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1 Lung Cancer 83 (2014) Contents lists available at ScienceDirect Lung Cancer journal homepage: Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up Emilio Minatel a, Marco Trovo a,, Jerry Polesel b, Tania Baresic c, Alessandra Bearz d, Giovanni Franchin a, Carlo Gobitti a, Imad Abu Rumeileh a, Annalisa Drigo e, Paolo Fontana f, Vittore Pagan g, Mauro G. Trovo a a Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Italy b Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Italy c Department of Nuclear Medicine, Centro di Riferimento Oncologico of Aviano, Italy d Department of Medical Oncology, Centro di Riferimento Oncologico of Aviano, Italy e Department of Medical Physics, Centro di Riferimento Oncologico of Aviano, Italy f Department of Thoracic Surgery, Mestre General Hospital, Italy g Department of Surgery, Centro di Riferimento Oncologico of Aviano, Italy article info abstract Article history: Received 15 April 2013 Received in revised form 10 October 2013 Accepted 19 October 2013 Keywords: Malignant pleural mesothelioma Pleurectomy/decortication Intensity modulated radiation therapy IMRT Tomotherapy Pneumonitis Purpose: We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication (P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy. Methods and materials: Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC). Results: The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2 3 pneumonitis were documented. Conclusions: High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma Elsevier Ireland Ltd. All rights reserved. 1. Introduction Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor of the pleura, mainly related to asbestos exposure [1]. Corresponding author at: Centro di Riferimento Oncologico CRO Aviano, Department of Radiation Oncology, via F. Gallini, 2, Aviano, PN, Italy. Tel.: ; fax: addresses: marcotrovo33@hotmail.com, marco.trovo@cro.it (M. Trovo). Extrapleural pneumonectomy (EPP) is a fundamental component of the therapeutic approach, showing prolonged survival in patients with epithelioid histology [2,3]. EPP is a highly invasive surgical option consisting of an en bloc removal of the lung, visceral and parietal pleura, pericardium, and diaphragm [3]. Due to the severe perioperative stress, the noticeable complication rate and the longterm detrimental anatomical and functional effects, EPP fallen out of favour among some surgeons [4]. The Mesothelioma and Radical Surgery (MARS) trial compared the best medical therapy with or without EPP [5]; the findings concluded by the authors suggest /$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.

2 E. Minatel et al. / Lung Cancer 83 (2014) that because of the high morbidity of EPP, it should be abandoned in the setting of trimodal therapy. Radical pleurectomy/decortication (P/D) is a lung-sparing surgery for MPM, that represents a cytoreductive treatment option with the aim of removing all gross disease and achieving macroscopic complete resection [6]. This operation includes macroscopic removal of the parietal and visceral pleural layer, along with the pericardium and diaphragm if needed, yet sparing the underlying lung. After this surgical procedure, residual microscopic disease is possibly left behind, and adjuvant radiation therapy is a therapeutic strategy that has been advocated; however, its use has been limited due the difficulty of irradiating such a large target volume with high radiation doses without exceeding the tolerance of the adjacent normal tissues, especially the ipsilateral intact lung [7]. We have recently reported the toxicity results of a prospective study in which Tomotherapy was used to deliver radical doses of radiation to the hemithorax with the intact lung, after radical P/D or surgical staging for MPM. We documented that the treatment was well-tolerated, and we reported only 7% of Grade 3 radiation pneumonitis, and no fatal toxicity [8]. In the present paper we report the long-term survival of radical P/D followed by high doses of radiotherapy delivered to the hemithorax of MPM patients with intact lung. Table 1 Relevant normal tissue dosimetric data (mean values). Treated lung V20 96% V30 87% 46 Gy Contralateral lung V5 19% 4 Gy Total lung (treated + contralateral) V20 36% V30 32% 20 Gy Spinal cord Maximum dose 39 Gy Esophagus 28 Gy Liver V30 for right treated lung 38% V30 for left treated lung 1% Ipsilateral kidney V30 27% Contralateral kidney V15 1% 2. Methods and materials This prospective study was conducted with the approval of our Institutional Review Board, and written informed consent was obtained from all the patients. Between March 2009 and December 2010, 20 consecutive patients were treated with radical P/D for a MPM and underwent adjuvant radiotherapy. All patients underwent radical P/D, with the resection of the entire parietal and visceral pleura, along with portions of the pericardium and diaphragm if involved by tumor. All patients underwent also internal mammary and mediastinal lymphadenectomy, whereas intercostal lymph nodes were not routinely dissected. Patients with tumor diffusion to the interlobar pleura, or patients with metastatic disease (Stage IVB) were not included in this study. Patient who underwent neoadjuvant or adjuvant chemotherapy were included in the present trial. Chemotherapy was not a component of the study and was administered elsewhere in the majority of the cases. Patients who experienced tumor progression during or after chemotherapy were not referred for radiation therapy. The radiation therapy technique was previously described in detail [8]. Briefly, the radiation oncologist drew the clinical target volume (CTV) from the lung apex to upper abdomen to include all areas of preoperative pleural surfaces. Interlobar pleura were not included in the CTV. Volumes also included the ipsilateral mediastinal lymph nodes in cases of pathological N1-2 disease. Thoracotomy scars were also included in the CTV. Particular attention was paid to defining the posterior/inferior extent of the CTV to include the insertion of the diaphragm, which was often in the vicinity of the L2 vertebral body. Medially, the CTV included the ipsilateral pericardium. Boost gross tumor volume was targeted on areas with positive margins or suspected residual disease, and foci of PETuptake on the restaging PET/CT done before radiation therapy. Planning target volume (PTV) was delineated by uniform margins of 5 mm around the CTV. The dose prescribed to the PTV was 50 Gy delivered in 25 fractions (2 Gy/fraction). Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost of radiotherapy to 60 Gy (2.4 Gy/fraction). Radiotherapy boost was delivered in 19 patients. All patients were treated by Helical Tomotherapy, a novel technique, which allows the delivering of image-guide intensity-modulated radiation therapy (IG-IMRT), resulting in a highly conformal radiation dose delivered [9]. A Megavolt CT-scan was also performed daily for each patient to image-guide the radiation treatment. Delivery quality assurance (DQA) was performed for all radiotherapy plans. DQA was performed with the Delta4 phantom, and clinical gamma criteria (3%/3 mm) were adopted [10]. The spinal cord, ipsilateral and contralateral kidney, contralateral lung and the dummy structure were the dose-limiting tissues. Specific dosimetric guidelines were the following: spinal cord maximum dose <45 Gy; ipsilateral and contralateral kidney V25 (percentage of kidney volume receiving 25 Gy) <40% and V10 < 10%, respectively; liver V30 < 40%; contralateral mean lung dose <7 Gy; dummy structure mean dose <36 Gy. No specific dosimetric constraints were required for ipsilateral lung or total lung. Dose-volume histograms (DVHs) were generated for all relevant structures for each of the 20 plans. Specific metrics were chosen to report dosimetric data in terms of dose distribution to the organs at risk (OAR) (Table 1). Patients were seen weekly during the radiotherapy course, and then at regular intervals to determine the presence of symptoms. Physicians evaluated clinical symptoms by Common Terminology Criteria of Adverse Events, version 3.0. Loco-regional and distant relapses were assessed using PET/CT. Follow-up PET/CT scans were evaluated by a 20-year experienced radiologist in the field of oncologic imaging and nuclear medicine. Relapse was defined by an increase in the FDG standardized uptake value (SUV) or by the appearance of new FDG-avid lesions. Loco-regional control (LRC) was defined as the absence of relapse in all areas of preoperative pleural surfaces or in the regional lymph nodes. The study end-points were LRC, progression-free survival (PFS), and overall survival (OS), and were estimated by the Kaplan Meier method, starting from the date of surgery until death or the last available follow-up examination. Patients who experienced tumor progression during or after chemotherapy were not referred for radiation therapy, and were not included in survival analysis. 3. Results Patients and tumor characteristics are listed in Table 2. The majority of the patients were male (90%) and had a median age of 68

3 80 E. Minatel et al. / Lung Cancer 83 (2014) Table 2 Patient and tumor characteristics (n = 20). Age median (y) 68 (52 80) Gender Male 18 Female 2 Performance status Laterality Right 11 Left 9 Histology Epithelioid 18 Non-epithelioid 2 Stage I 3 II 5 III 11 IV (T4) 1 Nodal status N0 17 N1 2 3 Gross residual disease after surgery No 17 Yes 3 Chemotherapy Yes 19 No 1 years. Ninety percent of the tumors were epithelioid; 8 (40%) were stages I II, and 12 (60%) were stages III IV. Gross tumor disease was documented in 3 (15%) cases after surgery. Nineteen (95%) patients received systemic chemotherapy, consisting of pemetrexed and cisplatin for three to six cycles according to the treating medical oncologist. Of these, 8 patients received both neoadjuvant and adjuvant chemotherapy and 11 received adjuvant chemotherapy only. Radiation therapy was delivered after the completion of chemotherapy. All patients completed the radiotherapy course having received the planned dose. With a median follow-up of 27 months (range 9 45 months) from surgery, the median OS was 33 months. The Kaplan Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively (Fig. 1). The median PFS was 29 months, and the estimates of PFS at 2 and 3 years were 65% and 46%, respectively (Fig. 2). The predominant pattern of failure was distant: 7 (35%) patients developed distant metastases as the first site of relapse, whereas only 3 (15%) patients experienced an isolated loco-regional recurrence. All the local relapses were judged to be within the radiation therapy field, and occurred in the chest wall as exemplified in Fig. 3. Patterns of failure were recorded as composite failures and are shown in Table 3. The Kaplan Meier estimates of LRC at 2 and 3 years were 68% and 59%, respectively, whereas the median LRC was not reached (Fig. 4). Fig. 1. Kaplan Meier estimates of overall survival. No fatal toxicity was reported. Five cases of Grades 2 3 pneumonitis were documented within 5 months after the completion of RT. A reduction in pulmonary function was documented in all the 5 patients who developed severe radiation pneumonitis. The mean pre-radiotherapy treatment FEV1 values were reduced from 70 l/min (pre-radiotherapy values) to 50 l/min after the development of lung toxicity. Patients without pneumonitis had a mean FEV1 reduction from 70 l/min to 60 l/min 6 months after the end of radiotherapy course. Two patients developed Grades 3 and 4 pericardial effusion, not associated with local recurrences in both cases. One patient experienced Grade 3 thrombocytopenia and one developed Grade 3 pain localized to the chest wall. There were no cases of Grade 3 esophagitis; rib fractures were not documented. Severe radiation toxicity is summarized in Table Discussion Although the real impact of extensive surgery (EPP) remains controversial, as documented by several studies [11 13], including a randomized trial [5], patients undergoing EPP and adjuvant high Table 3 Pattern of failure among study patients. Local 4 Local only 1 Local and nodal 1 Local and distant 0 Local, nodal and distant 2 Nodal 5 Nodal only 1 Nodal and distant 1 Distant 7 Distant only 4 Fig. 2. Kaplan Meier estimates of progression-free survival.

4 E. Minatel et al. / Lung Cancer 83 (2014) Fig. 3. An example of isolated local relapse (arrow) in the chest wall, within the radiation field. (a) Pre-treatment FDG-PET/CT, (b) FDG-PET/CT 6 months after the completion of radiotherapy documents an appearance of a new FDG-avid lesion. Fig. 4. Kaplan Meier estimates of loco-regional control. Table 4 Main severe radiation adverse effects. Grade 2 (%) Grade 3 (%) Grade 4 (%) Pneumonitis 3 (15%) 2 (10%) Pericardial effusion 1 (5%) 1 (5%) Thrombocytopenia 1 (5%) Chest wall pain 1 (5%) dose hemithoracic irradiation relapse predominantly in distant sites. Conversely, in patient undergoing P/D, disease progression occurs predominantly locally in the ipsilateral hemithorax [7]. This might be due to the impossibility of delivering adjuvant radiation therapy to the whole hemithorax because the radiation dose is limited by potential toxicity to the intact lung. We have previously shown that by using modern IG-IMRT technology [9] the delivery of full dose of radiotherapy becomes feasible [8]. We used Helical Tomotherapy to treated 28 MPM patients with high doses of radiation, who underwent lung sparing surgery, including P/D and surgical biopsy only; only 17% of the patients experienced severe respiratory symptoms. These good toxicity profile was reasonably due to the dose distribution to the organs at risk. We reported a mean lung dose (MLD) and a mean lung V20 of 20 Gy and 37%, respectively [8]. The MLD and lung V20 are considered robust predictors of radiation pneumonitis, and a MLD less than 20 Gy and a lung V20 less than 37% are associated with a risk of clinical pneumonitis that is considered acceptable [14,15]. In the present study we tested the hypothesis that a less invasive surgical approach than EPP, namely radical P/D, followed by high doses of radiation could lead to a high rate of loco-regional control, and that this could translate into an overall survival benefit. The high doses of radiation therapy delivered after radical P/D led to excellent loco-regional control and survival results in our MPM patients. We documented a median OS of 33 months and a 3-year OS rate of 49%, with the predominant pattern of failure being distant. These results are among the best observed in recent studies and are comparable with those reported with EPP followed by adjuvant radiotherapy. The authors from the Princess Margaret Hospital showed a median survival of 59 months for the 30 patients who had no mediastinal involvement and completed the entire trimodality therapy regimen; in contrast patients with N2 disease had a median survival of 12 months [16]. The median survival for all 60 patients intended to undergo the trimodality therapy was 14 months and the perioperative mortality rate was 6.7%. These results are comparable with those recently published by researchers of the Memorial Sloan Kettering Cancer Center, who reported a median survival of 17 months after induction chemotherapy followed by EPP and high radiation dose in 77 MPM patients [12]. Among the 40 patients who completed all therapy median survival was 29 months, and 2-year survival was 61%. The M.D. Anderson Cancer Center study on 86 consecutive patients treated with EPP followed by IMRT showed a median overall and 3-year survival of 14.7 months and 22%, respectively. Of these, node-negative patients with epithelioid histology (n = 18) had median and 3-year survival of 28 months and 41%, respectively [17]. Rosenzweig at al. recently published the toxicity and survival results on 36 MPM patients with two intact lungs who underwent pleural radiotherapy with a median dose of 46.8 Gy; 20 patients underwent radical P/D or pleurectomy [18]. With a median followup of 18 months, the median OS was 26 months and the 2-year OS was 53%; the predominant pattern of failure was local. The toxicity profile reported in this study is similar to ours. The authors conclude that the survival results obtained are encouraging and compare favorably with those reported in the multimodality studies. The more promising results obtained in our study can most likely be explained by the fact that firstly the higher doses of radiation employed may have a fundamental impact in terms of local control, and that this could translate into a survival benefit. In our study, all patients received a minimum dose of 50 Gy to the entire pleural surface, with a simultaneous boost up to 60 Gy to all regions of particular concern for residual disease. Secondly, the high rates of OS might be explained by the favorable surgical outcomes in our population, supporting the idea that an adequate surgery appears to be of crucial importance in determining the overall outcome: the majority of our patients underwent radical surgery with negative (85%) gross residual disease. Thirdly, patients included in this

5 82 E. Minatel et al. / Lung Cancer 83 (2014) series did not have unfavorable prognostic factors: only 2 (10%) had non-epithelioid histology and only 3 (15%) had a node positive disease. The main limit of our study is a possible patient selection bias. Patients who underwent radiotherapy in our department, which is a tertiary referral center for the radiotherapeutic cure of MPM, had surgery elsewhere. Thus, only patients with good performance status might have been referred to our center, and surgery or chemotherapy related toxicities and deaths were not considered in the analysis. Despite these limitations, this study shows that high dose radiation therapy following radical P/D led to excellent loco-regional control and survival in MPM patients. Our data support the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma. Conflict of interest All authors declare no financial disclosures or conflicts of interest. References [1] Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer 1999;79: [2] Sugarbaker DJ, Flores RM, Jacklitsch M. Resection margins, extrapleural nodal status and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117: [3] Stahel RA, Weder W, Lievens Y, Felip E. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21: [4] Hiddinga BI, van Meerbeeck JP. Surgery in mesothelioma where do we go after MARS? J Thorac Oncol 2013;8: [5] Treasure T, Lang-Lazdunski L, Waller D. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomized feasibility study. Lancet Oncol 2011;12(8): [6] Sugarbaker DJ, Wolf AS. Surgery for malignant pleural mesothelioma. Expert Rev Respir Med 2010;4: [7] Gupta V, Mychalczak B, Krug L. Hemithoracic radiation therapy after pleurectomy/decortications for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005;63: [8] Minatel E, Trovo M, Polesel J. Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung. J Thorac Oncol 2012;7: [9] Mackie TR, Holmes T, Swerdloff S. Tomotherapy: a new concept for delivery of conformal radiotherapy. Med Phys 1993;20: [10] Geurts M, Gonzalez J, Serrano-Ojeda P. Longitudinal study using a diode phantom for helical tomotherapy IMRT QA. Med Phys 2009;36: [11] Weder W, Stahel RA, Bernhard J. Swiss Group for Clinical Cancer Research. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18: [12] Krug LM, Pass HI, Rusch VW. Multicenter phase II trial of neo-adjuvant pemetrexed plus cisp0latin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27: [13] Van Schil PE, Baas P, Gaafar R. European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Group. Trimodality therapy for malignant pleural mesothelioma: results from a EORTC phase II multicentre trial. Eur Respir J 2010;36: [14] Graham MV, Purdy JA, Emami B. Clinical dose volume histogram analysis for pneumonitis after 3D treatment for non small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999;45: [15] Kwa SLS, Lebesque JV, Theuws JCM. Radiation pneumonitis as a function of mean dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 1998;42:1 9. [16] De Perrot M, Field R, Cho BC. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27: [17] Gomez DR, Hong DS, Allen PK. Pattern of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma. J Thor Oncol 2013;8: [18] Rosenzweig KE, Zauderer MG, Laser B. Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2012;83: