Gen Thorac Cardiovasc Surg DOI 10.1007/s11748-015-0535-x
ORIGINAL ARTICLE
Interim results of pleurectomy/decortication and intraoperative intrapleural hyperthermic cisplatin perfusion for patients with malignant pleural mesothelioma intolerable to extrapleural pneumonectomy Hironori Ishibashi • Masashi Kobayashi Chihiro Takasaki • Kenichi Okubo
•
Received: 30 November 2014 / Accepted: 27 February 2015 Ó The Japanese Association for Thoracic Surgery 2015
Abstract Objective Surgical procedure for malignant pleural mesothelioma (MPM) remains controversial. We reviewed our protocol including pleurectomy/decortication (P/D) for patients with malignant pleural mesothelioma who were intolerable to extrapleural pneumonectomy (EPP). Patients and methods From June 2010 to April 2014, 14 patients with MPM were intended to treat with multimodality therapy including surgery. Four patients who were intolerable to EPP received a protocol consisting of P/D and intraoperative intrapleural hyperthermic cisplatin perfusion, followed by systemic chemotherapy. Ten patients received trimodality treatment of EPP, systemic chemotherapy, and intensity modulated radiation therapy for hemithorax. Surgical outcomes of acute operative results and interim survivals were examined and compared between the groups. Results All patients obtained macroscopic complete resection and received multimodality treatment in P/D and EPP groups. Operation time was longer in P/D group; however, there were no differences in ICU stays or hospitalizations. Four patients in P/D group and seven patients in EPP group experienced postoperative complications; however, there was no operative morality. EPP group suffered from cardiac complications and P/D group had prolonged airleak. Full walk recovery was obtained earlier in P/D group. One patient in P/D group had a local recurrence 11 months after surgery, while the other three
H. Ishibashi M. Kobayashi C. Takasaki K. Okubo (&) Department of Thoracic Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan e-mail: [email protected]
patients survived 23–41 months with no evidence of diseases. Conclusions P/D and intraoperative intrapleural cisplatin perfusion achieved a favorable macroscopic resection in patients with MPM who were intolerable to EPP. Postoperative complications were manageable and survival could be promising. Further study warrants with a larger number of patients. Keywords Malignant pleural mesothelioma Pleurectomy/decortication Hyperthermia Intraoperative intrapleural chemotherapy Extrapleural pneumonectomy
Introduction Standard management of malignant pleural mesothelioma (MPM) remains unknown. Multimodality treatments have obtained median survivals of 19–35 months in selected patients with MPM since Sugarbaker et al. [1] reported combined treatment of extrapleural pneumonectomy (EPP), chemotherapy, and radiation therapy [2–5]. Improved technology in combined modality such as intensity modulated radiation therapy [6, 7] provided more efficient and less toxic treatment protocols. Recent reports from western countries demonstrate that radical pleurectomy, or pleurectomy/decortication (P/D), spares the lung while removing bulk tumor in both parietal and visceral pleura [8–10]. Macroscopic complete resection (MCR) and combined modality to control microscopic diseases have become the concept of treatment for this fetal malignancy [11]. We started a treatment protocol including P/D for patients with MPM who were intolerable to EPP 4 years ago. In addition to systemic chemotherapy, we planed
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intraoperative intrapleural hyperthermic cisplatin perfusion as a modality for patients who were difficult to receive radiation therapy. Although the accrual of patients is limited and follow-up duration is not long enough, we review the surgical outcomes of P/D protocol and compare them with those of EPP protocol for patients with MPM during the same period. To our knowledge, this is the first report of cumulative result of P/D with cure intent against MPM from Japan.
Patients and methods From June 2010 to April 2014, 14 patients with MPM were intended to treat with multimodality therapy including surgical therapy. Four patients were enrolled on the P/D protocol, indications of which were patients with histologically proven MPM, surgically resectable (T1-3N0-2) without distant metastasis, who were intolerable to EPP. The protocol consists of P/D, intraoperative intrapleural hyperthermic cisplatin perfusion, and postoperative systemic chemotherapy. The other ten patients with MPM received trimodality treatment including EPP. The EPP protocol consists of EPP, followed by systemic chemotherapy, and subsequent intensity modulated radiation therapy (IMRT) for the entire hemithorax. The indication included histologically proven MPM, surgically resectable (T1-3N0-2) without distant metastasis, tolerable cardiopulmonary reserve with predicted forced expiratory volume in 1 s of more than 1 L, and ECOG performance status (PS) 0–1 [12]. Preoperative assessment included thoracoabdominal computed tomography, brain magnetic resonance imaging (MR), and positron emission tomography (PET) scan. Pathological diagnosis was obtained through video-thoracoscopic biopsy in all patients and confirmed with an appropriate panel of immunohistochemical stains. Pulmonary function test was examined, and preoperative echocardiograph was employed as an assessment for radical surgery to mainly exclude heart dysfunction.
Surgical procedure of P/D P/D was performed via a posterolateral thoracotomy through the sixth intercostal space. The extrapleural plane was dissected normally from the apical regions first, with care not to injure the great vessels. In the right side care was taken to avoid injury to azygos vein and in the left to avoid injury to aorta and hemiazygos vein. Pericardium and diaphragm adjacent to the pleura were excised, when needed, and reconstructed with Gore-Tex patches (W. L. Gore and Associates Inc.) later. The extrapleural dissection was carried out to the lung at the hilar reflection. Then, whole visceral pleura including interlobar fissure was dissected from lung parenchyma to the hilar reflection. Both parietal and visceral pleura were removed and pleurectomy was completed. Systemic dissection of the hilar, mediastinal and internal mammary lymph nodes was routinely performed. Intraoperative intrapleural hyperthermic cisplatin perfusion After the whole pleura was removed, the pleural space was perfused with the solution of cisplatin (80 mg/m2) in 2 L of saline maintained at 42 °C for 1 h using a roller pump. The inflow and outflow catheters were placed in the caudal and cephalad positions, respectively. Plastic adhesive drape was used to create a seal around the thoracotomy incision. Body temperature was monitored with a rectal probe not to exceed 39 °C. Then, parenchymal airleak was controlled with direct sutures and fibrin-based glue. Before chest closure, two 24-F chest tubes were placed at the apex and base of the pleural cavity. Systemic chemotherapy Four cycles of intravenous chemotherapy, cisplatin 60 mg/ m2 and pemetrexed 500 mg/m2, were planned as protocol. The 1st cycle was planned to start within 5–10 weeks after the P/D and the following cycles were to repeat every 4 weeks. EPP group
P/D group They were 2 men and 2 women with the mean age of 72.5 years (range 68–77 years). One patient had a right side disease and three patients had a left side disease. In all patients radiographic findings were pleural effusion and the histological subtypes were epithelioid. The reasons for intolerable EPP were poor PS (ECOG grade 2) in 2, past history of myocardial infarction treated with a coronary stent in 1, and advanced age ([75 years) in 1. Patient characteristics are shown in the Table 1.
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They were 9 men and 1 woman, with a mean age of 59.2 years (range 50–70 years). Nine patients had a right side disease and one patient had a left side disease. Radiographic findings were pleural effusion in all patients, and histological subtypes were epithelioid in 9, and biphasic in 1. Surgical procedure of EPP EPP involved en-bloc excision of the affected lung, visceral and parietal pleura, ipsilateral pericardium and
Gen Thorac Cardiovasc Surg Table 1 Patient characteristics Patient
Age
Sex
Symptoms
Radiographic findings
1
68
M
–
Pleural effusion
Past history
Indication
Pathological stage
Diabetes mellitus
PS 2
T1bN0M0, stage I
Duodinal ulcer Lumbar disc herniation 2
72
F
Chest pain
Pleural effusion
–
PS 2
T1bN0M0, stage I
3
71
M
Chest pain
Pleural effusion
Myocardial infarction
Myocardial infarction
T1bN0M0, stage I
Hypertension
PS 1
Hyperlipidemia 4
76
F
–
Pleural effusion
–
Advanced age ([75)
T3N2M0, stage III
PS performance status
diaphragm. All procedures were performed through a large posterolateral thoracotomy. The pericardium was reconstructed with a 0.1 mm Gore-Tex patch (W. L. Gore and Associates Inc.) and the diaphragm was reconstructed with a 2 mm Gore-Tex patch (W. L. Gore and Associates Inc.) in all patients. Systemic dissection of mediastinal and internal mammary lymph nodes was performed. A 24-F chest tube was placed before the chest closure. Systemic chemotherapy and radiation therapy Four cycles of intravenous chemotherapy, cisplatin 60 mg/m2 and pemetrexed 500 mg/m2, were planned. The 1st cycle was to start within 5–10 weeks after EPP and the following cycles were to repeat every 4 weeks. Subsequently IMRT of 50.4 Gy (1.8 Gy 9 28 fractions, 5 days/week) was planned for the postoperative entire hemithorax. Post-treatment follow-up Patients were seen in ambulatory follow-up at 2 and 6–8 weeks after discharge and, subsequently 3-month intervals. A computed tomography of the chest and abdomen or PET scan was obtained every 6 months. Date of recurrence was considered to be the date of the first radiographic study on which recurrence was demonstrable. Perioperative parameters; blood loss, operation time, completeness of MCR, timing of extubation, ICU stay, time to free walk in the ward, chest tube removal, length of hospitalization; postoperative complications, and pulmonary functions at least 4 months after the surgery were examined in the P/D group and compared with those in the EPP group. Pathological stages, completeness of multimodality treatment and disease-free survival (DFS) were examined in P/D group and EPP group. Operative mortality is defined as the death of any reason within 30 days or the death without hospital discharge after surgery. DFS was
defined as the duration from the surgery to the date of recurrence or death with any reason. Continuous data are presented as mean ± SE, and categorical data are presented as exact numbers. Variables in the groups were compared using student’s t test, Fisher’s exact test, and Mann–Whitney test. Survival estimates were derived by Kaplan–Meier analysis. A probability value of less than 0.05 was considered statistically significant. The study was performed in accordance with the Declaration of Helsinki. Tokyo Medical and Dental University institutional review board approved the protocols. Informed consent was obtained from all patients.
Results Patient characteristics and perioperative variables Comparison of patient parameters and perioperative variables are shown in Table 2. Patients in the P/D group were significantly higher age and had left side diseases than those in the EPP group. MCR was completed in all patients in P/D group and EPP group. Operation time was longer in P/D group than in EPP group. Intratracheal tube for anesthesia was extubated until the next morning after surgery, and ICU stay was 1 day in all patients but one in EPP group. Full walk in the ward was obtained earlier in P/D group; however, chest tube removal was later in P/D group. There was no difference in the length of hospitalizations. Postoperative complications and pulmonary functions There was no operative mortality in P/D group or EPP group. Postoperative complications occurred in 4 patients in P/D group, while they occurred in 7 patients in EPP group. Details are shown in Table 3. In EPP group heart failure defined clinically occurred in 4 patients, and additional diuretic was used daily in 8 patients postoperatively,
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Gen Thorac Cardiovasc Surg Table 2 Patient parameters and operative variables Parameters
P/D group
EPP group
p value
Age (years)
71.8 ± 1.7
58.5 ± 2.5
0.0080
Sex: Male
2 (50 %)
9 (90 %)
Side: Right
1 (25 %)
9 (90 %)
Table 3 Postoperative complications, pulmonary function, and staging Complications
P/D group
EPP group
p value
0.1758
Heart failure
0 (0 %)
4 (40 %)
0.0410
Diuretics use
0 (0 %)
8 (80 %)
0.0150
Arrhythmia
3 (75 %)
4 (40 %)
0.5594 0.5055
0.2507
Radiographic findings: Effusion
4 (100 %)
10 (100 %)
[0.9999
Chylothorax
1 (25 %)
1 (10 %)
Symptoms: Present
2 (50 %)
6 (60 %)
[0.9999
Renal dysfunction
1 (25 %)
1 (10 %)
0.5055
Operation time (min)
745 ± 30
537 ± 30
0.0019
Reoperation
2 (50 %)
1 (10 %)
0.1758
Blood loss (ml) MCR completeness
3161 ± 470 4 (100 %)
3191 ± 476 0.9715 10 (100 %) [0.9999
Morbidity (any of above) Mortality
4 (100 %) 0 (0 %)
7 (70 %) 0 (0 %)
0.5055 [0.9999
Pulmonary function 100.4 ± 6.9
86.2 ± 6.4
Extubation (days)
0±0
0±0
N.A.
ICU stay (days)
1.0 ± 0
1.1 ± 0.1
0.5486
% VC
Full walk in the ward (days)
4.0 ± 1.1
6.0 ± 0.4
0.0470
Pre
Chest tube removal (days)
13.0 ± 2.9
2.9 ± 0.6
0.0002
Post
73.4 ± 6.2
43.4 ± 4.8
Hospitalization (days)
30.3 ± 6.8
23.1 ± 6.5
0.1988
Decrease
27.0 ± 7.2
42.8 ± 4.3
0.0823
I
3
0
0.0403
II
0
1
III
1
9
Data are expressed as mean ± SE P/D pleurectomy/decortication, EPP extrapleural pneumonectomy, MCR macroscopic complete resection, N.A. not available
while in P/D group no heart failure or additional diuretics use were seen. Arrhythmia, chylothorax, and renal dysfunction occurred in each group. Reoperation was required for prolonged airleak and diaphragmatic hernia in P/D group, and for chylothorax in EPP group. Decrease of % VC between pre- and postoperative pulmonary function tests in P/D group tended to be less than that in EPP group. Pathological staging and multimodality treatment Pathological stages in P/D group were stage I (T1bN0 3) in 3, stage III (T3N2) in 1. In EPP group pathological stages were stage II in 1 (T2N0) and stage III in 9 (T2N1 1, T2N2 1, T3N0 2, T3N1 1, T3N2 4). Stage distribution in two groups was significantly different (p = 0.0403). Three patients in P/D group received 4 cycles of cisplatin and pemetrexed according to the protocol. One patient with postoperative renal dysfunction received 4 cycles of gemcitabine 800 mg/m2, started 5 months after the surgery. In the EPP group 2 patients received preoperative 2 and 6 cycles each of cisplatin and pemetrexed chemotherapy in the previous hospitals. Nine patients received postoperative chemotherapy of cisplatin and pemetrexed. Total cycles of the chemotherapy were 2 in 1, 3 in 1, 4 in 7, and 6 in 1. Subsequently, all ten patients received IMRT of 50.4 Gy for the entire hemithorax. Survivals One patient in P/D group (#1 in Table 1) had a recurrence of intrapulmonary nodule 11 months after the P/D.
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Stage
Data are expressed as mean ± SE P/D pleurectomy/decortication, EPP extrapleural pneumonectomy, VC vital capacity
Although he received a redo-pulmonary resection and postoperative radiation therapy for uncertain resection margin, he developed multiple intrathoracic dissemination later and expired 35 months after the first surgery. The other three patients have been alive with no evidence of diseases 23–41 months after the surgery. DFS in P/D group and EPP group are shown in the Fig. 1. Two-year DFS in P/D group was 75 %, and median DFS did not reach. Twoyear DFS in EPP group was 27 %, and median DFS was 12.1 months. Pathological stages in P/D group and EPP group were so different that comparison of survivals is non-scientific, and not performed.
Discussion The role of radical surgery in MPM remains controversial. EPP and P/D are surgical procedures for MPM to achieve MCR [11]. Differences in EPP and P/D include surgical margin, operative mortality, and available combined modalities. Tumor margin in the parietal pleura is similar in EPP and P/D; however, margin in the visceral pleura appears enough in EPP and close in P/D. Operative mortality of EPP has been reported higher than that of P/D [8, 9, 13] and stable postoperative courses were reported after P/D [14]. Because we previously had a protocol of trimodality
Gen Thorac Cardiovasc Surg
Fig. 1 Disease-free survivals of P/D group (n = 4) and EPP group (n = 10)
treatment for patients with MPM who were tolerable to EPP, we started P/D for those who were intolerable to EPP. Therefore, we had two protocols simultaneously for patients with MPM; one for EPP-tolerable and the other for EPPintolerable. In this study we reviewed surgical outcomes focusing on acute operative results and interim survivals in two protocols during the same period. In P/D protocol we planned P/D and intraoperative hyperthermic cisplatin perfusion for patients who were intolerable to EPP. The reasons for the intolerability were poor PS, poor cardiopulmonary reserve, and advanced age. All patients tolerated the surgical procedure and obtained MCR in P/D group. Operation time was longer in P/D group; however, recovery after anesthesia was quick and smooth. Although all patients experienced some postoperative complications, they recovered eventually with appropriate treatment. Analyses of postoperative complications in P/D group and EPP group showed that cardiac event occurred frequently in EPP group and longer chest tube was imposed on P/D group. Because bilateral lungs were reserved in P/D group, postoperative course appeared to be stable without heart failure. Prolonged chest tube drainage was manageable as long as critical complications were excluded. It is of note that our patients were able to receive four cycles of postoperative chemotherapy following P/D, completing multimodality treatment, although they were supposed not to tolerate EPP. Multimodality is essential in the treatment of cure intent for MPM [11]. No single modality treatment has brought about long-term survival in this fetal malignancy [15–17]. Sugarbaker et al. [1] reported prolonged survival with trimodality treatment including EPP, chemotherapy, and radiation therapy. Subsequently several multimodality protocols including EPP were reported: modification of the timing of chemotherapy [18–21], inclusion of improved technology of radiation therapy such as IMRT [7, 22, 23], and intraoperative pleural chemotherapy and/or
hyperthermia [24, 25]. Combined modalities with P/D included systemic chemotherapy, intraoperative pleural chemotherapy and/or hyperthermia [14, 26], and intraoperative photodynamic therapy [27]. It is reasonable to apply modalities to control microscopic diseases after the achievement of MCR. Our protocol consisted of P/D, intraoperative intrapleural hyperthermic cisplatin perfusion, and systemic chemotherapy. Because radiation therapy for hemithorax is restricted by residual lung after P/D, we added intraoperative local treatment as well as postoperative systemic therapy. It is difficult to evaluate effectiveness or toxicity of each modality in the multimodality treatment setting. While one patient who had received maximum dose of non-steroidal anti-inflammatory drug for postoperative pain suffered from nonoliguric acute renal failure of serum creatinine 3.3 mg/dl after P/D and intraoperative intrapleural chemoperfusion, the other patients showed no adverse events in renal function. Further pharmacokinetic study is required to elucidate a toxicity of intrapleural chemoperfusion. Survival in P/D group was acceptable. One patient in P/D group recurred 11 months after the surgical procedure and the other patients survived with no evidence of disease 23–41 months after the surgery. On the contrary, in EPP group median DFS was 12 months. Although we did not compare DFS in these groups because of the stage difference, DFS in P/D group was comparable with literatures of surgical outcomes in MPM [28]. Longer follow-up with a larger number of patients is required to prove effectiveness of the protocol. In summary P/D could provide MCR and multimodality treatment for patients with MPM who were intolerable to EPP. Although all patients experienced some postoperative complications, they recovered eventually and the survival could be promising. Further study warrants with a larger number of patients. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, et al. 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;117:54–65. 2. Rusch VW, Rosenzweig K, Venkatraman E, 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. J Thorac Cardiovasc Surg. 2001;122:788–95. 3. Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Trimodality management of malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2001;19:346–50.
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Gen Thorac Cardiovasc Surg 4. Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma: single centre experience in 10 years. Eur J Cardiothorac Surg. 2002;22:298–305. 5. Okubo K, Sonobe M, Fujinaga T, Shoji T, Sakai H, Miyahara R, et al. Survival and relapse pattern after trimodality therapy for malignant pleural mesothelioma. Gen Thorac Cardiovasc Surg. 2009;57:585–90. 6. Ahamad A, Stevens CW, Smythe WR, Vaporciyan AA, Komaki R, Kelly JF, et al. Intensity modulated radiation therapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2003;55:768–75. 7. Rice DC, Stevens CS, Correa AM, Vaporciyan AA, Tsao A, Forster KM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2007;84:1685–93. 8. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, et al. Extrapleural pneumonectomy versus pleurectomy/ decortication in the management of pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008;135:620–6. 9. Luckraz H, Rahman M, Patel N, Szafranek A, Gibbs AR, Butchart EG. Three decades of experience in the surgical multimodality management of pleural mesothelioma. Eur J Cardiothorac Surg. 2010;37:552–6. 10. Bo¨lu¨kbas S, Manegold C, Eberlein M, Bergmann T, FisselerEckhoff A, Schirren J. Survival after trimodality therapy for malignant pleural mesothelioma: radical Pleurectomy, chemotherapy with cisplatin/pemetrexed and radiotherapy. Lung Cancer. 2011;71:75–81. 11. Rusch V, Baldini EH, Bueno R, De Perrot M, Flores R, Hasegawa S, et al. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11–14, 2012, Boston, Mass. J Thorac Cardiovasc Surg. 2013;145:909–10. 12. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55. 13. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, Snee M, 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;12:763–72. 14. Lang-Lazdunski L, Bille A, Lal R, Cane P, McLean E, Landau D, et al. Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma. J Thorac Oncol. 2012;7:737–43. 15. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–44. 16. Takagi K, Tsuchiya R, Watanabe Y. Surgical approach to pleural diffuse mesothelioma in Japan. Lung Cancer. 2001;31:57–65.
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17. Higashiyama M, Morinaga K. Survey of surgical treatment of malignant pleural mesothelioma in Japan. Kyobu Geka. 2007;60:19–24. 18. Weder W, Kestenholz P, Taverna C, Bodis S, Lardinois D, Jerman M, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol. 2004;22:3451–7. 19. de Perrot M, Feld R, Cho BC, Bezjak A, Anraku M, Burkes R, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation or malignant pleural mesothelioma. J Clin Oncol. 2009;27:1413–8. 20. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol. 2009;27:3007–13. 21. Van Schil PE, Baas P, Gaafar R, Maat AP, Van de Pol M, Hasan B, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J. 2010;36:1362–9. 22. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallie`res E, et al. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2009;88:870–6. 23. Chi A, Liao Z, Nguyen NP, Howe C, Gomez D, Jang SY, et al. Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol. 2011;6:1132–41. 24. Ratto GB, Civalleri D, Esposito M, Spessa E, Alloisio A, De Cian F, et al. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. J Thorac Cardiovasc Surg. 1999;117:759–65. 25. Tilleman TR, Richards WG, Zellos L, Johnson BE, Jaklitsch MT, Mueller J, et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: A phase II prospective study. J Thorac Cardiovasc Surg. 2009;138:405–11. 26. Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, 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. J Thorac Cardiovasc Surg. 2013;145:955–63. 27. Friedberg JS, Culligan MJ, Mick R, Stevenson J, Hahn SM, Sterman D, et al. Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2012;93:1658–67. 28. Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol. 2012;7:1631–9.
ORIGINAL ARTICLE
Interim results of pleurectomy/decortication and intraoperative intrapleural hyperthermic cisplatin perfusion for patients with malignant pleural mesothelioma intolerable to extrapleural pneumonectomy Hironori Ishibashi • Masashi Kobayashi Chihiro Takasaki • Kenichi Okubo
•
Received: 30 November 2014 / Accepted: 27 February 2015 Ó The Japanese Association for Thoracic Surgery 2015
Abstract Objective Surgical procedure for malignant pleural mesothelioma (MPM) remains controversial. We reviewed our protocol including pleurectomy/decortication (P/D) for patients with malignant pleural mesothelioma who were intolerable to extrapleural pneumonectomy (EPP). Patients and methods From June 2010 to April 2014, 14 patients with MPM were intended to treat with multimodality therapy including surgery. Four patients who were intolerable to EPP received a protocol consisting of P/D and intraoperative intrapleural hyperthermic cisplatin perfusion, followed by systemic chemotherapy. Ten patients received trimodality treatment of EPP, systemic chemotherapy, and intensity modulated radiation therapy for hemithorax. Surgical outcomes of acute operative results and interim survivals were examined and compared between the groups. Results All patients obtained macroscopic complete resection and received multimodality treatment in P/D and EPP groups. Operation time was longer in P/D group; however, there were no differences in ICU stays or hospitalizations. Four patients in P/D group and seven patients in EPP group experienced postoperative complications; however, there was no operative morality. EPP group suffered from cardiac complications and P/D group had prolonged airleak. Full walk recovery was obtained earlier in P/D group. One patient in P/D group had a local recurrence 11 months after surgery, while the other three
H. Ishibashi M. Kobayashi C. Takasaki K. Okubo (&) Department of Thoracic Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan e-mail: [email protected]
patients survived 23–41 months with no evidence of diseases. Conclusions P/D and intraoperative intrapleural cisplatin perfusion achieved a favorable macroscopic resection in patients with MPM who were intolerable to EPP. Postoperative complications were manageable and survival could be promising. Further study warrants with a larger number of patients. Keywords Malignant pleural mesothelioma Pleurectomy/decortication Hyperthermia Intraoperative intrapleural chemotherapy Extrapleural pneumonectomy
Introduction Standard management of malignant pleural mesothelioma (MPM) remains unknown. Multimodality treatments have obtained median survivals of 19–35 months in selected patients with MPM since Sugarbaker et al. [1] reported combined treatment of extrapleural pneumonectomy (EPP), chemotherapy, and radiation therapy [2–5]. Improved technology in combined modality such as intensity modulated radiation therapy [6, 7] provided more efficient and less toxic treatment protocols. Recent reports from western countries demonstrate that radical pleurectomy, or pleurectomy/decortication (P/D), spares the lung while removing bulk tumor in both parietal and visceral pleura [8–10]. Macroscopic complete resection (MCR) and combined modality to control microscopic diseases have become the concept of treatment for this fetal malignancy [11]. We started a treatment protocol including P/D for patients with MPM who were intolerable to EPP 4 years ago. In addition to systemic chemotherapy, we planed
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Gen Thorac Cardiovasc Surg
intraoperative intrapleural hyperthermic cisplatin perfusion as a modality for patients who were difficult to receive radiation therapy. Although the accrual of patients is limited and follow-up duration is not long enough, we review the surgical outcomes of P/D protocol and compare them with those of EPP protocol for patients with MPM during the same period. To our knowledge, this is the first report of cumulative result of P/D with cure intent against MPM from Japan.
Patients and methods From June 2010 to April 2014, 14 patients with MPM were intended to treat with multimodality therapy including surgical therapy. Four patients were enrolled on the P/D protocol, indications of which were patients with histologically proven MPM, surgically resectable (T1-3N0-2) without distant metastasis, who were intolerable to EPP. The protocol consists of P/D, intraoperative intrapleural hyperthermic cisplatin perfusion, and postoperative systemic chemotherapy. The other ten patients with MPM received trimodality treatment including EPP. The EPP protocol consists of EPP, followed by systemic chemotherapy, and subsequent intensity modulated radiation therapy (IMRT) for the entire hemithorax. The indication included histologically proven MPM, surgically resectable (T1-3N0-2) without distant metastasis, tolerable cardiopulmonary reserve with predicted forced expiratory volume in 1 s of more than 1 L, and ECOG performance status (PS) 0–1 [12]. Preoperative assessment included thoracoabdominal computed tomography, brain magnetic resonance imaging (MR), and positron emission tomography (PET) scan. Pathological diagnosis was obtained through video-thoracoscopic biopsy in all patients and confirmed with an appropriate panel of immunohistochemical stains. Pulmonary function test was examined, and preoperative echocardiograph was employed as an assessment for radical surgery to mainly exclude heart dysfunction.
Surgical procedure of P/D P/D was performed via a posterolateral thoracotomy through the sixth intercostal space. The extrapleural plane was dissected normally from the apical regions first, with care not to injure the great vessels. In the right side care was taken to avoid injury to azygos vein and in the left to avoid injury to aorta and hemiazygos vein. Pericardium and diaphragm adjacent to the pleura were excised, when needed, and reconstructed with Gore-Tex patches (W. L. Gore and Associates Inc.) later. The extrapleural dissection was carried out to the lung at the hilar reflection. Then, whole visceral pleura including interlobar fissure was dissected from lung parenchyma to the hilar reflection. Both parietal and visceral pleura were removed and pleurectomy was completed. Systemic dissection of the hilar, mediastinal and internal mammary lymph nodes was routinely performed. Intraoperative intrapleural hyperthermic cisplatin perfusion After the whole pleura was removed, the pleural space was perfused with the solution of cisplatin (80 mg/m2) in 2 L of saline maintained at 42 °C for 1 h using a roller pump. The inflow and outflow catheters were placed in the caudal and cephalad positions, respectively. Plastic adhesive drape was used to create a seal around the thoracotomy incision. Body temperature was monitored with a rectal probe not to exceed 39 °C. Then, parenchymal airleak was controlled with direct sutures and fibrin-based glue. Before chest closure, two 24-F chest tubes were placed at the apex and base of the pleural cavity. Systemic chemotherapy Four cycles of intravenous chemotherapy, cisplatin 60 mg/ m2 and pemetrexed 500 mg/m2, were planned as protocol. The 1st cycle was planned to start within 5–10 weeks after the P/D and the following cycles were to repeat every 4 weeks. EPP group
P/D group They were 2 men and 2 women with the mean age of 72.5 years (range 68–77 years). One patient had a right side disease and three patients had a left side disease. In all patients radiographic findings were pleural effusion and the histological subtypes were epithelioid. The reasons for intolerable EPP were poor PS (ECOG grade 2) in 2, past history of myocardial infarction treated with a coronary stent in 1, and advanced age ([75 years) in 1. Patient characteristics are shown in the Table 1.
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They were 9 men and 1 woman, with a mean age of 59.2 years (range 50–70 years). Nine patients had a right side disease and one patient had a left side disease. Radiographic findings were pleural effusion in all patients, and histological subtypes were epithelioid in 9, and biphasic in 1. Surgical procedure of EPP EPP involved en-bloc excision of the affected lung, visceral and parietal pleura, ipsilateral pericardium and
Gen Thorac Cardiovasc Surg Table 1 Patient characteristics Patient
Age
Sex
Symptoms
Radiographic findings
1
68
M
–
Pleural effusion
Past history
Indication
Pathological stage
Diabetes mellitus
PS 2
T1bN0M0, stage I
Duodinal ulcer Lumbar disc herniation 2
72
F
Chest pain
Pleural effusion
–
PS 2
T1bN0M0, stage I
3
71
M
Chest pain
Pleural effusion
Myocardial infarction
Myocardial infarction
T1bN0M0, stage I
Hypertension
PS 1
Hyperlipidemia 4
76
F
–
Pleural effusion
–
Advanced age ([75)
T3N2M0, stage III
PS performance status
diaphragm. All procedures were performed through a large posterolateral thoracotomy. The pericardium was reconstructed with a 0.1 mm Gore-Tex patch (W. L. Gore and Associates Inc.) and the diaphragm was reconstructed with a 2 mm Gore-Tex patch (W. L. Gore and Associates Inc.) in all patients. Systemic dissection of mediastinal and internal mammary lymph nodes was performed. A 24-F chest tube was placed before the chest closure. Systemic chemotherapy and radiation therapy Four cycles of intravenous chemotherapy, cisplatin 60 mg/m2 and pemetrexed 500 mg/m2, were planned. The 1st cycle was to start within 5–10 weeks after EPP and the following cycles were to repeat every 4 weeks. Subsequently IMRT of 50.4 Gy (1.8 Gy 9 28 fractions, 5 days/week) was planned for the postoperative entire hemithorax. Post-treatment follow-up Patients were seen in ambulatory follow-up at 2 and 6–8 weeks after discharge and, subsequently 3-month intervals. A computed tomography of the chest and abdomen or PET scan was obtained every 6 months. Date of recurrence was considered to be the date of the first radiographic study on which recurrence was demonstrable. Perioperative parameters; blood loss, operation time, completeness of MCR, timing of extubation, ICU stay, time to free walk in the ward, chest tube removal, length of hospitalization; postoperative complications, and pulmonary functions at least 4 months after the surgery were examined in the P/D group and compared with those in the EPP group. Pathological stages, completeness of multimodality treatment and disease-free survival (DFS) were examined in P/D group and EPP group. Operative mortality is defined as the death of any reason within 30 days or the death without hospital discharge after surgery. DFS was
defined as the duration from the surgery to the date of recurrence or death with any reason. Continuous data are presented as mean ± SE, and categorical data are presented as exact numbers. Variables in the groups were compared using student’s t test, Fisher’s exact test, and Mann–Whitney test. Survival estimates were derived by Kaplan–Meier analysis. A probability value of less than 0.05 was considered statistically significant. The study was performed in accordance with the Declaration of Helsinki. Tokyo Medical and Dental University institutional review board approved the protocols. Informed consent was obtained from all patients.
Results Patient characteristics and perioperative variables Comparison of patient parameters and perioperative variables are shown in Table 2. Patients in the P/D group were significantly higher age and had left side diseases than those in the EPP group. MCR was completed in all patients in P/D group and EPP group. Operation time was longer in P/D group than in EPP group. Intratracheal tube for anesthesia was extubated until the next morning after surgery, and ICU stay was 1 day in all patients but one in EPP group. Full walk in the ward was obtained earlier in P/D group; however, chest tube removal was later in P/D group. There was no difference in the length of hospitalizations. Postoperative complications and pulmonary functions There was no operative mortality in P/D group or EPP group. Postoperative complications occurred in 4 patients in P/D group, while they occurred in 7 patients in EPP group. Details are shown in Table 3. In EPP group heart failure defined clinically occurred in 4 patients, and additional diuretic was used daily in 8 patients postoperatively,
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Gen Thorac Cardiovasc Surg Table 2 Patient parameters and operative variables Parameters
P/D group
EPP group
p value
Age (years)
71.8 ± 1.7
58.5 ± 2.5
0.0080
Sex: Male
2 (50 %)
9 (90 %)
Side: Right
1 (25 %)
9 (90 %)
Table 3 Postoperative complications, pulmonary function, and staging Complications
P/D group
EPP group
p value
0.1758
Heart failure
0 (0 %)
4 (40 %)
0.0410
Diuretics use
0 (0 %)
8 (80 %)
0.0150
Arrhythmia
3 (75 %)
4 (40 %)
0.5594 0.5055
0.2507
Radiographic findings: Effusion
4 (100 %)
10 (100 %)
[0.9999
Chylothorax
1 (25 %)
1 (10 %)
Symptoms: Present
2 (50 %)
6 (60 %)
[0.9999
Renal dysfunction
1 (25 %)
1 (10 %)
0.5055
Operation time (min)
745 ± 30
537 ± 30
0.0019
Reoperation
2 (50 %)
1 (10 %)
0.1758
Blood loss (ml) MCR completeness
3161 ± 470 4 (100 %)
3191 ± 476 0.9715 10 (100 %) [0.9999
Morbidity (any of above) Mortality
4 (100 %) 0 (0 %)
7 (70 %) 0 (0 %)
0.5055 [0.9999
Pulmonary function 100.4 ± 6.9
86.2 ± 6.4
Extubation (days)
0±0
0±0
N.A.
ICU stay (days)
1.0 ± 0
1.1 ± 0.1
0.5486
% VC
Full walk in the ward (days)
4.0 ± 1.1
6.0 ± 0.4
0.0470
Pre
Chest tube removal (days)
13.0 ± 2.9
2.9 ± 0.6
0.0002
Post
73.4 ± 6.2
43.4 ± 4.8
Hospitalization (days)
30.3 ± 6.8
23.1 ± 6.5
0.1988
Decrease
27.0 ± 7.2
42.8 ± 4.3
0.0823
I
3
0
0.0403
II
0
1
III
1
9
Data are expressed as mean ± SE P/D pleurectomy/decortication, EPP extrapleural pneumonectomy, MCR macroscopic complete resection, N.A. not available
while in P/D group no heart failure or additional diuretics use were seen. Arrhythmia, chylothorax, and renal dysfunction occurred in each group. Reoperation was required for prolonged airleak and diaphragmatic hernia in P/D group, and for chylothorax in EPP group. Decrease of % VC between pre- and postoperative pulmonary function tests in P/D group tended to be less than that in EPP group. Pathological staging and multimodality treatment Pathological stages in P/D group were stage I (T1bN0 3) in 3, stage III (T3N2) in 1. In EPP group pathological stages were stage II in 1 (T2N0) and stage III in 9 (T2N1 1, T2N2 1, T3N0 2, T3N1 1, T3N2 4). Stage distribution in two groups was significantly different (p = 0.0403). Three patients in P/D group received 4 cycles of cisplatin and pemetrexed according to the protocol. One patient with postoperative renal dysfunction received 4 cycles of gemcitabine 800 mg/m2, started 5 months after the surgery. In the EPP group 2 patients received preoperative 2 and 6 cycles each of cisplatin and pemetrexed chemotherapy in the previous hospitals. Nine patients received postoperative chemotherapy of cisplatin and pemetrexed. Total cycles of the chemotherapy were 2 in 1, 3 in 1, 4 in 7, and 6 in 1. Subsequently, all ten patients received IMRT of 50.4 Gy for the entire hemithorax. Survivals One patient in P/D group (#1 in Table 1) had a recurrence of intrapulmonary nodule 11 months after the P/D.
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Stage
Data are expressed as mean ± SE P/D pleurectomy/decortication, EPP extrapleural pneumonectomy, VC vital capacity
Although he received a redo-pulmonary resection and postoperative radiation therapy for uncertain resection margin, he developed multiple intrathoracic dissemination later and expired 35 months after the first surgery. The other three patients have been alive with no evidence of diseases 23–41 months after the surgery. DFS in P/D group and EPP group are shown in the Fig. 1. Two-year DFS in P/D group was 75 %, and median DFS did not reach. Twoyear DFS in EPP group was 27 %, and median DFS was 12.1 months. Pathological stages in P/D group and EPP group were so different that comparison of survivals is non-scientific, and not performed.
Discussion The role of radical surgery in MPM remains controversial. EPP and P/D are surgical procedures for MPM to achieve MCR [11]. Differences in EPP and P/D include surgical margin, operative mortality, and available combined modalities. Tumor margin in the parietal pleura is similar in EPP and P/D; however, margin in the visceral pleura appears enough in EPP and close in P/D. Operative mortality of EPP has been reported higher than that of P/D [8, 9, 13] and stable postoperative courses were reported after P/D [14]. Because we previously had a protocol of trimodality
Gen Thorac Cardiovasc Surg
Fig. 1 Disease-free survivals of P/D group (n = 4) and EPP group (n = 10)
treatment for patients with MPM who were tolerable to EPP, we started P/D for those who were intolerable to EPP. Therefore, we had two protocols simultaneously for patients with MPM; one for EPP-tolerable and the other for EPPintolerable. In this study we reviewed surgical outcomes focusing on acute operative results and interim survivals in two protocols during the same period. In P/D protocol we planned P/D and intraoperative hyperthermic cisplatin perfusion for patients who were intolerable to EPP. The reasons for the intolerability were poor PS, poor cardiopulmonary reserve, and advanced age. All patients tolerated the surgical procedure and obtained MCR in P/D group. Operation time was longer in P/D group; however, recovery after anesthesia was quick and smooth. Although all patients experienced some postoperative complications, they recovered eventually with appropriate treatment. Analyses of postoperative complications in P/D group and EPP group showed that cardiac event occurred frequently in EPP group and longer chest tube was imposed on P/D group. Because bilateral lungs were reserved in P/D group, postoperative course appeared to be stable without heart failure. Prolonged chest tube drainage was manageable as long as critical complications were excluded. It is of note that our patients were able to receive four cycles of postoperative chemotherapy following P/D, completing multimodality treatment, although they were supposed not to tolerate EPP. Multimodality is essential in the treatment of cure intent for MPM [11]. No single modality treatment has brought about long-term survival in this fetal malignancy [15–17]. Sugarbaker et al. [1] reported prolonged survival with trimodality treatment including EPP, chemotherapy, and radiation therapy. Subsequently several multimodality protocols including EPP were reported: modification of the timing of chemotherapy [18–21], inclusion of improved technology of radiation therapy such as IMRT [7, 22, 23], and intraoperative pleural chemotherapy and/or
hyperthermia [24, 25]. Combined modalities with P/D included systemic chemotherapy, intraoperative pleural chemotherapy and/or hyperthermia [14, 26], and intraoperative photodynamic therapy [27]. It is reasonable to apply modalities to control microscopic diseases after the achievement of MCR. Our protocol consisted of P/D, intraoperative intrapleural hyperthermic cisplatin perfusion, and systemic chemotherapy. Because radiation therapy for hemithorax is restricted by residual lung after P/D, we added intraoperative local treatment as well as postoperative systemic therapy. It is difficult to evaluate effectiveness or toxicity of each modality in the multimodality treatment setting. While one patient who had received maximum dose of non-steroidal anti-inflammatory drug for postoperative pain suffered from nonoliguric acute renal failure of serum creatinine 3.3 mg/dl after P/D and intraoperative intrapleural chemoperfusion, the other patients showed no adverse events in renal function. Further pharmacokinetic study is required to elucidate a toxicity of intrapleural chemoperfusion. Survival in P/D group was acceptable. One patient in P/D group recurred 11 months after the surgical procedure and the other patients survived with no evidence of disease 23–41 months after the surgery. On the contrary, in EPP group median DFS was 12 months. Although we did not compare DFS in these groups because of the stage difference, DFS in P/D group was comparable with literatures of surgical outcomes in MPM [28]. Longer follow-up with a larger number of patients is required to prove effectiveness of the protocol. In summary P/D could provide MCR and multimodality treatment for patients with MPM who were intolerable to EPP. Although all patients experienced some postoperative complications, they recovered eventually and the survival could be promising. Further study warrants with a larger number of patients. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, et al. 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;117:54–65. 2. Rusch VW, Rosenzweig K, Venkatraman E, 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. J Thorac Cardiovasc Surg. 2001;122:788–95. 3. Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Trimodality management of malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2001;19:346–50.
123
Gen Thorac Cardiovasc Surg 4. Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma: single centre experience in 10 years. Eur J Cardiothorac Surg. 2002;22:298–305. 5. Okubo K, Sonobe M, Fujinaga T, Shoji T, Sakai H, Miyahara R, et al. Survival and relapse pattern after trimodality therapy for malignant pleural mesothelioma. Gen Thorac Cardiovasc Surg. 2009;57:585–90. 6. Ahamad A, Stevens CW, Smythe WR, Vaporciyan AA, Komaki R, Kelly JF, et al. Intensity modulated radiation therapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2003;55:768–75. 7. Rice DC, Stevens CS, Correa AM, Vaporciyan AA, Tsao A, Forster KM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2007;84:1685–93. 8. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, et al. Extrapleural pneumonectomy versus pleurectomy/ decortication in the management of pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008;135:620–6. 9. Luckraz H, Rahman M, Patel N, Szafranek A, Gibbs AR, Butchart EG. Three decades of experience in the surgical multimodality management of pleural mesothelioma. Eur J Cardiothorac Surg. 2010;37:552–6. 10. Bo¨lu¨kbas S, Manegold C, Eberlein M, Bergmann T, FisselerEckhoff A, Schirren J. Survival after trimodality therapy for malignant pleural mesothelioma: radical Pleurectomy, chemotherapy with cisplatin/pemetrexed and radiotherapy. Lung Cancer. 2011;71:75–81. 11. Rusch V, Baldini EH, Bueno R, De Perrot M, Flores R, Hasegawa S, et al. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11–14, 2012, Boston, Mass. J Thorac Cardiovasc Surg. 2013;145:909–10. 12. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55. 13. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, Snee M, 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;12:763–72. 14. Lang-Lazdunski L, Bille A, Lal R, Cane P, McLean E, Landau D, et al. Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma. J Thorac Oncol. 2012;7:737–43. 15. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–44. 16. Takagi K, Tsuchiya R, Watanabe Y. Surgical approach to pleural diffuse mesothelioma in Japan. Lung Cancer. 2001;31:57–65.
123
17. Higashiyama M, Morinaga K. Survey of surgical treatment of malignant pleural mesothelioma in Japan. Kyobu Geka. 2007;60:19–24. 18. Weder W, Kestenholz P, Taverna C, Bodis S, Lardinois D, Jerman M, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol. 2004;22:3451–7. 19. de Perrot M, Feld R, Cho BC, Bezjak A, Anraku M, Burkes R, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation or malignant pleural mesothelioma. J Clin Oncol. 2009;27:1413–8. 20. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol. 2009;27:3007–13. 21. Van Schil PE, Baas P, Gaafar R, Maat AP, Van de Pol M, Hasan B, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J. 2010;36:1362–9. 22. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallie`res E, et al. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2009;88:870–6. 23. Chi A, Liao Z, Nguyen NP, Howe C, Gomez D, Jang SY, et al. Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol. 2011;6:1132–41. 24. Ratto GB, Civalleri D, Esposito M, Spessa E, Alloisio A, De Cian F, et al. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. J Thorac Cardiovasc Surg. 1999;117:759–65. 25. Tilleman TR, Richards WG, Zellos L, Johnson BE, Jaklitsch MT, Mueller J, et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: A phase II prospective study. J Thorac Cardiovasc Surg. 2009;138:405–11. 26. Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, 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. J Thorac Cardiovasc Surg. 2013;145:955–63. 27. Friedberg JS, Culligan MJ, Mick R, Stevenson J, Hahn SM, Sterman D, et al. Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2012;93:1658–67. 28. Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol. 2012;7:1631–9.
