CHIRURGIA ITALIANA 2004 - VOL. 56 N. 6 PP 781-786 781 Pleurectomy/decortication plus chemotherapy: outcomes of 40 cases of malignant pleural mesothelioma FLAVIO COLAUT a, LAMBERTO TONIOLO a, GIOVANNI VICARIO b, ANTONIO SCAPINELLO c, CRISTIANA VISENTIN d, PAOLO MANENTE b, CARLO A. SARTORI a a Thoracic Surgery b Medical Oncology c Pathology d Biostatistics City Hospital - Castelfranco Veneto (Treviso) Riassunto Il mesotelioma pleurico maligno presenta a tutt oggi una prognosi infausta. Nonostante la buona selezione dei pazienti e un approccio terapeutico multimodale il controllo locale della malattia rimane un problema. Sia che i pazienti vengano sottoposti a pleurectomia/decorticazione o a pneumonectomia extrapleurica, la progressione di malattia si verifica in tutti i casi. Il ruolo della chemio/radioterapia rimane dubbio. Tra il 1985 e il 2002 40 pazienti sono stati trattati con pleurectomia/decorticazione associata a chemioterapia intracavitaria. La pleurectomia è stata eseguita per rimuovere la massa tumorale o per ottenere un debulking significativo. La parziale o totale pleurectomia della pleura viscerale è dipesa dall estensione della malattia. La chemioterapia sistemica è stata praticata al verificarsi della progressione di malattia. Tutti i pazienti hanno avuto progressione di malattia, sempre dovuta a recidiva locale. Per le valutazioni statistiche è stato utilizzato il metodo Kaplan-Meyer. La terapia è stata relativamente ben tollerata e la qualità di vita dopo l intervento soddisfacente. Fino a quando non si è verificata progressione di malattia i pazienti non hanno accusato dolore toracico importante, versamento pleurico o dispnea. La sopravvivenza globale è stata del 28% a 2 anni e del 17% a 3 anni. L istologia è risultata essere l unico fattore prognostico significativo. La bassa morbidità e mortalità riportate nel periodo intra/perioperatorio e la buona qualità di vita dopo il trattamento rendono la pleurectomia/decorticazione associata alla chemioterapia intracavitaria e sistemica non solo un approccio radicale nei primi stadi, ma anche un buon trattamento palliativo nel mesotelioma pleurico avanzato, specialmente nei pazienti non candidabili a pneumonectomia extrapleurica. Parole chiave: mesotelioma pleurico, pleurectomia/decorticazione, chemioterapia Correspondence to: Dr. Flavio Colaut - Thoracic Surgery - City Hospital - Via Ospedale, 1-31033 Castelfranco Veneto (Treviso).
782 PLEURECTOMY/DECORTICATION PLUS CHEMOTHERAPY Summary Pleurectomy/decortication plus chemotherapy: outcomes of 40 cases of malignant pleural mesothelioma. F. Colaut, L. Toniolo, G. Vicario, A. Scapinello, C. Visentin, P. Manente, C.A. Sartori Malignant pleural mesothelioma still has a dismal prognosis. Despite good patient selection and a multimodality approach, local disease control remains a problem. Whether submitted to pleurectomy/decortication or to extrapleural pneumonectomy, disease progression occurred in all 40 patients in this study. The role of radio-chemotherapy remains uncertain. Between 1985 and 2002, 40 patients underwent pleurectomy/decortication in combination with intracavitary chemotherapy. Pleurectomy was performed to remove all gross tumour, or to achieve significant debulking. Partial or total pleurectomy of the visceral pleura depended on the extent of the tumour. Systemic chemotherapy was administered when disease progression occurred. All 40 patients had disease progression, due in all cases to local recurrence. The Kaplan-Meyer method was used for statistical evaluation. Treatment was relatively well tolerated and quality of life satisfactory. Until disease progression, no important chest pain, pleural effusion, or dyspnoea occurred. Overall survival was 28% at 2 years and 17% at 3 years. Histological sub-type is the only significant prognostic factor for survival. Low morbidity and mortality and good quality of life after treatment make pleurectomy/decortication with intracavitary and systemic chemotherapy not only a radical approach in early stages, but also a good palliative treatment in advanced malignant pleural mesothelioma, especially in patients who are unsuitable for extrapleural pneumonectomy. Key words: pleural mesothelioma, pleurectomy/decortication, chemotherapy Chir Ital 2004; 56, 6: 781-786 Introduction Despite numerous attempts to find an effective treatment for malignant pleural mesothelioma in the last 20 years, its prognosis remains dismal. Surgical resection with chemotherapy and radiotherapy seems to significantly improve overall survival in well-selected patients 1-3. But despite good patient selection and a multimodality approach, local disease control remains a problem. Neither intracavitary and/or systemic adjuvant chemotherapy 4-6, nor other recent strategies, such as immunochemotherapy and photodynamic therapy 7, are able to prevent local recurrence after pleurectomy/decortication or extrapleural pneumonectomy. Discouraging results have also been obtained with adjuvant low-dose radiotherapy 8 or high-dose radiotherapy after extrapleural pneumonectomy 9-11. All this suggests we are still a long way from finding a treatment for malignant pleural mesothelioma. Materials and methods From 1985 to 2002, 40 patients with malignant pleural mesothelioma were admitted for pleurectomy/decortication combined with intracavitary chemotherapy. The chemotherapeutic drug of choice has changed over this time period. Until 1994 intracavitary chemotherapy consisted in the administration of cisplatinum + cytarabine C (Ara C) 12,13 (18 patients treated). Later, interferon (IFN) alpha-2a replaced Ara C (22 patients treated), as its antiproliferative activity on malignant pleural mesothelioma cells has been well demonstrated, and the combination of IFN with cisplatinum has revealed improved cytotoxic activity on mesothelioma cells 14,15. The patients were 28 males and 12 females, aged 38-78 years (mean age: 60 years). Surgical pleurectomy was performed to remove all gross tumour or to obtain significant debulking. Partial or total pleurectomy of the visceral pleura depended on the extent of the tumour. The histological subtypes were 17 epithelial, 19 mixed, and 4 sarcomatous. Performance status: all patients were 2 according to the ECOG scale. Twenty-five patients received systemic chemotherapy on disease progression: Sixteen patients were treated with adryamicin and mytomicin until 1994. Four patients received carboplatin and IFN alpha-2a from 1995 to 1996. Later, the other 5 patients received carboplatin and gemci-
CHIRURGIA ITALIANA 2004 - VOL. 56 N. 6 PP 781-786 783 tabin. The remaining 15 patients received no systemic chemotherapy due to co-morbidity (non-optimal renal clearance, inadequate bone marrow reserve, cardiovascular disease) and/or poor compliance. Because of the poor radio-responsiveness of malignant pleural mesothelioma, low-dose radiotherapy was administered for pain relief in only 10 patients with disease progression not responding to other medical care. The Kaplan-Meier method was used for statistical evaluation. Results Postoperative staging (redone for early patients) was done according to the TNM staging system as updated by the IMIG in 1995 16. Twenty-four patients were stage I, 7 patients stage II, 4 patients stage III, and 5 patients stage IV. The Kaplan-Meier method demonstrated 2-year and 3-year overall survival rates of 28% and 17%, respectively (Fig. 1). At 2 years postoperatively only 14% of the patients had no disease progression (Fig. 2). Disease progression was due in all cases to local disease recurrence. Histological subtype was the only significant (p = 0.047) prognostic factor for survival (Fig. 3), but does not influence disease progression (Fig. 4). Two years postoperatively, 20% of patients with the epithelial subtype, and 10% of those with mixed histology had disease progression, while the 4 sarcomatous patients had progression of disease within 8 months of surgery. T was not a significant prognostic factor even though 54% of the T1a/1b patients (24 patients) had disease progression 6 months postoperatively, while 65% of the T2/T3/T4 patients (16 patients) had progression of disease before 6 months. Complications: 2 patients had renal failure (one died of tubulonecrosis). After surgery and until disease progression, none of the patients had important chest pain, pleural effusions and/or dyspnoea. Quality of life was also satisfactory. Discussion Our data confirm the dismal prognosis for malignant pleural mesothelioma. Only histological subtype constitutes a reliable prognostic factor. In the past, pleurectomy/decortication plus intracavitary and systemic chemotherapy was a good method for symptom palliation. The treatment was quite well tolerated, low mortality and morbidity were reported, and patients had a satisfactory quality of life with no major chest pain, pleural effusions or dyspnoea until disease progression occurred. The length of hospital stay was acceptable (mean: 12 days). Survival has always been determined by disease progression due to local recurrence. In conclusion, pleurectomy/decortication associated with intracavitary and systemic chemotherapy can still be considered not only a radical approach in early stages, but also a good palliative treatment in advanced malignant pleural mesothelioma espe- 0 1 2 3 4 5 6 Legend: Product Limit Estimate Curve Censored Observation Fig. 1. Patients alive 2 years after surgery 28%, 3 years after surgery 17%.
784 PLEURECTOMY/DECORTICATION PLUS CHEMOTHERAPY Fig. 2. Only 14% of patients had no disease progression 2 years postoperatively; the percentage decreases to 5% at 3 years postoperatively. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Legend: Product Limit Estimate Curve Censored Observation 0 1 2 3 4 5 6 STRATA: ISTO = 1 ISTO = 2 Censored ISTO = 1 ISTO = 3 Fig. 3. Graph showing that survival differs considerably according to histological subtype (p = 0.047). Two years after surgery 43% of patients with the epithelial subtype (isto = 1) were alive; at 3 years this percentage decreases to 36%. Fifteen percent of patients with the mixed subtype (isto = 3) were still alive 2 years after surgery, and 5% 3 years postoperatively. Sarcomatous patients (isto = 2) were only 4 in number, and all died during within less than 1 year of surgery. cially in patients unsuitable for extrapleural pneumonectomy. Optimal diagnosis, pre-operative staging (VATS, MRI, PET), initial disease, epithelial histology, absence of co-morbidity, no contraindications to chemotherapy, and good performance status, will probably make for better outcomes. Acknowledgement The authors wish to thank Mrs Barbara Silvestri-Thomson (Bpharm; MPS, NZ), North Shore Hospital, Auckland, NZ, for kindly reviewing the English.
CHIRURGIA ITALIANA 2004 - VOL. 56 N. 6 PP 781-786 785 Fig. 4. Graph showing that histological subtype does not affect disease progression (p = 0.12). 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 STRATA: ISTO = 1 ISTO = 2 Censored ISTO = 1 ISTO = 3 References 1. Rush VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996; 111: 815-26. 2. Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Arrison L, Bains MS, Downey RJ, Ginsberg RJ. A phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for malignant pleural mesothelioma. J Thor Cardiov Surg 2001; 122: 788-95. 3. Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, Decamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ. 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 Thor Cardiov Surg 1999; 117: 54-65. 4. Pass HI, Kranda K, Temeck BK, Feverstein I, Steinberg SM. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997; 4: 215-22. 5. Rusch VW, Saltz L, Venkatraman E, Ginsberg R, McCormack P, Burt M, Markman M and Kelsen D. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 1994; 12: 1165-73. 6. Rice TW, Adelstein DJ, Kirby TJ, Saltarelli MG, Murthy SR, Van Kirk MA, Wiedemann HP, Weick JK. Aggressive multimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1994; 58: 24-9. 7. Pass HI, Temeck BK, Kranda K, Thomas G, Russo A, Smith P, Friauf W, Steinberg SM. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997; 4: 628-33. 8. Baldini EH, Recht A, Strauss GM, Decamp MM Jr, Swanson SJ, Liptay MJ, Mentzer SJ, Sugarbaker DJ. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997; 63: 334-8. 9. Maasilta P. Deterioration in lung function following hemithorax irradiation for pleural mesothelioma. Int J Radiat Oncol Biol Phys 1991; 20: 433-8. 10. De Graaf-Strukowska L, Van Der Zee J, Van Puten W, Seen S. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura a single institution experience with 189 patients. Int J Radiat Oncol Biol Phys 1999; 45: 511-6. 11. Kutcher GJ, Kestler C, Greenblatt D, Brenner H, Hilaris BS, Nori D. Technique for external beam treatment for mesothelioma. Int J Radiat Oncol Biol Phys 1987; 13: 1747-52.
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