Extrapleural Pneumonectomy for Malignant Mesothelioma: An Italian Multicenter Retrospective Study Lorenzo Spaggiari, MD, PhD, Giuseppe Marulli, MD, Pietro Bovolato, MD, Marco Alloisio, MD, Vittore Pagan, MD, Alberto Oliaro, MD, Giovanni Battista Ratto, MD, Francesco Facciolo, MD, Rocco Sacco, MD, Daniela Brambilla, MS, Patrick Maisonneuve, Eng, Felice Mucilli, MD, Gabriele Alessandrini, MD, Giacomo Leoncini, MD, Enrico Ruffini, MD, Paolo Fontana, MD, Maurizio Infante, MD, Gian Luca Pariscenti, MD, Monica Casiraghi, MD, and Federico Rea, MD, PhD Thoracic Surgery Division, European Institute of Oncology, Milan; Department of Cardiologic, Thoracic and Vascular Sciences, University of Padua, Padua; Thoracic Surgery Unit, Community Hospital, Brescia; Division of Thoracic Surgery, Humanitas Research Hospital-Rozzano, Milan; Division of Thoracic Surgery, Ospedale di Mestre, Venezia-Mestre; Department of Thoracic Surgery, University of Turin, San Giovanni Battista Hospital, Turin; Division of Thoracic Surgery, IRCCS AOU “San Martino” IST, Genoa; Thoracic Surgery Unit, Department of Surgical Oncology, National Cancer Institute, Rome; Division of Surgery, Universita–ASL, Chieti; and Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
Background. This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. Methods. We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). Results. In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after
surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). Conclusions. The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.
M
Extrapleural pneumonectomy (EPP) is a difficult surgical procedure, involving an en bloc resection of the lung, parietal pleura, pericardium, and diaphragm that is currently considered the treatment of choice for selected patients with resectable MPM [2–5]. The purpose of this type of surgery is to achieve radical cytoreduction and maximize the effect of postoperative radiotherapy. Extrapleural pneumonectomy is a technically challenging operation, associated, even in experienced hands, with a perioperative mortality ranging from 0% to 11%, and perioperative morbidity rates ranging from 22% to 82%, with no survival advantage when performed alone and not as part of a multimodality treatment [3, 6–9]. A systematic review of EPP for MPM conducted in 2010 by Cao and associates [2] suggested that selected patients
alignant pleural mesothelioma (MPM) is an aggressive tumor mostly related to asbestos exposure. It is associated with a poor prognosis, with a median survival of less than 12 months [1]. The management of MPM patients is still under discussion. To date, the optimal surgical approach and different combinations of induction and adjuvant treatments remain controversial, considering the difficulties of conducting randomized controlled trials in such a small and heterogeneous group of patients. Accepted for publication Jan 17, 2014. Address correspondence to Dr Spaggiari, Thoracic Surgery Division, European Institute of Oncology, Via G. Ripamonti 435, Milan 20141, Italy; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.01.050
2
SPAGGIARI ET AL MALIGNANT PLEURAL MESOTHELIOMA
with MPM might benefit from EPP, especially when combined with induction chemotherapy and adjuvant chemotherapy or radiotherapy. The success of EPP in combination with a multimodality treatment is not only related to the possibility to obtain a macroscopic complete resection and prevent relapses, but also depends on the selection of patients with appropriate fitness and technically favorable conditions for surgery. The aim of this multicenter study, including nine of the most prominent referral centers for thoracic surgery in Italy, was to assess perioperative outcome and survival in a large series of MPM patients who underwent EPP, and to identify prognostic factors allowing better patient selection.
Ann Thorac Surg 2014;-:-–-
guidelines. Induction chemotherapy was administered to 271 patients (52%). Adjuvant treatments were administered to 373 patients (72%): radiotherapy alone was performed for 213 patients (41.1%), chemotherapy for 43 patients (8.3%) and both for 117 patients (22.6%). All adjuvant treatments were given not less than 30 days after surgery and considering the general status of the patient. Three-dimensional conformal or intensity-modulated radiotherapy, based on different technologies available at the study centers, was delivered with a median total dose of 50.4 Gy (range, 21 to 68 Gy). Adjuvant chemotherapy was, like induction therapy, mostly based on cisplatin and pemetrexed regimens.
Statistical Methods Patients and Methods The Institutional Review Board approved this study, and individual consent was obtained. We retrospectively collected clinical and surgical data from nine of the major referral centers for thoracic surgery in Italy, which agreed to share their data. All the referral centers performed no fewer than 25 EPP in the last 10 years. Data from 573 MPM patients who were candidates for EPP with radical intent (R0 or R1) between 2000 and 2010 were collected centrally, and checked for consistency by an independent data manager. Forty-six patients (8%) underwent explorative thoracotomy, and therefore were not included in the study, and 9 patients (1.7%) were lost during the followup, leaving 518 patients (median age 61 years; range, 31 to 78) for the analysis. Clinical and pathologic staging was coded according to the sixth edition of the American Joint Commission on Cancer cancer staging handbook. For all patients, clinical stage was based on total body computed tomography (CT) scan findings. Pathologic staging was based on pathologic evaluation of the specimens and on the surgeon’s intraoperative findings. Three hundred and twenty-five patients (62.7%) underwent video-assisted thoracoscopic surgical biopsy, whereas in the other patients, the diagnosis was achieved with percutaneous CT or ultrasound-guided fine-needle biopsy. During thoracoscopic biopsy of the pleura, 325 patients underwent pleurodesis. All 518 patients underwent EPP with en bloc excision of the parietal pleura with the entire lung, ipsilateral hemidiaphragm, and pericardium. The majority of the centers reconstructed diaphragm and pericardium using a synthetic mesh or bovine prosthesis. Each center used a different surgical access to the chest, varying between a double lateral thoracotomy (using the same skin incision or not) and a single thoracotomy (posterolateral, lateral, or vertical) to obtain a better exposure of the diaphragm. Lymph node dissection was performed in all patients. Postoperative complications were classified as minor or major [10, 11]. Chemotherapy regimens differed over the years, varying with the introduction of new drugs and the development of different institutional treatment
Overall survival was defined from the date of surgery to the date of last contact or death. Overall survival curves were plotted using the Kaplan-Meier method, and the log rank test was used to assess differences in survival between groups. Univariable and multivariable Cox proportional hazards regression models were used to assess the association between various presurgical (referral center, age, sex, smoking status, asbestos exposure, comorbidities, tumor histologic subtype, induction therapy) and postsurgical (surgical complications, tumor size, nodal status, presence of metastasis, tumor stage, adjuvant treatment) characteristics and overall survival. Only variables significantly associated with overall survival at univariable analysis were retained in the multivariable models. Risk estimates obtained from both multivariable models were subsequently used to predict the postoperative survival of a typical set of patients. Multivariable Cox regression was also used to evaluate the impact of postsurgical complications on short-term mortality, restricting the analysis to the 90 days after surgery. All analyses were performed with SAS software (version 8.2; SAS Institute, Cary, NC). All p values were two-sided.
Results In all, 518 MPM patients who underwent EPP in nine centers were available for analysis. Distribution of patients according to tumor histology and pathologic stage is summarized in Table 1. Most patients had an epithelial tumor (84.4%) and a right-sided tumor (53.9%). Three hundred and fifty-two patients (68.0%) had pathologic stage 3 disease, mostly due to lymph node involvement. Fifty-four patients (10.4%) had stage 4 disease, including 50 patients with large tumors (pT4) found intraoperatively and 4 patients with distant metastasis. Trimodality treatment including induction chemotherapy, surgery, and adjuvant radiotherapy was completed in 185 patients (35.7%), whereas 55 patients (10.6%) underwent surgery alone and 133 patients (25.7%) underwent surgery followed by radiotherapy; 56 patients (10.8%) who had induction chemotherapy and surgery were not given postoperative radiotherapy owing to poor performance status.
Ann Thorac Surg 2014;-:-–-
Table 1. Pathologic Characteristics of 518 Patients Who Underwent Extrapleural Pneumonectomy in Nine Italian Referral Centers Between 2000 and 2010
Characteristics Total Primary tumor pT0 pT1 pT2 pT3 pT4 Missing Regional lymph nodes N0 N1 N2 Missing Pathologic stage Stage 0b Stage 1 Stage 2 Stage 3 Stage 4
3
SPAGGIARI ET AL MALIGNANT PLEURAL MESOTHELIOMA
All n (%)
Epithelioid n (%)
Other Histologiesa n (%)
518 (100)
437 (100)
81 (100)
4 27 126 308 50 3
(0.8) (5.2) (24.3) (59.5) (9.7) (0.7)
3 26 103 257 45 3
(0.7) (5.9) (23.6) (58.8) (10.3) (0.7)
1 1 23 51 5 0
(1.2) (1.2) (28.4) (63.0) (6.2) (0.0)
305 65 146 2
(58.9) (12.6) (29.0) (0.4)
253 56 127 1
(57.9) (12.9) (30.0) (0.2)
52 9 19 1
(64.2) (11.2) (23.4) (1.2)
4 24 84 352 54
(0.8) (4.6) (16.2) (68.0) (10.4)
3 23 66 297 48
(0.7) (5.3) (15.1) (68.0) (10.9)
1 1 18 55 6
(1.2) (1.2) (22.2) (68.0) (7.4)
a
Other histologies include 69 biphasic, 7 sarcomatoid, and 5 desmoplastic b mesotheliomas. Four patients had no pathologic evidence of residual disease after neoadjuvant chemotherapy.
Major complications after EPP were observed in 136 patients (26.3%); 87 of these (16.8%) underwent rethoracotomy because of hemothorax in 39 patients (7.5%), bronchopleural fistula in 14 (2.7%), empyema in 12 (2.3%), gastric herniation in 12 (2.3%), cardiac herniation in 5 (1%), and chylothorax in 5 (1%). Minor complications occurred in 338 patients (65.3%), and were the sole complications in 270 patients (52.1%). Blood transfusion was the most frequent complication (53.1%), followed by atrial fibrillation (18.7%) and bronchial secretions necessitating aspiration (12%). Two patients (0.4%) died intraoperatively, of myocardial infarction in the one case and uncontrolled bleeding in the other. Postoperative mortality frequency during hospitalization and within 30 days from surgery was 3.9% and 0.2%, respectively; all collected data were consecutive series with no missing cases. Patients were followed after surgery for a median duration of 1.4 years (range, 0 to 11.5), contributing to 988 person-years of follow-up. Information on duration of induction chemotherapy was available for 113 (41.7%) of the 271 patients who received induction chemotherapy. For these patients, the median duration of induction chemotherapy was 106 days (range, 12 to 295). The median overall survival after surgery was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively; actuarial survivals according to presurgical and perioperative characteristics are available in Table 2 and Figure 1.
Table 2. Actuarial Overall Survival of 518 Patients Who Underwent Extrapleural Pneumonectomy in Nine Italian Referral Centers Between 2000 and 2010 According to Presurgical and Postsurgical Characteristics Characteristics All Sex Men Women Age, years
Background. This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. Methods. We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). Results. In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after
surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). Conclusions. The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.
M
Extrapleural pneumonectomy (EPP) is a difficult surgical procedure, involving an en bloc resection of the lung, parietal pleura, pericardium, and diaphragm that is currently considered the treatment of choice for selected patients with resectable MPM [2–5]. The purpose of this type of surgery is to achieve radical cytoreduction and maximize the effect of postoperative radiotherapy. Extrapleural pneumonectomy is a technically challenging operation, associated, even in experienced hands, with a perioperative mortality ranging from 0% to 11%, and perioperative morbidity rates ranging from 22% to 82%, with no survival advantage when performed alone and not as part of a multimodality treatment [3, 6–9]. A systematic review of EPP for MPM conducted in 2010 by Cao and associates [2] suggested that selected patients
alignant pleural mesothelioma (MPM) is an aggressive tumor mostly related to asbestos exposure. It is associated with a poor prognosis, with a median survival of less than 12 months [1]. The management of MPM patients is still under discussion. To date, the optimal surgical approach and different combinations of induction and adjuvant treatments remain controversial, considering the difficulties of conducting randomized controlled trials in such a small and heterogeneous group of patients. Accepted for publication Jan 17, 2014. Address correspondence to Dr Spaggiari, Thoracic Surgery Division, European Institute of Oncology, Via G. Ripamonti 435, Milan 20141, Italy; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.01.050
2
SPAGGIARI ET AL MALIGNANT PLEURAL MESOTHELIOMA
with MPM might benefit from EPP, especially when combined with induction chemotherapy and adjuvant chemotherapy or radiotherapy. The success of EPP in combination with a multimodality treatment is not only related to the possibility to obtain a macroscopic complete resection and prevent relapses, but also depends on the selection of patients with appropriate fitness and technically favorable conditions for surgery. The aim of this multicenter study, including nine of the most prominent referral centers for thoracic surgery in Italy, was to assess perioperative outcome and survival in a large series of MPM patients who underwent EPP, and to identify prognostic factors allowing better patient selection.
Ann Thorac Surg 2014;-:-–-
guidelines. Induction chemotherapy was administered to 271 patients (52%). Adjuvant treatments were administered to 373 patients (72%): radiotherapy alone was performed for 213 patients (41.1%), chemotherapy for 43 patients (8.3%) and both for 117 patients (22.6%). All adjuvant treatments were given not less than 30 days after surgery and considering the general status of the patient. Three-dimensional conformal or intensity-modulated radiotherapy, based on different technologies available at the study centers, was delivered with a median total dose of 50.4 Gy (range, 21 to 68 Gy). Adjuvant chemotherapy was, like induction therapy, mostly based on cisplatin and pemetrexed regimens.
Statistical Methods Patients and Methods The Institutional Review Board approved this study, and individual consent was obtained. We retrospectively collected clinical and surgical data from nine of the major referral centers for thoracic surgery in Italy, which agreed to share their data. All the referral centers performed no fewer than 25 EPP in the last 10 years. Data from 573 MPM patients who were candidates for EPP with radical intent (R0 or R1) between 2000 and 2010 were collected centrally, and checked for consistency by an independent data manager. Forty-six patients (8%) underwent explorative thoracotomy, and therefore were not included in the study, and 9 patients (1.7%) were lost during the followup, leaving 518 patients (median age 61 years; range, 31 to 78) for the analysis. Clinical and pathologic staging was coded according to the sixth edition of the American Joint Commission on Cancer cancer staging handbook. For all patients, clinical stage was based on total body computed tomography (CT) scan findings. Pathologic staging was based on pathologic evaluation of the specimens and on the surgeon’s intraoperative findings. Three hundred and twenty-five patients (62.7%) underwent video-assisted thoracoscopic surgical biopsy, whereas in the other patients, the diagnosis was achieved with percutaneous CT or ultrasound-guided fine-needle biopsy. During thoracoscopic biopsy of the pleura, 325 patients underwent pleurodesis. All 518 patients underwent EPP with en bloc excision of the parietal pleura with the entire lung, ipsilateral hemidiaphragm, and pericardium. The majority of the centers reconstructed diaphragm and pericardium using a synthetic mesh or bovine prosthesis. Each center used a different surgical access to the chest, varying between a double lateral thoracotomy (using the same skin incision or not) and a single thoracotomy (posterolateral, lateral, or vertical) to obtain a better exposure of the diaphragm. Lymph node dissection was performed in all patients. Postoperative complications were classified as minor or major [10, 11]. Chemotherapy regimens differed over the years, varying with the introduction of new drugs and the development of different institutional treatment
Overall survival was defined from the date of surgery to the date of last contact or death. Overall survival curves were plotted using the Kaplan-Meier method, and the log rank test was used to assess differences in survival between groups. Univariable and multivariable Cox proportional hazards regression models were used to assess the association between various presurgical (referral center, age, sex, smoking status, asbestos exposure, comorbidities, tumor histologic subtype, induction therapy) and postsurgical (surgical complications, tumor size, nodal status, presence of metastasis, tumor stage, adjuvant treatment) characteristics and overall survival. Only variables significantly associated with overall survival at univariable analysis were retained in the multivariable models. Risk estimates obtained from both multivariable models were subsequently used to predict the postoperative survival of a typical set of patients. Multivariable Cox regression was also used to evaluate the impact of postsurgical complications on short-term mortality, restricting the analysis to the 90 days after surgery. All analyses were performed with SAS software (version 8.2; SAS Institute, Cary, NC). All p values were two-sided.
Results In all, 518 MPM patients who underwent EPP in nine centers were available for analysis. Distribution of patients according to tumor histology and pathologic stage is summarized in Table 1. Most patients had an epithelial tumor (84.4%) and a right-sided tumor (53.9%). Three hundred and fifty-two patients (68.0%) had pathologic stage 3 disease, mostly due to lymph node involvement. Fifty-four patients (10.4%) had stage 4 disease, including 50 patients with large tumors (pT4) found intraoperatively and 4 patients with distant metastasis. Trimodality treatment including induction chemotherapy, surgery, and adjuvant radiotherapy was completed in 185 patients (35.7%), whereas 55 patients (10.6%) underwent surgery alone and 133 patients (25.7%) underwent surgery followed by radiotherapy; 56 patients (10.8%) who had induction chemotherapy and surgery were not given postoperative radiotherapy owing to poor performance status.
Ann Thorac Surg 2014;-:-–-
Table 1. Pathologic Characteristics of 518 Patients Who Underwent Extrapleural Pneumonectomy in Nine Italian Referral Centers Between 2000 and 2010
Characteristics Total Primary tumor pT0 pT1 pT2 pT3 pT4 Missing Regional lymph nodes N0 N1 N2 Missing Pathologic stage Stage 0b Stage 1 Stage 2 Stage 3 Stage 4
3
SPAGGIARI ET AL MALIGNANT PLEURAL MESOTHELIOMA
All n (%)
Epithelioid n (%)
Other Histologiesa n (%)
518 (100)
437 (100)
81 (100)
4 27 126 308 50 3
(0.8) (5.2) (24.3) (59.5) (9.7) (0.7)
3 26 103 257 45 3
(0.7) (5.9) (23.6) (58.8) (10.3) (0.7)
1 1 23 51 5 0
(1.2) (1.2) (28.4) (63.0) (6.2) (0.0)
305 65 146 2
(58.9) (12.6) (29.0) (0.4)
253 56 127 1
(57.9) (12.9) (30.0) (0.2)
52 9 19 1
(64.2) (11.2) (23.4) (1.2)
4 24 84 352 54
(0.8) (4.6) (16.2) (68.0) (10.4)
3 23 66 297 48
(0.7) (5.3) (15.1) (68.0) (10.9)
1 1 18 55 6
(1.2) (1.2) (22.2) (68.0) (7.4)
a
Other histologies include 69 biphasic, 7 sarcomatoid, and 5 desmoplastic b mesotheliomas. Four patients had no pathologic evidence of residual disease after neoadjuvant chemotherapy.
Major complications after EPP were observed in 136 patients (26.3%); 87 of these (16.8%) underwent rethoracotomy because of hemothorax in 39 patients (7.5%), bronchopleural fistula in 14 (2.7%), empyema in 12 (2.3%), gastric herniation in 12 (2.3%), cardiac herniation in 5 (1%), and chylothorax in 5 (1%). Minor complications occurred in 338 patients (65.3%), and were the sole complications in 270 patients (52.1%). Blood transfusion was the most frequent complication (53.1%), followed by atrial fibrillation (18.7%) and bronchial secretions necessitating aspiration (12%). Two patients (0.4%) died intraoperatively, of myocardial infarction in the one case and uncontrolled bleeding in the other. Postoperative mortality frequency during hospitalization and within 30 days from surgery was 3.9% and 0.2%, respectively; all collected data were consecutive series with no missing cases. Patients were followed after surgery for a median duration of 1.4 years (range, 0 to 11.5), contributing to 988 person-years of follow-up. Information on duration of induction chemotherapy was available for 113 (41.7%) of the 271 patients who received induction chemotherapy. For these patients, the median duration of induction chemotherapy was 106 days (range, 12 to 295). The median overall survival after surgery was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively; actuarial survivals according to presurgical and perioperative characteristics are available in Table 2 and Figure 1.
Table 2. Actuarial Overall Survival of 518 Patients Who Underwent Extrapleural Pneumonectomy in Nine Italian Referral Centers Between 2000 and 2010 According to Presurgical and Postsurgical Characteristics Characteristics All Sex Men Women Age, years
