Prospective results of trimodality treatment for malignant pleural mesothelioma Risultati prospettici del trattamento trimodale del mesotelioma maligno pleurico Vittore Pagan*, Alessandro Busetto*, Paolo Fontana*, Otorino Nascimben**, Giangiuseppe Pizzi*** * Thoracic Surgery Unit, Umberto I General Hospital, Venezia-Mestre, Italy ** Oncology Unit, Umberto I General Hospital, Venezia-Mestre, Italy *** Radiotherapy Unit, Umberto I General Hospital, Venezia-Mestre, Italy Summary Although associated with substantially prolonged survival, the favourable results of Sugarbaker s trimodality treatment for malignant pleural mesothelioma (MPM) are controversial and not yet extensively replicated. The aim of this study is to evaluate the prospective reproducibility of trimodality treatment results in a significative group of patients staged with the International Mesothelioma Interest Group (IMIG) classification. Fortythree patients with MPM have been candidated to extended pleuropneumonectomy (EPP), followed by CT (paclitaxel + carboplatin) and RT (50 Gy total dose). At thoracotomy, 33 out of the 43 surgical candidates underwent EPP; 30 have already entered the complete protocol and are evaluable, and 71% of the operated patients have completed the adjuvant chemotherapy. The perioperative mortality rate was 6.6% (2 deaths) and that of major morbidity 33%. After 5 years, the global survival of the 30 patients submitted to EPP is 13% with prevalence of epithelial pi and pii IMIG stages. Epithelial, N 0-1, radically resected MPM showed a 5-year survival rate of 60%. Clinical understaging has been considerable. Most of disease recurrences are due to incomplete local postsurgical radicality. This series confirms the reproducibility of trimodality treatment for MPM, which is associated with prolonged survival for early-stage tumours with an acceptable complication rate. Early diagnosis, accurate staging, preoperative induction and better local control are directions to explore for the curability of pleural mesothelioma to be implemented. Key-words: mesothelioma, surgery, pleural neoplasms surgery, pneumonectomy, pleura Riassunto Sebbene comportino un aumento significativo della sopravvivenza, i risultati favorevoli del trattamento trimodale di Sugarbaker per il mesotelioma maligno della Address/Indirizzo: Prof. V. Pagan, Thoracic Surgery Unit, Umberto I General Hospital, Venezia-Mestre- ULSS 12, Via Circonvallazione 50, 30174 Mestre, Italia - Tel. 0039/041/2607280 - Fax 0039/041/2607290 E-mail: ocme.chtor@ulss12.ve.it 71
Eur. J. Oncol. Library, vol. 3 pleura (MMP) sono controversi e non ancora confermati estesamente. Lo scopo di questo studio è quello di valutare la riproducibilità prospettica dei risultati del trattamento trimodale in un gruppo significativo di pazienti stadiati secondo la classificazione dell International Mesothelioma Interest Group (IMIG). Quarantatre pazienti con MMP sono stati candidati ad una pleuropnemonectomia estesa (PPE) seguita da CT (paclitaxel + carboplatino) e RT (dose totale 50 Gy). Alla toracotomia, 33 dei 43 pazienti candidati all intervento sono stati sottoposti a PPE; 30 sono già entrati nel protocollo completo e sono valutabili, ed il 71% dei pazienti operati ha completato la chemioterapia adiuvante. Il tasso di mortalità perioperatoria è stato del 6,6% (2 morti) e la morbilità importante del 33%. La sopravvivenza globale a 5 anni dei 30 pazienti sottoposti a PPE è del 13%, con prevalenza degli stadi IMIG pi e pii epiteliale. Il MMP epiteliale, N 0-1, asportato radicalmente, ha mostrato una sopravvivenza a 5 anni del 60%. La sottostadiazione clinica è stata notevole. La maggioranza delle recidive della malattia è dovuta ad una radicalità postchirurgica locale incompleta. Questa serie conferma la riproducibilità del trattamento trimodale del MMP, che comporta un aumento di sopravvivenza nei tumori in stadio iniziale con un tasso di complicazioni accettabile. La diagnosi precoce, la stadiazione accurata, l induzione preoperatoria ed un migliore controllo locale sono le vie da sviluppare per migliorare la curabilità del mesotelioma pleurico. Parole chiave: mesotelioma, chirurgia, chirurgia delle neoplasie pleuriche, pneumonectomia, pleura Introduction Malignant pleural mesothelioma (MPM) is considered today no longer an uncommon pathology: 800 to 1000 new cases/year are expected in Italy until 2020 and, in particular areas, this is the highest rate in the world 1. With palliative treatment the median survival is poor: 30 weeks; this may exceptionally reach 3-4 years if treated in the early stages 2. Recently Sugarbaker et al 3 reported a substantial survival (up to 46% at 5 years) in patients undergoing trimodality therapy, based on radical extended extrapleural pneumonectomy (EPP) followed by chemotherapy and radiation. Despite these results, the trimodality treatment of MPM remains controversial, both because it lacks reproducibility, and because of the need of a uniform and pre-surgical staging; for this reason the IMIG classification 2 is becoming increasingly adopted. The aim of this study is to report the prospective middle and long term results of the Sugarbaker trimodality treatment applied to a significative series of patients with malignant pleural mesothelioma, staged by the IMIG system. Methods From May 1997 to June 2002, 88 patients with malignant pleural mesothelioma were observed at the Thoracic Surgery Unit of Umberto I General Hospital (Venezia-Mestre); 46 (52%) resulted eligible for trimodality treatment. 72
V. Pagan, A. Busetto, P. Fontana, et al: Trimodality treatment of malignant pleural mesothelioma The selection criteria were: Karnofsky index >80%; absence of severe metabolic insufficiency; po 2 > 70 and pco 2 <44 mmhg; residual FEV 1 and DLCO not inferior to half of the theoretical value; cardiac ejection fraction >45%; epithelial or mixed histology; tumour judged to be completely resectable (I to III non-n 2 IMIG stages). Each patient was evaluated by means of: thoracic and abdominal CT scan; thoracic MRI; echocardiography; bronchoscopy with bronchial bacteriology; respiratory functional tests (DLCO included); radionuclide ventilation-perfusion scanning. Complementary tests (TBNA, mediastinoscopy, contralateral videothoracoscopy, laparoscopy) were performed in the case of suspected adenopathy or multi-serosal invasion. We are evaluating the accuracy of PET-CT in staging pleural neoplastic diseases. Extrapleural pneumonectomy starts with a full thickness resection of any previous diagnostic parietal tract and scar. A vertical mid-axillary line incision is preferred for its many advantages: easy access to the usually necessary double intercostal space approach (the fifth space for lung and the ninth-tenth space for diaphragmatic resection); preservation of chest wall muscles. Post-thoracotomy pain and cosmetic impairment are considerably reduced in comparison with standard postero-lateral thoracotomy and, in the case of empyema, myoplastic procedures can be performed any time. Afterwards, the main oncological resectability criteria must be carefully assessed (even with intraoperative histology) by checking: the visceral pericardium, epicardium and intrapericardial vessels, thoracic fascia and parietal muscles, mediastinum, and the abdominal side of the diaphragm. If the disease is reputed radically excisable, an en-bloc resection of the parietal pleura, the lung with visceral pleura, the ipsilateral pericardium and the diaphragm (sometimes a peritoneal cap is included in the specimen) is performed. A prosthetic substitute is necessary for the reconstruction of the pericardium (PTFE) and diaphragm (PTFE or polyglycolic-acid mesh). Special care is given to bronchial stump protection with an autologous flap (usually thymic residuals) and endothoracic haemostasis. Radical lymphadenectomy is performed according to the ATS map, also adding the internal mammary and peri-diaphragmatic nodes; thoracic drain, chest closure and post-operative assistance does not differ from a standard pneumonectomy for lung cancer. Systematic pathologic analysis is undertaken for each margin of all specimens: pericardium, bronchus, diaphragm, previous parietal tracks, and pericardial and peritoneal fluid (when collectable). Multiple samples are taken from the chest wall muscles and thoracic fascia, abdominal and visceral aspects of the diaphragm and pericardium, respectively, and the mediastinal tissue. Adjuvant therapy starts 40 days after surgery: chemotherapy (carboplatinum AUC=5 and taxol 175 mg for 2 cycles at 3 weeks distance) followed by radiation therapy (on the affected hemi thorax, thoracotomic incision and areas of possible R 1 or nodal involvement) for a total of 50 Gy in 25 fractions, with concurrent taxol 60 mg/m 2 /week, for 5 weeks. Four weeks after completion of radiation therapy, 2 additional carbo-taxol cycles are given. Statistical analysis of survival (overall and disease-free), measured from the date of operation until the date of the patient s last follow-up contact or death, are performed by means of the Kaplan-Meyer life-table method. For operative mortality we consider any death which occurs within 30 days or in hospital. Results Among 46 patients eligible for extended extrapleural pneumonectomy, 13 (28%) resulted not resectable at thoracotomy: 10 of them for diffuse chest wall and fascia infiltration, 73
Eur. J. Oncol. Library, vol. 3 variously associated to mediastinal/pericardial invasion with or without nodal involvement, 2 for direct mediastinal invasion and 1 for epicardial extension. In these patients a parietal pleurectomy, as extended as possible, was performed only for palliative purposes. Therefore EPP was performed in 33 patients (30 males and 3 females), aged 41 to 75 years (median: 62), 18 on the right and 15 on the left side. The exeresis was also extended to a thoracic wall tract (3 cases), the aortic wall (1), the left atrium (1), the superior vena cava (1) - in which reconstruction was done by bovine pericardial patch - the apex of the peritoneum, fused but not infiltrated with the diaphragm (10). The latissimus dorsi muscle was rotated intrathoracically as a myoplastic substitute of the diaphragm because of concomitant pleural empyema in one patient. In 22% of the EPPs all the surgical manoeuvres were done through a single access (the sixth intercostal space). Mean surgical time was 5 hours. In 5 cases, intra-operative blood transfusions were necessary. The mean post-operative hospital stay was 11.5 days. Three patients have not reached yet the 30-day survival landmark (or are not yet enrolled in the post-operative CT+RT protocol); therefore our study concerns the 30 patients whose data are completely available. Our 30-day and in-hospital mortality was 6.6% (2/30), entirely due to residual lung pneumonia with respiratory failure. Both cases belonged to the first group of 15 operated patients, in which we accepted a post-operative FEV 1 of 1 litre. Thereafter we had adopted in the subsequent cases more rigid criteria (FEV 1 and DLCO half of the theoretical value) along with systematic endo-bronchial bacteriology research and treatment, with remarkable decrease of serious complications in the second group of 15 patients. Major morbidity rate was 36.6% (11/30) and was defined as a fatal event or one leading to re-exploration and/or longer hospital stay: pneumonia occurred in 4 patients (2 deaths); atrial fibrillation in 5; bleeding in 2 (both re-explored); parietal wall instability in 1; chylothorax in 1 (re-explored). Minor morbidity included: blood transfusion (7); transient arrythmias (2); atelectasis requiring bronchoscopy (2); seroma (1); diaphragmatic patch overdistension (1); Bernard- Horner syndrome (1). Overall (minor plus major) morbidity rate was 50%. At definitive histology the pre-operative staging resulted incorrect in 19 of the 30 patients: 18 patients were understaged for one or multiple of the following parameters: macro/microscopic multifocal parietal wall infiltration (13); N 2 (8); mediastinal or posterior-inferior diaphragmatic invasion (4). Macro-microscopic radicality (R 0 ) was achieved in 10 cases; 11 cases turned out with positive resection margins (R 1 ), and macroscopic residual tumor (R 2 ) was left in 9 patients. After EPP 71% of the operated surviving patients have completed the adjuvant treatment; no major toxicity occurred so that the post-operative programme had to be suspended. Follow-up is complete in 26 patients (2 post-op deaths excluded; 2 patients not evaluable) and ranged between 1 and 49 (median 15) months: 11 patients are still alive and disease-free; 15 are dead (5 for other causes and 10 for recurrence/progression of mesothelioma). Median survival was 19 months. The overall 3-year survival was 33% and the 5-year survival was 13% (fig.1). For more favourable cases (epithelial, N 0-1 radically resected) the 5-year survival was 60% (fig. 2). Of the 5/15 patients operated since 3 or more years and still living at 36 months from surgery, 2 are epithelial and stage I (1 T1a and 1 T1b); 2 stage II (1 epithelial, 1 mixed); 1 stage III, epithelial. All these cases resulted R 0. Therefore at the 3-year follow-up landmark of actual, and not only the projected survival, we find alive and disease-free all pi and pii stages; 11% of piii and none of piv stages. 74
V. Pagan, A. Busetto, P. Fontana, et al: Trimodality treatment of malignant pleural mesothelioma Fig. 1. Kaplan-Mejer overall survival analysis Fig. 2. Kaplan-Mejer overall survival of patients (7) with epithelial type histology, N 0-1, radically excised Among the 26 patients with complete follow-up, 11 had disease progression/recurrence (that involved the homolateral hemithorax in 11 cases, the abdomen in 5, the contralateral hemithorax in 3); the brain was the only distant site with metastasis a. a After this paper was accepted, 3 other patients have been operated on, bringing the total to 39, 36 of whom can be evaluated. The Kaplan-Meier 5-year survival rate is presently at 19%, and it is 50% for epithelial, non N 2, R 0 cases 75
Eur. J. Oncol. Library, vol. 3 Discussion The EEP operation, in spite of any meticulous preoperative selection, implies 4 the removal of an entire anatomical district and is associated with a formidable incidence of complications, in particular an operative mortality 4-7 between 5 and 7.5%, reduced by Sugarbaker 3 to an outstanding 3.8%. Our mortality, including the in-hospital fatalities, is 6.6% and therefore still less than what is commonly accepted (7%) as a maximum after a standard pneumonectomy for lung cancer 2. Even limiting our analysis to the 30 patients completely evaluable (out of the 33 operated on), the 3-year survival of 30% as previously reported 5 (and 25% disease-free) appears promising and corresponding to that reported by Sugarbaker 3. The same reproducibility of results 3 are confirmed for the projected 5-year survival (13%) and the 60% for the patients with epithelial type, N 0-1, radically resected (fig. 2). Worthy of note is the fact that even apparently too advanced disease (such as invasion of pericardium or thoracic fascia) classified as II or III IMIG stage still can obtain middle or long term cure. Our results confirm that the natural history of stage I and II MPM can be favourably modified by the trimodality treatment and therefore the implementation of early diagnosis, even if present screening methods are limited, is critical for a better prognosis as for any solid tumour of the chest. In our series, 40% of the patients exhibited recurrence of the disease in the form of locoregional invasion in the same or in the contralateral hemithorax or in the abdomen, due to the peculiar MPM serosal diffusion or to cell seeding during surgery. At any rate it is absolutely mandatory to achieve a better post-surgical local control 8. Rusch 7 reports a 3-fold decrease of local recurrence in stage I and II with post-operative 50 Gy RT, and a 3-year survival of 30%. Provided it is performed by dedicated surgical equipes, operative complication rate of EPP has been progressively decreasing, and some Authors 2 consider it as the best palliative treatment available at present, as it permits adjuvant therapies, which in turn increase survival and quality of life. In our experience we have to emphasize that symptoms of recurrence became relevant mostly 3 months before death and only in half of the deceased patients hospitalisation became necessary, which compares very favourably with the miserable life of patients whose asphyxiating MPM is left uncontrolled. In conclusion, our prospective study replicates the results at 3 and 5 years reported by Sugarbaker et al 3 with the trimodality treatment of malignant pleural mesothelioma. References 1. Merler E, Logazio C, Biggeri A. Andamento temporale della mortalità per tumore primitivo pleurico e incidenza del mesotelioma pleurico in Italia. Epidemiol Prev 1999; 23: 316-26. 2. Rusch VW. Indications for extrapleural pneumonectomy. Chest Surg Clin North Am 1999; 2: 237-8. 3. Sugarbaker DJ, Flores MA, Jaklitsch MT, et al. Resections 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. 4. Pagan V, Cappelli R. Trattamento trimodale del mesotelioma pleurico: riproducibilità prospettica di risultati. Chirurgia Italiana 2003; 55: 13-20. 5. Pagan V. Trattamento trimodale prospettico del mesotelioma pleurico: sopravvivenza a tre anni. Rass Patol Appar Resp 2002; 17: 178-85. 6. Maggi G, Casadio C, Giobbe R, et al. Malignant pleural mesothelioma: results of 66 patients operated on during the last 4 years. J Cardiovasc Surg 2002; 43 suppl. 1: 126-9. 7. Rusch VW. A phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for MPM. J Thorac Cardiovasc Surg 2001; 122: 788-95. 8. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant mesothelioma. Ann Thorac Surg 1997; 63: 334-8. 76