Surgery For Mesothelioma Research Articles

Induction radiotherapy and mesothelioma surgery

Malignant pleural mesothelioma (MPM) continues to be one of the most difficult malignancies to diagnose and treat. Despite many attempts to improve the prognosis, the disease remains almost uniformly fatal with little hope for long-term survival. Many studies of radiation and surgery, either alone or combined, have been performed, but the results of treatment remain poor and most patients recur either locally or distally. In an effort to prolong survival and improve the prognosis of MPM, the Surgery for Mesothelioma After Radiation Therapy (SMART) trial was developed. Based on the idea that local control, and potentially overall survival, could be improved with high-dose radiation followed by aggressive surgery, this protocol involves a total of 25 Gy of radiation delivered in 5 daily fractions over one 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. Within two weeks of completion of the radiation therapy, extra-pleural pneumonectomy (EPP) is performed. The interim results of this study have shown encouraging outcomes for select patients with MPM.

Patient selection for radical surgery for mesothelioma—prognostic factors in a multimodality approach

Research has focused on identification of selection criteria for surgery in a multimodality therapy approach since 1976, when Butchart in Newcastle, UK described the importance of precise patient selection for surgery. He was one of the pioneers in mesothelioma surgery and concluded, after a series of 29 patients undergoing pleuropneumonectomy, that death could have been prevented by better case selection, alteration in surgical technique, and better postoperative management (1). To optimize patient selection, many factors have to be taken into account: the patients’ performance status (PS), the stage of disease, and also availability and access to different treatment approaches. In the following chapter, clinical and pathological staging and prognostic factors will be summarized.

Surgery for mesothelioma: the evidence base and a pragmatic approach to surgical treatment

The authors were invited to provide a summary of the current evidence and an evidence-based approach to practice. Clinical practice guidelines are not available for India and a formal approach to these would require a properly constituted guideline development group rather than an opinion piece from three surgeons. What we have provided is a critical view of current practice and some pointers to a realistic pragmatic approach intended to avoid non-evidence-based practice and excessive harm to no advantage.

P3.09-007 Thoracic Asymmetry and Its Impact on Survival after Radiation and Surgery for Malignant Pleural Mesothelioma

Staging for malignant pleural mesothelioma (MPM) remains a challenge due to poor prognostic utility. Other clinical factors may improve and refine the staging system. We investigate the impact thoracic asymmetry at time of initial presentation prior to therapy on survival in MPM patients treated with multimodal therapy. We reviewed 93 consecutive treatment naïve MPM patients treated with Surgery for Mesothelioma after Radiation Therapy (SMART protocol) from Sep 2008 to Jul 2015. The right and left axial thoracic areas (defined as the product of the ant-post and med-lat extent of hemithoraces at the level of carina) were used to calculate the asymmetric thoracic ratio (ATR, where 1 is more symmetric, Fig 1). Significant factors were determined using univariate (log rank), multivariate (Cox proportional hazards) as well as recursive partition analysis (RPA). Continuous variables were discretized into binary categories split by its median value. After a median follow-up of 15.6 months, 63 (68%) patients recurred, 56 (60%) died. The median ATR was 0.85, ranging from 0.52 to 1.00. On univariate analysis, histology (p=0.003 and 0.0002), gross tumor volume (GTV, p=0.004 and 0.001), and ATR (p=0.00001 and 0.0000002) all significantly impacted both overall and disease free survival, respectively, while mediastinal nodal involvement (p=0.03) was significantly associated with DFS only. On multivariate analysis, histology (p=0.01 and 0.005) and GTV (p=0.02 and 0.016) significantly impacted both overall and disease free survival, respectively. ATR significantly impacted disease free survival (p=0.02, HR=0.06 95% CI 0.02-0.20) and was suggestive of a trend for overall survival (p=0.07). On RPA, ATR<0.848 was significantly (p<0.001) associated with poorer DFS. A low asymmetric ratio (ATR<0.848) is significantly associated with poorer outcomes, specifically disease free survival, and is independent of histology and tumor volume. Further study is needed to validate this parameter.

OA 02.06 Radioimmunotherapy Combining CTLA-4 Blockade or Low-Dose Cyclophosphamide with Local Radiation in Murine Malignant Mesothelioma

Our group has developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. The impact on the immune system of high-dose hypofractionated radiation therapy is expected to open the door for new combination therapy of immunotherapy and radiation to optimize their synergism on the immune system. The aim of this study is to investigate the antitumor effect of non-ablative hypofractionated radiation combined with anti-CTLA-4 antibody (a-CTLA-4) or low-dose cyclophosphamide (LD-CTX) in murine malignant mesothelioma model.

Video assisted thoracoscopic and open chest surgery in diagnosis and treatment of malignant pleural diseases.

Parenchymal cancers of lung, breast, gastrointestinal tract and ovaries as well as lymphomas and mesotheliomas are among the most common cancer types causing malignant effusions, though almost all tumour types have been reported to cause a malignant effusion. The prognosis heavily depends on patients' response to systemic therapy however, regardless of the causing pathology and histopathologic form, malignant pleural disease is normally associated with a poor prognosis. To date, there are not sufficient data to allow accurate predictions of survival that would facilitate decision making for managing patients with malignant pleural diseases. Interventions are directed towards drainage of the effusion and, when appropriate, concurrent or subsequent pleurodesis or establishing long-term drainage to prevent re-accumulation. The rate of re-accumulation of the pleural effusion, the patient's prognosis, and the severity of the patient's symptoms should guide the subsequent choice of therapy. In contemporary medicine, not many cancers have managed to generate as intense debates concerning treatment, as malignant pleural mesothelioma. The relative advantages of surgery, radiation, chemotherapy and any combination of the three are continuously reassessed and reconsidered, even though not always based on scientific evidence. The aim of surgery in mesothelioma may be prolongation of life, in addition to palliation of symptoms. Longer recovery periods from more extensive surgical procedures could be justified, in carefully selected patients. Surgical options include: Video assisted thoracoscopic (VATS) pleurodesis, VATS partial pleurectomy (VATS PP)-both parietal and visceral; open pleurectomy decortication (PD)-with an extended option (EPD) and extrapleural pneumonectomy (EPP). Current evidence implies that EPD can be performed reliably in specialised centres with good results, both in terms of mortality and survival; however, no operation has yet been shown to be beneficial in a prospective randomized controlled clinical trial.

The impact of surgical approach on quality of life for pleural malignant mesothelioma.

A comprehensive review of quality of life (QoL) after surgery for malignant pleural mesothelioma (MPM) was conducted to assess differences between pleurectomy decortication (P/D) and extrapleural pneumonectomy (EPP). Original research studies on quality of life after mesothelioma surgery were identified through June 2016; 15 articles and 12 distinct datasets, for a total of 523 patients, were retrieved. QoL data was available for 102 patients treated with EPP and 296 with P/D. Two studies directly compared QoL outcomes between the two techniques. Symptoms, lung function parameters, and physical and social functioning were still compromised 6 months following surgery. However, P/D patients fared better than EPP patients across QoL measures. Quality of life is generally better for patients undergoing P/D compared to EPP, for an extended period following surgery. Given the need for multimodality therapy and the aggressive nature of MPM, QoL outcomes should be strongly considered when recommending type of surgery for patients with this disease.

Randomized controlled trials in malignant pleural mesothelioma surgery-mistakes made and lessons learned.

Randomized surgical trials are of the most difficult to design and recruit, however, they are the only robust method available to establish a new surgical procedure. Mesothelioma is a disease with a perceived poor prognosis for which surgical intervention has relatively high complications and not insignificant mortality. This review will consider the mesothelioma and radical surgery (MARS) 1 and 2 trials, SAKK 17/04 trial and the EORTC 1205 trial all aimed at assessing the potential benefit of radical surgery for malignant pleural mesothelioma. In addition, MesoVATS and MesoTRAP will be explored assessing the value of debulking surgery for malignant pleural mesothelioma. We also endeavour to identify the mistakes made and the lessons learned which will inform future randomized controlled clinical trials in the field of malignant pleural mesothelioma. Despite the insurmountable problems with randomized controlled clinical trials, we show that they are possible and continuing with uncontrolled experiments will perpetuate unproven and potentially harmful operations.

Adjuvant Immunotherapy with Surgery Improves Survival in Murine Models of Thoracic Malignancies

Abstract Objectives Immunotherapy is an alternative therapy for thoracic malignancies, but results in humans have not been as impressive as anticipated. We hypothesized that adjuvant immunotherapy with surgery debulking can improve efficacy and long term response rates. Methods We retrospectively reviewed our group’s experience with human immunotherapy trials for NSCLC and mesothelioma. We developed murine models of NSCLC and mesothelioma surgery to evaluate clinically applicable immunotherapy approaches (tumor vaccination and checkpoint inhibitors) and optimized regimen. Outcomes were assessed for overall survival and tumor progression. Flow Cytometry, ELISA, PCR and in vivo neutralization assays were utilized to determine immune responses. Results The most important predictor of immunotherapy response in human trials was minimal disease at the time of immunotherapy. Surgery generates a state of minimum disease, thus we used a murine cancer surgery model to evaluate clinically available adjuvant immunotherapy approaches in a controlled setting. Adjuvant vaccination strategies were associated with decreased tumor volumes (p&amp;lt;0.01) and were associated with an increase in postoperative survival (42 days vs 24 days, p=0.03). In vivo lymphocyte assays demonstrated only partial cytotoxic activity of CD8+ T-cells postoperatively. The addition of checkpoint inhibitor (CTLA4i) with tumor vaccination improved potency and nearly tripled post-operative survival (54 days vs 19 days; p=0.004). Additionally, 34% of mice receiving combination immunotherapy with surgery were cured (p=0.03). Conclusion This evidence supports a new approach to thoracic malignancies including multi modal immunotherapy with surgical resection.

Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma.

Tumour thickness was assessed to determine if this parameter could refine patients' selection for multimodality therapy in malignant pleural mesothelioma.We reviewed 65 consecutive treatment-naïve malignant pleural mesothelioma patients undergoing surgery for mesothelioma after radiation therapy (SMART). Total tumour thickness was determined by measuring the maximal thickness on nine predefined sectors on the chest wall, mediastinum and diaphragm.After a median follow-up of 19 months, 40 patients (62%) developed recurrence and 36 died (55%). Total tumour thickness, ranging between 2.4 and 21 cm (median 6.9 cm), correlated with tumour volume (p<0.0001, R2=0.29) and maximum standardised uptake value (p=0.006, R2=0.11). Total tumour thickness had a significant impact on overall survival and disease-free survival in univariate analysis. In multivariate analysis, total tumour thickness remained an independent predictor of survival (p=0.02, hazard ratio (HR) 1.12, 95% CI 1.02-1.23) and disease-free survival (p=0.01, HR 1.13, 95% CI 1.03-1.24) along with epithelial histologic subtype (p<0.0001, HR 0.25, 95% CI 0.13-0.50) and pN2 disease (p=0.03, HR 2.15, 95% CI 1.07-4.33). Diaphragmatic tumour thickness correlated best with time to recurrence (p=0.002, R2=0.22) and time to death (p=0.003, R2=0.2).The impact of tumour thickness on survival and disease-free survival independent of histologic subtypes and nodal disease is extremely encouraging. This parameter could potentially be used to refine the clinical staging of malignant pleural mesothelioma and optimise patient selection for radical treatment.

NU03.01 Supporting Patients Undergoing Radical Treatments EPD – MARS Study

NU03.01 Supporting Patients Undergoing Radical Treatments EPD – MARS Study

61: Lung sparing surgery for mesothelioma is a safe and effective modality in the treatment of malignant mesothelioma

61: Lung sparing surgery for mesothelioma is a safe and effective modality in the treatment of malignant mesothelioma

Symptoms, signs and radiologic findings in patients having reoperative surgery for malignant peritoneal mesothelioma

BackgroundA reasonable estimate is that 50% of patients treated with cytoreductive surgery (CRS) and perioperative chemotherapy for malignant peritoneal mesothelioma will recur. Recognition of this recurrence and knowledgeable selection for additional surgical intervention is important in improving survival of patients who progress. Material and methodsPatients treated for malignant peritoneal mesothelioma with CRS and perioperative chemotherapy were placed in follow-up for assessment of symptoms and signs and radiologic abnormalities by CT. The data were prospectively maintained and retrospectively reviewed. ResultsFrom a database of 130 patients with malignant peritoneal mesothelioma, 38 patients who had 50 reoperations with disease recurrence that was histologically confirmed were studied. The median time to first recurrence was 14 months with a range of 3–102. Considering 50 reoperative events the most common symptoms or signs were abdominal pain (40%) and abdominal distention (34%). The most common radiologic finding was a tumor mass (56%). Patients with an abdominal or pelvic mass had a reduced prognosis (p = 0.006) and patients with an absence of radiologic abnormalities had an improved survival (p = 0.047). ConclusionsIn patients having reoperative surgery, symptoms, signs and radiologic abnormalities associated with recurrent (progressive) malignant peritoneal mesothelioma are abdominal pain, abdominal distention, and a tumor mass. An abdominal or pelvic mass was associated with a reduced prognosis and an absence of radiologic abnormalities with an improved prognosis.

The Next Generation of Mesothelioma Surgeons Roundtable Discussion

DR. PASS: The topic for this roundtable discussions for Seminars in Thoracic and Cardiovascular Surgery is going to be surgery for mesothelioma. Our participants are Joe Friedberg, University of Maryland; Andrea Wolf, Icahn School of Medicine at Mount Sinai; David Rice, MD Anderson Cancer Center; and Wickii Vigneswaran, Loyola University Health System. All 4 of these surgeons were trained and are presently at high volume mesothelioma centers. Drs. Wolf and Friedberg were trained by Dr. Sugarbaker. Dr. Vigneswaran was trained at Mayo, and performed a large volume of surgical cases at the University of Chicago where he has a lot of cases that are both surgical as well as medical. Dr. Rice practices at MD Anderson and was one of the innovators of postoperative intensity-modulated radiotherapy (IMRT).

Surgery for Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is a locally aggressive asbestos-related cancer that has a worldwide distribution and an overall poor prognosis. The average median survival for patients receiving the current best nonsurgical therapy, cisplatin/pemetrexed chemotherapy, is between 7 and 13 months. In selected patients with early stage disease and favorable tumor characteristics, aggressive surgical management in combination with adjuvant or neoadjuvant therapy extends survival in up to 20% of patients. Despite the benefits of surgery for mesothelioma, many patients are not suitable for operative intervention due to advanced stage disease at presentation or the inability to tolerate aggressive surgical resection. The frontiers of mesothelioma research and treatment include an urgent search for biomarkers that can reliably detect early stage cancer in at-risk populations, clinical tests or indices that can reliably predict prognosis among surgical candidates and the development of efficacious drugs and targeted therapies that offer more durable local disease control.

Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors

To prospectively assess the survival, patterns of failure, and prognostic factors in a large cohort of patients with malignant pleural mesothelioma who had undergone a novel trimodal therapeutic approach, including lung-sparing surgery, chemotherapy, and subsequent treatment with high doses of intensity modulated radiation therapy (IMRT) to the whole hemithorax. The analysis was conducted on the data from 69 patients. Of the 69 patients, 35 underwent extended pleurectomy/decortication (P/D), with resection of the entire pleura, along with portions of the pericardium and diaphragm and 34, partial pleurectomy, defined as partial removal of parietal or visceral pleura for diagnostic purposes, leaving gross tumor behind in all cases. All patients received cisplatin/pemetrexed chemotherapy. Postoperative IMRT was delivered to the entire hemithorax, excluding the intact lung. The IMRT dose was 50 Gy in 25 fractions. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. The median follow-up duration was 19 months. No difference was seen in overall survival and locoregional control between the extended P/D group and the partial pleurectomy group. The 2-year overall survival was 65% and 58% in the extended P/D and partial pleurectomy groups, respectively (P=.94). Locoregional control at 2 years was 65% and 64% in the extended P/D and partial pleurectomy groups, respectively (P=.75). The predominant pattern of failure was distant: 19 patients (27.5%) developed distant metastases as the first site of relapse. Gross residual disease after surgery was significantly associated with overall survival (hazard ratio 3.45). One fatal pneumonitis was reported; 14 cases (20%) of grade 2 to 3 pneumonitis were documented. Radical IMRT after lung-sparing surgery and chemotherapy for malignant pleural mesothelioma leads to promising survival results and acceptable toxicity rates. The similarity of survival between patients treated with extended P/D or partial pleurectomy observed in our study is intriguing.

Surgical controversies in mesothelioma: MesoVATS addresses the role of surgical debulking.

Contemporary multi-modality treatment of malignant mesothelioma remains challenging. The merits of surgical resection and the particular extent of resection continue to be debated topics. To date few randomized surgical trials have been completed to address many lingering issues concerning surgery in mesothelioma. Recently, the MesoVATS trial shows us that a minimally invasive thoracoscopic procedure for curative resection in mesothelioma is of limited benefit. Results of ongoing clinical trials are awaited.

SU‐E‐T‐776: Use of Quality Metrics for a New Hypo‐Fractionated Pre‐Surgical Mesothelioma Protocol

Purpose:The “SMART” (Surgery for Mesothelioma After Radiation Therapy) approach involves hypo‐fractionated radiotherapy of the lung pleura to 25Gy over 5 days followed by surgical resection within 7. Early clinical results suggest that this approach is very promising, but also logistically challenging due to the multidisciplinary involvement. Due to the compressed schedule, high dose, and shortened planning time, the delivery of the planned doses were monitored for safety with quality metric software.Methods:Hypo‐fractionated IMRT treatment plans were developed for all patients and exported to Quality Reports™ software. Plan quality metrics or PQMs™ were created to calculate an objective scoring function for each plan. This allows for an objective assessment of the quality of the plan and a benchmark for plan improvement for subsequent patients. The priorities of various components were incorporated based on similar hypo‐fractionated protocols such as lung SBRT treatments.Results:Five patients have been treated at our institution using this approach. The plans were developed, QA performed, and ready within 5 days of simulation. Plan Quality metrics utilized in scoring included doses to OAR and target coverage. All patients tolerated treatment well and proceeded to surgery as scheduled. Reported toxicity included grade 1 nausea (n=1), grade 1 esophagitis (n=1), grade 2 fatigue (n=3). One patient had recurrent fluid accumulation following surgery. No patients experienced any pulmonary toxicity prior to surgery.Conclusion:An accelerated course of pre‐operative high dose radiation for mesothelioma is an innovative and promising new protocol. Without historical data, one must proceed cautiously and monitor the data carefully. The development of quality metrics and scoring functions for these treatments allows us to benchmark our plans and monitor improvement. If subsequent toxicities occur, these will be easy to investigate and incorporate into the metrics. This will improve the safe delivery of large doses for these patients.

Invited Commentary

In this issue of The Annals of Thoracic Surgery, Taioli and colleagues [1Taioli E. Wolf A.S. Flores R.M. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.Ann Thorac Surg. 2015; 99: 472-481Google Scholar] present a meta-analysis of extrapleural pneumonectomy (EPP) versus pleurectomy/decortication (P/D) in patients with malignant pleural mesothelioma. The authors decided to exclude from this analysis 38 papers dealing with single-procedure series. This decision is debatable because some of the largest series in the literature and most representative experiences are indeed single-arm studies. Moreover, many factors such as induction or adjuvant therapies, intraoperative adjuncts, and curative versus palliative nature of surgery were not analyzed. No significant difference in 2-year mortality was found between EPP and P/D. Taioli and colleagues [1Taioli E. Wolf A.S. Flores R.M. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.Ann Thorac Surg. 2015; 99: 472-481Google Scholar] conclude that P/D is associated with a 2.5-fold lower short-term mortality than EPP is, and they suggest that P/D should therefore be preferred over EPP, when possible. Earlier this year, another meta-analysis and systematic review of the literature reported significantly lower perioperative mortality (2.9% versus 6.8%; p = 0.02) and morbidity (27.9% versus 62%; p < 0.0001) for extended P/D versus EPP [2Cao C. Tian D. Park J. et al.A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.Lung Cancer. 2014; 83: 240-245Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar]. Median overall survival was 13 to 29 months for extended P/D and 12 to 22 months for EPP, with a trend favoring extended P/D [2Cao C. Tian D. Park J. et al.A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.Lung Cancer. 2014; 83: 240-245Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar]. The article by Taioli and colleagues [1Taioli E. Wolf A.S. Flores R.M. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.Ann Thorac Surg. 2015; 99: 472-481Google Scholar] represents another plea against EPP, generating substantially higher mortality and providing no survival advantage over P/D [1Taioli E. Wolf A.S. Flores R.M. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.Ann Thorac Surg. 2015; 99: 472-481Google Scholar]. One of the principles taught in medical schools is primum non nocere, which can be translated as “firstly do not harm.” I believe that this principle should be applied to mesothelioma surgery. If EPP provided a substantial survival advantage, then it might be worth the extra mortality and morbidity. Decades of practice have showed that EPP cannot cure malignant pleural mesothelioma, except perhaps in a few patients. Although highly criticized for its methodology and conclusions, the MARS feasibility study reported an EPP-related mortality of 10.5%, which is not dissimilar from the mortality reported in 34 studies [3Treasure T. Lang-Lazdunski L. Waller D.A. et al.Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.Lancet Oncol. 2011; 12: 763-772Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar]. A recent analysis of the society of thoracic surgeons database showed higher mortality (10.5% versus 3.1%; p = 0.03) for EPP versus P/D [4Burt B.M. Cameron R.B. Mollberg N.M. 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: 30-35Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. It is accepted that in few centers of expertise, mortality and morbidity might be lower, but still higher than the ones related to P/D. In view of the evidence provided, we should refrain from subjecting patients to increased risks of mortality and morbidity when there is no evident long-term benefit for EPP. It is reasonable to adopt total P/D as the default procedure in clinical trials of multimodal therapy. Additional studies should help to clarify the role of P/D in malignant pleural mesothelioma. Meta-Analysis of Survival After Pleurectomy Decortication Versus Extrapleural Pneumonectomy in MesotheliomaThe Annals of Thoracic SurgeryVol. 99Issue 2PreviewThis comprehensive meta-analysis was conducted to answer the question as to which procedure, pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP) is more beneficial to malignant pleural mesothelioma patients’ outcome. Full-Text PDF

A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy: The “SMART” Approach for Resectable Malignant Pleural Mesothelioma

We developed an innovative approach for malignant pleural mesothelioma (MPM) with a short accelerated course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). This phase I/II study assessed the feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART). All resectable clinical T1-3N0M0 histologically proven, previously untreated MPMs were eligible. Patients received 25 Gy in five daily fractions during 1 week to the entire ipsilateral hemithorax with concomitant 5 Gy boost to areas at risk followed by EPP within 1 week of completing neoadjuvant IMRT. Adjuvant chemotherapy was offered to ypN2 patients on final pathologic findings. The primary end point was treatment-related mortality and secondary end points were overall survival, disease-free survival, treatment-related morbidity, and patterns of failure. Targeted accrual of 25 patients was completed between November 2008 and October 2012. All patients completed SMART. IMRT was well tolerated with no grade 3+ toxicities. EPP was performed 6 ± 2 days after completing IMRT without any perioperative mortality. Thirteen patients developed grade 3+ surgical complications. One patient (4%) died from treatment-related toxicity (empyema) during follow-up. All but one patient had stage III or IV disease on final pathologic findings. Five of 13 ypN2 patients received adjuvant chemotherapy. After a median follow-up of 23 months (range, 6-51), the cumulative 3-year survival reached 84% in epithelial subtypes compared with 13% in biphasic subtypes (p = 0.0002). SMART is feasible in resectable MPM patients. This innovative protocol presents encouraging results and supports future studies looking at long-term outcome in patients with epithelial subtypes.