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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3451-3457 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.071 Neoadjuvant Chemotherapy Followed by Extrapleural Pneumonectomy in Malignant Pleural MesotheliomaFrom the Division of Thoracic Surgery, Clinic and Policlinic for Radiation Oncology, and Clinic and Policlinic for Oncology, University Hospital, Zurich, Switzerland Address reprint requests to Rolf Stahel, MD, Clinic and Policlinic for Oncology, University Hospital, CH-8901 Zurich, Switzerland; e-mail: rolf.stahel{at}usz.ch
PURPOSE: To investigate neoadjuvant chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy with or without radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had MPM with clinical stage T1-3, N0-2, M0 disease considered to be completely resectable and a WHO performance status of 0 to 2. Neoadjuvant chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1 and gemcitabine 1,000 mg/m2 on days 1, 8, and 15, given every 28 days. Surgery had to consist of a complete extrapleural pneumonectomy, including resection of pericardium and diaphragm. Postoperative radiotherapy was to be considered for all patients. RESULTS: Nineteen patients with MPM were included in this pilot study. According to the European Organization for Research and Treatment of Cancer prognostic score, two patients were in the good prognosis group, and 17 patients were in the poor prognosis group. The response rate to neoadjuvant chemotherapy was 32%. The major toxicity was thrombocytopenia. Extrapleural pneumonectomy was performed in 16 patients with no perioperative mortality. Major surgical complications occurred in six patients, and all were treated successfully. Thirteen patients received postoperative radiotherapy. The median survival time was 23 months. Two patients remain alive and free of disease 41 and 38 months after initiation of therapy. CONCLUSION: For patients with potentially operable MPM, the availability of active and well-tolerated chemotherapy regimens, the fact that extrapleural pneumonectomy can be safely performed after neoadjuvant chemotherapy in an experienced center, and the promising results regarding survival in our pilot study warrant further investigation of the role of neoadjuvant chemotherapy in a multimodality strategy.
There is no uniformly accepted standard therapy for malignant pleural mesothelioma (MPM). The best-documented potentially curative approach to MPM has been extrapleural pneumonectomy, followed by chemotherapy and radiotherapy (trimodality approach) in selected patients with earlier stages of disease.1 Extrapleural pneumonectomy involves the removal of the complete pleural envelope and all of its contents, including the ipsilateral lung, diaphragm, and a portion of the pericardium. The perioperative mortality of this procedure was reported to be up to 31% in an initial series2 and 15% in the 1980s,3 but with more experience and better preoperative management, the perioperative mortality has decreased to 4% to 7% in recent series.4-8 Extrapleural pneumonectomy followed by adjuvant combination chemotherapy and radiotherapy (trimodality approach) has been pioneered by Sugarbaker et al.9 A recent update from this group included 183 patients who were to receive the trimodality approach.4 The median survival time in the 176 patients alive after surgery was 19 months, and the estimated 2- and 5-year survival rates were 38% and 15%, respectively. Our group initiated a trimodality approach for MPM in 1996, which was modeled after the report of Sugarbaker et al. Over a 2-year period, 12 patients with MPM underwent extrapleural pneumonectomy followed by four cycles of chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (10 patients) and radiotherapy (eight patients).10 The median survival was 13 months, and all patients eventually died of recurrent disease. The difficulty in providing adjuvant therapy as intended in this group of patients led us to investigate a neoadjuvant approach. We felt that such an approach was justified because of our good experience with neoadjuvant chemotherapy in patients with stage IIIA non–small-cell lung cancer11 and the availability of an apparently effective regimen for patients with advanced MPM in terms of induction of remission. In 1999, Byrne et al12 reported a 47% response rate and a median survival time of 44 weeks in 21 patients with advanced MPM treated with cisplatin and gemcitabine. Furthermore, we hypothesized that maximal activity of the drug will be at the contact surface of the tumor with the healthy tissue, which is exactly at the plane of resection. Here we report the experience of our pilot study with the first 19 MPM patients treated with neoadjuvant chemotherapy, including cisplatin and gemcitabine, followed by extrapleural pneumonectomy with or without consolidating radiotherapy from May 1999 until August 2000.
Patients were eligible for the study if they had a histologically confirmed diagnosis of MPM, including all subtypes, and clinical T1-3, N0-2, M0 disease considered to be completely resectable as evaluated by our thoracic oncology tumor board.13 Other requirements included a WHO performance status of 0 to 2, a serum creatinine within normal limits, no major organ dysfunction, a predicted postoperative forced expiratory volume in 1 second more than 40% based on spirometry, and informed consent. Patients were not eligible if they had had prior pleurectomy or lung resection (except for diagnostic purposes), contraindications to surgery, or prior chemotherapy. Neoadjuvant chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1 and gemcitabine 1,000 mg/m2 on days 1, 8, and 15, given every 28 days. Dose modification was mandated as follows. Cisplatin was to be reduced to 50% for a serum creatinine more than 120 µmol/L and omitted for a serum creatinine more than 150 µmol/L. The dose of gemcitabine was to be reduced to 75% for a neutrophil count less than 1.5 x 109/L or a platelet count less than 100 x 109/L and omitted for a neutrophil count less than 1.0 x 109/L or a platelet count less than 75 x 109/L. Tumor response was assessed by computed tomography (CT) after completion of neoadjuvant therapy using unidimensional measurement of the pleural thickness perpendicular to the chest wall and Response Evaluation Criteria in Solid Tumors.14 All patients were scheduled to undergo extrapleural pneumonectomy. Reasons for inoperability were a predicted postoperative forced expiratory volume in 1 second less than 40%, based on immediate preoperative spirometry and lung perfusion scan, and unresectability as a result of tumor progression documented on chest CT scan after chemotherapy. The extrapleural pneumonectomy was defined as an en-bloc resection of the entire pleura, lung, ipsilateral diaphragm, and pericardium. It was performed via an extended anterolateral thoracotomy through the bed of the resected sixth rib. Previous biopsy sites were handled with limited chest-wall resection. The pleural sac was bluntly dissected in the extrapleural plane between the parietal pleura and the endothoracic fascia. In cases of localized chest-wall infiltration, this region was excised in total with the specimen or subsequently resected. From the apex, the mediastinal pleura was stripped down towards the hilum. Anteriorly, the pericardium was opened and excised widely. Hilar structures were dealt with in a standard fashion, as in any intrapericardial pneumonectomy. Vessels, as well as the bronchus, were closed using stapling devices. The infracarinal lymph nodes were resected. Posteriorly, the extrapleural dissection was continued to the hilum with the dissection of the posterior pericardium. The diaphragm was completely dissected between the muscle and the peritoneum. The latter was sutured in case of a perforation. At the end, the diaphragm was resected at its insertion to the chest wall, enabling the removal of the whole tumor-containing structures. The diaphragm was replaced by a Mersilene mesh (Mersilene; Ethicon, Inc, Somerville, NJ), and the pericardium was reconstructed with a xenopericard patch (Supple Peri-guard; Synovis Surgical Innovations, St Paul, MN). Patients found to have a multilevel invasion of the chest wall or mediastinal structures at thoracotomy were not resected. Final pathologic staging was performed according to the tumor-node-metastasis staging system.13 Treatment planning for adjuvant radiotherapy was based on CT. Patients were to receive three-dimensional conformal radiotherapy using a 6-MV linear accelerator equipped with a multileaf collimator. Patients with a multilevel high-risk situation of residual mesothelioma received a radiation dose of 30 Gy to the ipsilateral hemithorax and a boost dose of 20 Gy. The boost dose was delivered to the area of highest risk (involved field), which was defined by the thoracic surgeon performing the operation. The fractionation schedule used was 2 Gy/d, five times a week. Radiation treatment was delivered with two equally weighted, opposed anteroposterior-posteroanterior fields, and critical organ structures were shielded with multileaf collimators. Patients with a single high-risk area, again defined by the thoracic surgeon performing the operation and based on histologically confirmed local infiltration beyond the endothoracic fascia, received involved-field radiotherapy of 45 to 60 Gy. Fractionation was 1.8 to 2 Gy/d, five times per week, using the same treatment technique. The total dose and fractionation varied according to the status of the resection margins after radical surgery and the planning target volume.
Twenty patients with MPM were treated from May 1999 until August 2000. One patient was excluded from the analysis because the examination of the extrapleural pneumonectomy specimen did not reveal mesothelioma and the final diagnosis after histologic review was fibromatosis with desmoplastic mesothelium. The characteristics of the other 19 patients are listed in Table 1. The median age was 57 years. Histology of the pleural biopsy specimen showed epithelial mesothelioma in 14 patients, sarcomatous mesothelioma in two patients, and biphasic mesothelioma in three patients. Clinical staging based on chest CT suggested T1 tumors in three patients, T2 tumors in 15 patients, and a T3 tumor in one patient. No patient had radiologic evidence of N2 disease or clinical or radiologic evidence of peritoneal extension or metastasis. The last eight patients of the series underwent mediastinoscopic evaluation. None of these patients had pN2 or pN3 disease. Using the European Organization for Research and Treatment of Cancer classification by taking into account the five prognostic factors of poor performance status (2 v 0-1), high WBC count (> 8.3 x 109/L at study entry), a definitive diagnosis of mesothelioma (all patients in this study), male sex, and histologic subtype (sarcomatous v epithelial or biphasic), two patients were in the good prognosis group, and 17 patients were in the poor prognosis group.15
Eighteen patients received the three courses of neoadjuvant chemotherapy as intended. In one patient, the third course was omitted because of thrombocytopenia. A dose reduction of gemcitabine because of hematologic toxicity was necessary in 18 (32%) of 56 cycles. The hematologic toxicities are listed in Table 2. None of the patients had to be admitted to the hospital for complications of chemotherapy. Six patients (32%) had a partial response to chemotherapy, seven patients had stable disease, and six patients had progressive disease.
Sixteen patients underwent extrapleural pneumonectomy as intended. The resection of the tumor containing pleura was generally more difficult after induction chemotherapy compared with primary surgery. The plane of dissection was obliterated by dense fibrosis, and this observation was also true for the mediastinum, especially along the aorta and the vena cava. The median duration of hospitalization was 17 days (range, 9 to 38 days). R0 resections (microscopically no residual tumor left) were achieved in 12 patients, and R1 resections (microscopically residual tumor left) were achieved in four patients. The pathologic stage after induction therapy (prefix y) of these patients was ypT1pN0 in two patients, ypT2pN0 in eight patients, ypT2pN1 in two patients, ypT2pN2 in one patient, and ypT3pN0 in three patients. Histology of the extrapleural pneumonectomy specimen showed epithelial mesothelioma in nine patients, sarcomatous mesothelioma in one patient, and biphasic mesothelioma in six patients. One patient with tumor progression after chemotherapy was judged inoperable at thoracotomy, and two patients did not undergo surgery because of massive tumor progression in one patient and cardiac risk factors in the other patient. There was no perioperative death; however, one patient with an otherwise uneventful course died of pulmonary embolism 7 weeks after surgery. After this event, it was decided to treat patients with prophylactic oral anticoagulation postoperatively for 3 months. Major complications included chylothorax in three patients (two on the right and one on the left side), thrombosis of the brachiocephalic vein in one patient operated on the left side, bronchopleural fistula on the right side in one patient on day 32, and pyothorax on the left side without evidence of bronchopleural fistula in another patient. Chylothoraces were treated successfully with total parenteral nutrition. The patient who suffered from a bronchopleural fistula was readmitted to hospital and was reoperated. Pyothorax occurred in one patient after insertion of a chest tube because of a mediastinal shift caused by chylothorax. Both patients required planned reoperations including radical debridement of the pleural cavity and packing with wet dressings of povidoneiodine. This was repeated in the operating room every second day. In both cases, the chest cavity was macroscopically clean after two reoperations. The bronchial stump insufficiency was closed and secured by omentopexy. Finally, the pleural space was obliterated with antibiotic solution. The technique is described in detail elsewhere.5 Three patients required rehospitalization within 30 days after surgery; two patients were rehospitalized for bleeding intrathoracically and retroperitoneally while on anticoagulation therapy; and one patient, who had not received oral anticoagulation therapy after the operation, was rehospitalized for pulmonary embolism 2 months after surgery. Thirteen patients were treated with postoperative radiotherapy. Six patients received hemithoracic radiotherapy, including four patients with a local boost. Seven patients received local radiotherapy to an area of risk identified by the surgeon (six patients at dose of 48 to 50 Gy and one patient with a pT3 tumor at a dose of 60 Gy). Reasons for no postoperative radiotherapy were no resection in three patients, early death in one patient, and ypT1 disease only in three patients. In general, postoperative hemithoracic and involved-field radiotherapy was well tolerated. No grade 3 to 4 toxicities were observed. In six of 13 patients (three poor prognosis and three good prognosis patients), grade 1 to 2 upper gastrointestinal toxicity was observed. One patient had a grade 2 pericarditis. There were 12 tumor relapses out of 13 patients treated with radiotherapy. Of the six patients treated with hemithorax plus or minus local boost radiation, the site of relapse was infield in three patients and outfield in three patients. Of the seven patients treated with involved-field radiotherapy to the high-risk area, five patients had a relapse within the radiotherapy field, and one patient had a relapse outside the radiotherapy field. Three years after the last patient entered onto the study, two patients were alive and free of disease 41 and 38 months after initiation of therapy. This included one patient with ypT2pN0R0 disease of epithelial type MPM at resection with partial response to neoadjuvant chemotherapy and local postoperative radiotherapy and one patient with ypT1N0R0 disease of sarcomatous type MPM at resection with a partial response to chemotherapy and local postoperative radiotherapy. One patient was alive with recurrent disease. He had stable disease after chemotherapy, ypT3pN0RO epithelial type MPM at resection, and local postoperative radiotherapy. The median time to confirmation of recurrent disease in the 16 patients who underwent extrapleural pneumonectomy was 16.5 months, with a range of 9 to 29 months (Fig 1). The survival curve for all 19 patients is depicted in Figure 2. The median survival was 23 months. The 1- and 2-year survival rates were 79% and 37%, respectively.
The use of neoadjuvant chemotherapy has been widely accepted as standard therapy for stage IIIA lung cancer and is under investigation as therapy for earlier stages of disease. The exploration of neoadjuvant chemotherapy can only be justified if a chemotherapy regimen with sufficient activity is available. We began our study after the publication of Byrne et al,12 who reported a response rate of 47% to cisplatin and gemcitabine in a series of 21 patients with MPM. These results were superior with regard to response compared with published results reviewed earlier,16 including the combination of mitomycin, doxorubicin, and cisplatin17 and the combination of mitomycin, vinblastine, and cisplatin.18 Also, the results were surprisingly far superior to either carboplatin or gemcitabine alone.19-21 Since this time, the activity of the combination of cisplatin and gemcitabine has been re-examined in a multicenter study. This study, which included 53 patients with pleural mesothelioma, reported a response rate of 33%, a median survival time of 11 months, and an improvement in quality-of-life measurements.22 An Italian study on 50 patients examined the combination of carboplatin and gemcitabine and reported a response rate of 26% and a median survival time of 66 weeks.23 Admittedly, it can be difficult to apply conventional response criteria in MPM because often a two-dimensional measurement of disease is not possible. Using Response Evaluation Criteria in Solid Tumors, the objective response rate in our series of patients was 32%, again providing confirmation of the activity of cisplatin and gemcitabine in this disease. For our trial, the schedule of gemcitabine administered on days 1, 8, and 15 every 4 weeks was used. With one exception, all of our patients were able to receive the three intended courses of neoadjuvant chemotherapy, which is not usually the case in adjuvant settings. The gemcitabine administration had to be reduced or omitted in 30% of treatment courses because of hematologic toxicity, which usually occurred on day 15. This is similar to the Australian multicenter study, in which 41% of gemcitabine administrations were omitted.22 Based on the hematotoxicity observed on day 15, it might be reasonable for future studies to change to a triweekly regimen with cisplatin on day 1 and gemcitabine on days 1 and 8, which is now generally used in non–small-cell lung cancer.24 As a consequence, the number of treatment courses could be increased to four in future studies. A big concern at the outset of our study was the question of whether the preoperative chemotherapy might adversely affect the resectability of the tumor and lead to higher perioperative morbidity. On the basis of our preliminary experience, we are pleased to state that we had no perioperative mortality, and the surgical complications were within the range of what is expected after these extensive resections. All complications could be corrected with adequate treatment. The presence of sarcomatous disease and extrapleural mediastinal nodal metastasis have been recognized as adverse prognostic factors for patients with MPM.25 We included in our study all subtypes of mesothelioma. Given the small number of patients, no subgroup analysis according to histology was performed. However, it is of note that one of our two patients who was alive and free of disease more than 2 years after therapy had sarcomatous type of mesothelioma, which also responded to neoadjuvant chemotherapy. Given this observation and the report of long-term survivors with sarcomatous mesothelioma in other series,4 we feel that patients with sarcomatous MPM should not be excluded from further studies with neoadjuvant chemotherapy. The series of Sugarbaker et al4 reported no long-term survivors when extrapleural lymph node metastases were present. Our study initially did not require mediastinoscopic evaluation of mediastinal disease. Because the correlation between CT and mediastinoscopic evaluation of lymph node metastasis is relatively poor and mediastinoscopy in MPM has a higher sensitivity and specificity than CT,26 we mandated this procedure during the later part of our study, although we remained aware of its limitation, especially regarding lymph nodes in the anterior mediastinum, paraesophageal, or subaortal regions. In five of the 16 patients who underwent extrapleural pneumonectomy, the histologic type of MPM differed from the original biopsy. It changed from epithelial to biphasic type in four patients and from biphasic to epithelial type in one patient. Whether this reflects a sampling error of the initial biopsy or a change in morphology as a result of the effect of chemotherapy remains to be determined. Radiotherapy can be effective for local palliation and has been of proven benefit for the prevention of relapse after thoracoscopy.27,28 Relapse in the ipsilateral hemithorax after extrapleural pneumonectomy has remained a major problem, despite the fact that adjuvant radiotherapy has been part of trimodality therapy since its inception with different fields and dose schedules used.29,30 Eight of 12 patients with a recurrence after radiotherapy had the site of recurrence within the field of radiation. Radiotherapy to the operated hemithorax with higher doses of up to 54 Gy has been reported to be tolerable and might decrease the rate of local failure.7 Whether such an approach is feasible after neoadjuvant chemotherapy and is indeed superior to local radiotherapy to high-risk areas needs to be confirmed in further studies. Since our study was initiated, several other regimens with activity in MPM have been reported. These reports include a series of 55 previously untreated patients who had a response rate of 20% and a median survival time of 11 months with oxaliplatin and raltitrexed,30 a series of 29 patients who had a response rate of 24% and a median survival time of 11 months with vinorelbine,31 and a series of 45 patients with stage II disease who had a response rate of 38% and a median survival time of 16 months to cisplatin, mitomycin, fluorouracil, and etoposide.32 Until recently, there has been no randomized study performed in MPM. On the basis of single-agent activity of pemetrexed in MPM observed in two phase I studies, a large prospective trial including 456 patients comparing cisplatin alone with cisplatin and pemetrexed was performed.33 The response was evaluated by measuring the thickness of the pleural rim at three different levels, as initially proposed by Byrne et al.12 Response and survival were significantly improved with combination therapy, with a response rate of 17% with cisplatin alone and 41% with cisplatin and pemetrexed, and a median survival time of 9.3 months with cisplatin alone versus 12.1 months with the combination of cisplatin and pemetrexed. One fifth of the patients had stage I or stage II disease; however, the survival of this group was not given separately. Our study reports a median survival time of 23 months for patients with MPM treated with neoadjuvant cisplatin and gemcitabine, extrapleural pneumonectomy, and optional radiotherapy by intent-to-treat analysis. These results are far superior to our own experience with extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy, where the median survival time was only 13 months.10 The survival time was also slightly better than the largest report of trimodality chemotherapy by Sugarbaker et al,4 in which the median survival time for 176 patients was 19 months; however, this survival time excluded the seven patients from the analysis who died perioperatively. Chemotherapy was well tolerated, and there was no perioperative mortality in our trial. Two patients remain alive and free of disease more than 3 years after the start of treatment. On the basis of these favorable results, we conducted a Swiss multicenter study on neoadjuvant chemotherapy in MPM that has just been closed after completing the planned accrual of 62 patients. This study should determine the feasibility of this approach in a multicenter setting and will provide information about the quality of life of patients who have undergone this aggressive treatment. The approach to MPM is changing. Given the survival benefit of cisplatin and pemetrexed over cisplatin alone,33 the improvement of quality of life with chemotherapy,34,18 and recent phase II studies documenting the activity of combination chemotherapies, observation and supportive care alone may no longer be justified for most patients with advanced MPM. For patients with potentially operable disease, the availability of active and well-tolerated chemotherapy regimens, such as cisplatin and gemcitabine or cisplatin and pemetrexed, the fact that extrapleural pneumonectomy plus postoperative local radiotherapy can be safely performed after neoadjuvant chemotherapy in an experienced center, and the promising results regarding survival in our pilot study warrant further investigation into the role of neoadjuvant chemotherapy in patients with MPM.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Rolf A. Stahel, Eli Lilly & Co.
W.W. and P.K. contributed equally to this work. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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33. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636-2644, 2003 34. Gralla RJ, Hollen PJ, Liepa AM, et al: Improving quality of life in patients with malignant pleural mesothelioma: Results of the randomized pemetrexed and cisplatin vs. cisplatin trial using the LCSS-meso instrument. Proc Am Soc Clin Oncol 22:621, 2003 (abstr 2496) Submitted October 8, 2003; accepted June 1, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
