med. 2017;23(4):334-338.

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