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Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma

Open ArchivePublished:October 16, 2015DOI:https://doi.org/10.1016/j.jtcvs.2015.09.129

      Abstract

      Objective

      To evaluate a new protocol of accelerated hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for patients with resectable malignant pleural mesothelioma (MPM).

      Methods

      A total of 25 Gy of radiation was delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax with concomitant boost of 5 Gy to volumes at high risk based on computed tomography and positron emission tomography scan findings. EPP was performed at 6 ± 2 days after the end of radiation therapy. Adjuvant chemotherapy was offered to patients with ypN2 disease.

      Results

      A total of 62 patients were included between November 2008 and October 2014. One patient died in the hospital 2 months after EPP, for an operative mortality of 1.6%, and 2 died after discharged from the hospital for an overall treatment-related mortality (grade 5 toxicity) of 4.8%. Twenty-four patients (39%) developed grade 3 to 5 (grade 3+) complications. On final pathology, 94% of the patients were stage III or IV, and 52% had ypN2 disease. The median survival for all patients as an intention-to-treat analysis was 36 months. The median overall survival and disease-free survival was 51 and 47 months, respectively, in epithelial subtypes, compared with 10 and 8 months in biphasic subtypes (P = .001). Ipsilateral chest recurrence occurred in 8 patients.

      Conclusions

      Accelerated hemithoracic IMRT followed by EPP has become our preferred approach for resectable MPM. The results have been encouraging in patients with epithelial subtype.

      Key Words

      Abbreviations and Acronyms:

      CT (Computed tomography), EBUS-TBNA (Endobronchial ultrasound–transbronchial needle aspiration biopsy), EPD (Extended pleurectomy-decortication), EPP (Extrapleural pneumonectomy), FDG-PET (Fluorodeoxyglucose positron emission tomography), GTV (Gross tumor volume), IMRT (Intensity modulated radiation therapy), MPM (Malignant pleural mesothelioma), SMART (Surgery for mesothelioma after radiation therapy)

      CTSNet classification

      Figure thumbnail fx1
      Surgery for mesothelioma after radiation therapy.
      Accelerated hemithoracic intensity-modulated radiation therapy followed by extrapleural pneumonectomy is feasible, and the results are encouraging for epithelial mesothelioma.
      We present a new protocol of accelerated hemithoracic intensity-modulated radiation therapy followed by extrapleural pneumonectomy for patients with resectable malignant pleural mesothelioma.
      See Editorial Commentary page 476.
      See Editorial page 307.
      Although asbestos use has been regulated over the last 3 decades in industrialized countries, the burden of disease related to its use continues to rise rapidly.
      • Stayner L.
      • Welch L.S.
      • Lemen R.
      The worldwide pandemic of asbestos-related diseases.
      In particular, malignant pleural mesothelioma (MPM) remains a major health problem. Despite aggressive therapy, including surgery, radiation, and chemotherapy, the prognosis of MPM remains extremely poor, with a median survival ranging between 17 and 20 months in 3 recent phase II prospective multi-institutional trials exploring the feasibility of a multimodality approach with induction chemotherapy followed by extrapleural pneumonectomy (EPP) and adjuvant hemithoracic radiation.
      • van Meerbeeck J.P.
      • Scherpereel A.
      • Surmont V.F.
      • Baas P.
      Malignant pleural mesothelioma: the standard of care and challenges for future management.
      Encouraged by the improved rate of local control achieved with high-dose hemithoracic radiation in the adjuvant setting after EPP, we developed a new protocol of surgery for mesothelioma after radiation therapy (SMART). The rationale behind the development of this protocol was to optimize the delivery of radiation to the whole tumor bed, sterilize the edges of the tumor to limit the risk of spillage at the time of surgery, develop a shorter treatment plan, and potentiate activation of the immune system by using a hypofractionated regimen.
      SMART entails a total of 25 Gy of radiation delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax by intensity-modulated radiation therapy (IMRT), with a concomitant boost of 5 Gy to volumes at high risk based on computed tomography (CT) and positron emission tomography (PET) scan findings. EPP is performed within 2 weeks after the end of radiation therapy before the development of radiation pneumonitis. Adjuvant chemotherapy with cisplatin and an antifolate (pemetrexed or raltitrexed) doublet are administered selectively to patients with ypN2 disease on final pathology. The initial results of a seamless phase I/II trial demonstrated that this protocol is feasible and safe.
      • Cho B.C.J.
      • Feld R.
      • Leighl N.
      • Opitz I.
      • Anraku M.
      • Tsao M.S.
      • et al.
      A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma.
      The present analysis provides an update of our ongoing phase II expansion study with midterm outcome according to histological subtype and TNM status.

      Materials and Methods

      Patients eligible for the SMART approach were at least 18 years of age and had an Eastern Cooperative Oncology Group performance status of 0 to 2, with good pulmonary function tests (defined as forced expiratory volume in 1 second >40% predicted or diffusing capacity for carbon monoxide >45% predicted), a new histological diagnosis of MPM previously untreated, clinical stage T1-3N0M0, suitable for combined modality therapy, and able to give informed consent. Clinical stage was determined by high-resolution CT scan of the chest and abdomen, fluorodeoxyglucose (FDG)-PET/CT scan, and brain magnetic resonance imaging or CT. Preoperative nodal sampling with endobronchial ultrasound–transbronchial needle aspiration biopsy (EBUS-TBNA) or mediastinoscopy was not performed routinely up to December 2013. Between November 2008 and December 2013, EBUS (n = 6) or mediastinoscopy (n = 2) was performed in 8 patients with enlarged paratracheal nodes to rule out N2 disease before entering the study. Starting in December 2013, EBUS became part of our routine staging to analyze the impact of this procedure on clinical staging, and thus the last 8 patients of the study had a negative EBUS result before entering the study. The clinical trial was approved by our hospital's Institutional Review Board.
      Of note, patients were carefully evaluated before proceeding with induction radiation, to ensure that the tumor was resectable and to avoid the need for exploratory thoracotomy and the potential risk of fatal radiation pneumonitis. Patient selection was based on clinical symptoms, chest CT findings, and laboratory values. The imaging results were first reviewed to ensure that the patient had no evidence of chest wall, peritoneal, or mediastinal extension, particularly along the main bronchus. The clinical evaluation focused primarily on the degree of chest pain to ensure that it was limited and not requiring high doses of opioids. The laboratory values were also reviewed before starting radiation therapy, to ensure the absence of any major abnormality, particularly in the white blood cell, red blood cell, and platelet counts.
      The clinical target volume was defined as the ipsilateral hemithorax, from the thoracic inlet down to the diaphragmatic insertion, including biopsy and drainage tract sites. The chest wall (ribs and intercostal muscles) was included in the radiation field. The gross tumor volume was defined as any tumor seen on CT and FDG-PET. The prescribed dosage to the clinical target volume was 25 Gy in 5 daily fractions over 1 week, with a concomitant boost of 5 Gy to the gross tumor volume and tract sites. A multibeam IMRT technique was used for all patients.
      All patients underwent EPP within 2 weeks of completing neoadjuvant IMRT. Surgery was performed following a standard technique with resection and reconstruction of the diaphragm and pericardium.
      • de Perrot M.
      • Uy K.
      • Anraku M.
      • Tsao M.S.
      • Darling G.
      • Waddell T.K.
      • et al.
      Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.
      The bronchial stump was always covered either with the posterior pericardium, according to a technique that we recently described, or with a flap from the omentum or thymus.
      • de Perrot M.
      Use of the posterior pericardium to cover the bronchial stump after right extrapleural pneumonectomy.
      In our initial cohort, partial wound dehiscence occurred in 4 of 25 patients (16%) after surgery; a modification of our surgical technique has resolved this problem.
      • Cho B.C.J.
      • Feld R.
      • Leighl N.
      • Opitz I.
      • Anraku M.
      • Tsao M.S.
      • et al.
      A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma.
      In brief, the thoracotomy wound is closed with Ticron sutures (Covidien, Ontario, Canada) for the muscle and subcutaneous tissue layers. Each port site is radiated preoperatively to a diameter of 6 cm around the port site. Port sites are then resected only in the presence of gross disease, preserving the skin and subcutaneous tissue to ensure adequate closure without tension. The localized chest wall defect is closed with a small patch of 1-mm Gore-Tex mesh (W.L. Gore and Associates, Flagstaff, Ariz) to seal the pleural space and prevent the development of chest wall seroma.
      Histological diagnosis and staging was based on the 2004 World Health Organization classification system and the seventh edition of the TNM staging system.
      Patients demonstrating mediastinal lymph node involvement on final pathology (ie, ypN2) were offered adjuvant chemotherapy with cisplatin combined with an antifolate agent, either raltitrexed or pemetrexed (at the discretion of the medical oncologist), for at least 3 cycles within 24 weeks after EPP.
      After completing therapy, patients were followed at least every 3 months up to 2 years and then every 6 months up to 5 years. CT of the thorax and abdomen were performed at 3, 6, 12, 18, and 24 months and then yearly afterward. Additional tests were performed at the discretion of the investigators. Recurrences were diagnosed clinically, usually by serial imaging and proven pathologically when feasible. Recurrences were treated off protocol. Follow-up was completed up to October 2014.
      The study was designed as an expansion study to assess efficacy following a seamless phase I/II study demonstrating the safety of this protocol. The seamless phase I/II study included 25 patients and was reported previously.
      • Cho B.C.J.
      • Feld R.
      • Leighl N.
      • Opitz I.
      • Anraku M.
      • Tsao M.S.
      • et al.
      A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma.
      The primary endpoint of the present expansion study was overall survival. Secondary endpoints included disease-free survival, treatment-related morbidity and mortality, and pattern of treatment failure. All patients who provided consent for the SMART protocol during the phase I/II study, the expansion study, and the transition period between both studies were recorded and followed prospectively in a similar fashion.
      Demographic and treatment data, adverse event data, and survival data were reported as mean ± SD or median and range. Categorical variables were compared using the χ2 test, and continuous variables were compared using the Student t test. Treatment-related adverse events were reported using the Common Terminology Criteria for Adverse Events, version 4.0.

      National Cancer Institute. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed November 3, 2015.

      Overall survival was estimated using the Kaplan–Meier method. Survival was calculated from the starting day of radiation therapy for all patients, including 2 patients who underwent chemotherapy before radiation and surgery. Differences in survival were tested for significance using the log-rank test. Statview V (Abacus Concepts, Berkeley, Calif) was used for all analyses. A P value < .05 was considered significant.

      Results

      Of the 256 patients with MPM seen in our institution between November 2008 and October 2014, 62 (24%) were deemed suitable candidates for the SMART approach (Figure 1). The vast majority of patients were males, with a median age of 64 years (Table 1). The clinical stage was T1N0M0 in 10 patients, T2N0M0 in 35 patients, and T3N0M0 in 13 patients. In 6 patients, the protocol was extended to include patients with tumor extending to the chest wall (cT4N0M0; n = 2), evidence of mediastinal lymph nodes involvement on PET scan (cT3N2M0; n = 2), or after completing 1 or 2 lines of chemotherapy (n = 2). One patient completed 6 cycles of cisplatin-pemetrexed, and the second completed 6 cycles of cisplatin-pemetrexed, followed by 4 cycles of carboplatin-pemetrexed, before starting the SMART protocol.
      Figure thumbnail gr1
      Figure 1Consort diagram showing the flow of patients through the study. SMART, Surgery for mesothelioma after radiation therapy.
      Table 1Patient characteristics (n = 62)
      CharacteristicValue
      Age, y, median (range)64 (41-75)
      Sex, n (%)
       Male52 (84)
       Female10 (16)
      Clinical stage, n (%)
       T1N010 (16)
       T2N035 (57)
       T3N013 (21)
       T4N02 (3)
       T3N22 (3)
      Laterality, n (%)
       Right45 (73)
       Left17 (27)
      Histology, n (%)
       Epithelial44 (71)
       Biphasic18 (29)
      Chemotherapy, n (%)
       None47 (76)
       Before SMART2 (3)
       Adjuvant (for ypN2)13 (21)
      SMART, Surgery for mesothelioma after radiation therapy.
      All 62 patients completed their intended IMRT and EPP. No patient dropped out between radiation and surgery. EPP was performed a mean of 6 ± 2 days after completion of IMRT. All but 1 patient underwent resection and reconstruction of the diaphragm, and all but 4 patients underwent resection and reconstruction of the pericardium. In 2 patients, a chest wall resection of 3 ribs was required to achieve complete macroscopic resection. Incomplete macroscopic resection (R2) was observed in 4 patients. The bronchial stump was covered by the posterior pericardium in 57 patients, by an omentum flap in 3 patients, and by a thymic flap in 2 patients. The median length of stay after surgery was 11 days (range, 5-102 days).
      A total of 24 patients (39%) developed grade 3 + complications (Table 2). The main complication was atrial fibrillation, occurring in 12 patients. Four patients developed an empyema, but none demonstrated evidence of bronchopleural fistula on further investigation. No patients died within 30 days of surgery.
      Table 2Grade 3+ complications after SMART
      Complication typesComplications
      TotalGrade 3Grade 4Grade 5
      Patients with grade 3+ complications, n24
      Type of complication, n
      Six patients had more than one grade 3+ complication.
       Atrial fibrillation121200
       Empyema4211
       Pulmonary emboli3210
       Chylothorax2200
       Hemothorax2020
       Wound complications2200
       Pneumonia2011
       Renal dysfunction1100
       Diaphragmatic patch dehiscence1010
       Platypnea-orthodeoxia syndrome1010
      Clostridium difficile colitis1100
      Six patients had more than one grade 3+ complication.
      Treatment-related death (grade 5 toxicity) occurred in 3 patients (4.8%). One patient who underwent 10 cycles of chemotherapy before SMART developed an empyema and died in the hospital from pneumonia at 2 months after surgery, for a postoperative hospital mortality of 1.6%. One patient who required chest wall resection and reconstruction for a biphasic mesothelioma was readmitted after discharge from the hospital with an empyema and died. A third patient died from an unwitnessed cardiac arrest at home.
      On final pathology, 57 patients (92%) presented with stage III (n = 25) or IV (n = 32), and 5 patients presented with stage I (n = 3) or II (n = 2). A total of 32 patients (52%) had evidence of ypN2 disease on final pathology, and 3 (5%) had ypN1 disease. Adjuvant chemotherapy was completed in 41% of the patients with ypN2 disease (n = 13). The remaining patients with ypN2 disease did not undergo adjuvant chemotherapy owing to ongoing fatigue (n = 11), postoperative complications (n = 3), or early recurrence (n = 3). In addition, 1 patient started chemotherapy but stopped after a single cycle, and 1 patient with ypN2 disease completed chemotherapy before proceeding to SMART.
      The current estimated median survival is 36 months, with 36 patients alive at last follow-up (Figure 2). No patient was lost to follow-up. The overall survival and disease-free survival were significantly better in patients with the epithelial subtype compared with those with the biphasic subtype (Figure 3). Among patients with cT1-3N0M0 previously untreated MPM (n = 56), the median disease-free survival was 47 months and overall survival was 51 months in patients with the epithelial subtype, compared to only 8 and 10 months, respectively, in patients with the biphasic subtype. Among patients with the epithelial subtype, the disease-free survival reached 66% at 3 years in patients with ypN0 disease, compared with 48% in patients with ypN + disease (Figure 4).
      Figure thumbnail gr2
      Figure 2Overall survival as an intention-to-treat analysis for all 62 patients who started accelerated hemithoracic radiation therapy as part of the SMART protocol between November 2008 and October 2014.
      Figure thumbnail gr3
      Figure 3Overall survival (A) and disease-free survival (B) according to histological subtype in 56 treatment-naïve patients with cT1-3N0M0. Six patients with tumor extending to the chest wall on preoperative CT (cT4N0M0; n = 2), evidence of mediastinal lymph node involvement on PET scan (cT3N2M0; n = 2), or undergoing SMART after completing chemotherapy (n = 2) were excluded from this analysis. DFS, disease free survival.
      Figure thumbnail gr4
      Figure 4Overall survival (A) and disease-free survival (B) in previously untreated cT1-3N0M0 patients with epithelial disease according to nodal status on final pathology. DFS, Disease free survival.
      A total of 30 patients developed recurrence. The primary sites of recurrence were the contralateral chest (n = 9), the abdomen (n = 8), and both the contralateral chest and abdomen (n = 7). Abdominal recurrence was characterized by the presence of ascites (n = 7), retroperitoneal nodes (n = 5), peritoneal mass (n = 3), or liver mass (n = 2). Contralateral chest recurrence was characterized by parenchymal lung nodules (n = 13) or pleural-based disease (n = 3). Recurrence was seen within the ipsilateral chest in 8 patients, either alone (n = 5) or in combination with an abdominal recurrence (n = 3). Local recurrence in the ipsilateral chest was seen predominantly in patients with biphasic subtypes (n = 5) and/or ypT4N2 disease (n = 3). Other sites of recurrence included the pericardium (n = 2) and mediastinal lymph nodes (n = 2) in combination with the contralateral chest recurrence.

      Discussion

      This study demonstrates that the SMART approach in patients with MPM is safe and compares favorably with other multimodality approach. In our experience, the overall survival as an intention-to-treat analysis was improved compared with our previous results with the trimodality approach using induction chemotherapy and adjuvant hemithoracic radiation after EPP.
      • de Perrot M.
      • Feld R.
      • Cho B.C.
      • Bezjak A.
      • Anraku M.
      • Burkes R.
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      This analysis demonstrates that the SMART approach is particularly encouraging for patients with an epithelial subtype. In contrast, patients with a biphasic subtype had a dismal prognosis, with a median disease-free survival of only 8 months. Therefore, we currently exclude patients with a biphasic subtype from the SMART approach.
      In our initial experience with the trimodality approach, we observed that adjuvant hemithoracic radiation achieved excellent local control and was potentially associated with improved survival in patients completing hemithoracic radiation in the absence of mediastinal nodal involvement.
      • de Perrot M.
      • Uy K.
      • Anraku M.
      • Tsao M.S.
      • Darling G.
      • Waddell T.K.
      • et al.
      Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.
      • de Perrot M.
      • Feld R.
      • Cho B.C.
      • Bezjak A.
      • Anraku M.
      • Burkes R.
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      However, adjuvant hemithoracic radiation after 2 therapies (preoperative chemotherapy and surgery) was difficult to administer, and only one-half of the patients who started with induction chemotherapy completed the adjuvant radiation therapy.
      • de Perrot M.
      • Feld R.
      • Cho B.C.
      • Bezjak A.
      • Anraku M.
      • Burkes R.
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      In addition, approximately 25% of the patients experienced disease progression during induction chemotherapy, thereby precluding them from surgery.
      • de Perrot M.
      • Feld R.
      • Cho B.C.
      • Bezjak A.
      • Anraku M.
      • Burkes R.
      • et al.
      Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      Encouraged by the results of adjuvant hemithoracic radiation on local control,
      • Rusch V.W.
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      • Leon L.
      • Raben A.
      • Harrison L.
      • et al.
      A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      • Rice D.C.
      • Stevens C.W.
      • Correa A.M.
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      • Tsao A.
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      • et al.
      Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma.
      • Buduhan G.
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      Trimodality therapy for malignant pleural mesothelioma.
      as well as other evidence in the literature suggesting that MPM are radiosensitive tumors,
      • Jenkins P.
      • Milliner R.
      • Salmon C.
      Re-evaluating the role of palliative radiotherapy in malignant pleural mesothelioma.
      we designed this new trial to deliver radiation preoperatively to patients with surgically resectable tumors. Considering the risk of disease progression on induction chemotherapy, we felt that switching the order of therapy was potentially a better option for patients with surgically resectable disease, and thus started with preoperative radiation and reserving chemotherapy for the adjuvant setting. Given that the entire hemithorax including the lung had to be radiated, posing a risk of potentially fatal radiation pneumonitis, the radiation course was accelerated and EPP performed shortly thereafter. Adjuvant chemotherapy was proposed in the adjuvant setting for patients with ypN2 disease owing to the potentially poorer prognosis in these patients. However, this trial demonstrated once again the difficulty of administering a third therapy in this patient population, with only 41% of the patients with ypN2 disease completing the adjuvant chemotherapy.
      Several institutions have used a similar protocol of accelerated radiotherapy for rectal cancer with excellent results.
      Swedish Rectal Cancer Trial
      Improved survival with preoperative radiotherapy in resectable rectal cancer.
      • Minsky B.D.
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      • Valentini V.
      Short-course radiation versus long-course chemoradiation for rectal cancer.
      A recent randomized control trial in patients with rectal carcinoma found that a short course of induction radiation of 25 Gy in 5 daily fractions provided similar survival as a standard course of concurrent chemoradiation therapy followed by surgery.
      • Ngan S.Y.
      • Burmeister B.
      • Fisher R.J.
      • Solomon M.
      • Goldstein D.
      • Joseph D.
      • et al.
      Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04.
      Considering the short interval between the end of radiation therapy and surgery, the goal of preoperative radiation is not to downstage the tumor, but rather theoretically to induce a tumorostatic and tumoricidal effect on the tumor to prevent or delay the successful implantation of metastasis to distant sites at the time of surgery and thereafter.
      Over the past few years, the role of EPP in MPM has been increasingly called into question,
      • Treasure T.
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      • et al.
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      • Weder W.
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      • de Perrot M.
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      and lung-sparing radical resection with extended pleurectomy-decortication (EPD) has become more popular. Several groups have developed intraoperative therapies in combination with radical surgery. Friedberg et al
      • Friedberg J.S.
      • Culligan M.J.
      • Mick R.
      • Stevenson J.
      • Hahn S.M.
      • Sterman D.
      • et al.
      Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma.
      have reported good results by combining EPD with intraoperative photodynamic therapy, Sugarbaker et al
      • Sugarbaker D.J.
      • Gill R.R.
      • Yeap B.Y.
      • Wolf A.S.
      • DaSilva M.C.
      • Baldini E.H.
      • et al.
      Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection.
      have perfected the use of intraoperative hyperthermic chemotherapy, and Lang-Lazdunski et al
      • Lang-Lazdunski L.
      • Bille A.
      • Papa S.
      • Marshall S.
      • Lal R.
      • Galeone C.
      • et al.
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      have used hyperthermic povidone-iodine in combination with radical surgery. Despite the use of intraoperative therapy, EPD remains associated with a high rate of local recurrence compared with EPP, and some centers have begun to explore the possibility of adjuvant hemithoracic radiation after EPD to improve local control.
      • Rimner A.
      • Spratt D.E.
      • Zauderer M.G.
      • Rosenzweig K.E.
      • Wu A.J.
      • Foster A.
      • et al.
      Failure patterns after hemithoracic pleural intensity-modulated radiation therapy for malignant pleural mesothelioma.
      • Chance W.W.
      • Rice D.C.
      • Allen P.K.
      • Tsao A.S.
      • Fontanilla H.P.
      • Liao Z.
      • et al.
      Hemithoracic intensity-modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis.
      • Minatel E.
      • Trovo M.
      • Polesel J.
      • Baresic T.
      • Bearz A.
      • Franchin G.
      • et al.
      Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma: final results with long-term follow-up.
      This strategy has been associated with a risk of severe pneumonitis, however, and contributes to a decline in function of the preserved lung.
      • Chance W.W.
      • Rice D.C.
      • Allen P.K.
      • Tsao A.S.
      • Fontanilla H.P.
      • Liao Z.
      • et al.
      Hemithoracic intensity-modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis.
      • Rosenzweig K.E.
      • Zauderer M.G.
      • Laser B.
      • Krug L.M.
      • Yorke E.
      • Sima C.S.
      • et al.
      Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma.
      The present study has some inherent limitations related to its design as a single-center trial with a single treatment arm.
      • Treasure T.
      • Utley M.
      Ten traps for the unwary in surgical series: a case study in mesothelioma reports.
      A longer follow-up is needed before definitive conclusions can be drawn about the success of this approach. Nonetheless, in our experience, this approach has been very encouraging and has become our primary option for patients with surgically resectable MPM. Owing to the lack of a clear benefit, patients with evidence of biphasic disease on the initial pleural biopsy or with clinical N2 disease are currently excluded from the SMART approach. This approach also carries the potential risk of severe toxicities, and thus we recommend that it remain confined to centers with extensive experience in hemithoracic radiation and surgery for MPM.
      In conclusion, EPP can be performed after induction hemithoracic radiation therapy, and this approach is associated with encouraging overall survival and disease-free survival in patients with epithelial cT1-3N0M0 mesothelioma. These encouraging results should support further studies to determine the role of hypofractionated radiation and surgery in the treatment of MPM.

      Conflict of Interest Statement

      Ronald Feld reports consulting fees from AstraZeneca Canada. Thomas K. Waddell reports consulting fees from United Therapeutics. Andrew Hope reports consulting and lecture fees from Elekta Inc. All other authors have nothing to disclose with regard to commercial support.
      You can watch a Webcast of this AATS meeting presentation by going to: http://webcast.aats.org/2015/Video/Monday/04-27-15_6C_1615_De_Perrot.mp4.
      We thank Lea Dungao and Pat Merante for their assistance.

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