Japanese Journal of Clinical Oncology Advance Access published online on January 8, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn145
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author (2009). Published by Oxford University Press. All rights reserved
A Feasibility Study of Induction Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Postoperative Hemithoracic Radiation for Malignant Pleural Mesothelioma
1 Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka
2 Department of Thoracic Surgery, Hyogo Cancer Center, Hyogo
3 Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima
4 Department of Radiation Oncology, Hyogo Cancer Center, Hyogo
5 Department of Radiation Oncology, Hyogo College of Medicine, Hyogo
6 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
For reprints and all correspondence: Takashi Nakano, Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan. E-mail: t-nakano{at}hyo-med.ac.jp
Received July 14, 2008; accepted November 30, 2008
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
A prospective multi-institutional study has been commenced in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable malignant pleural mesothelioma. The study was initiated on May 2008 and 40 patients will be recruited over 3 years. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. Secondary endpoints include treatment completion rate, adverse events, response rate by chemotherapy and 2-year overall and relapse-free survival.
Key Words: extrapleural pneumonectomy • induction chemotherapy • radiotherapy • malignant pleural mesothelioma
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
Optimal management for resectable malignant pleural mesothelioma (MPM) continues to be a topic of ongoing debate, with large agreement in terms of poor disease control by any single-modality therapy alone. Current standard for possible cure of the disease has shifted to a multi-disciplinary approach combining extrapleural pneumonectomy (EPP) with chemotherapy and/or radiotherapy (RT). However, the perioperative mortality of EPP has been reported as up to 7% in recent series (1), suggesting a careful management of this approach. Sugarbaker et al. have published their landmark experience of their trimodality regimen with EPP followed by adjuvant chemotherapy and RT (2), whereas others reported the difficulty in providing postoperative treatment in this group of patients (3). These findings have spurred a neoadjuvant strategy to MPM and led investigators to carry out single-institutional studies of induction chemotherapy with the combination of gemcitabine plus cisplatin, which has shown an encouraging response rate for advanced MPM, followed by EPP and adjuvant RT (4,5). Subsequently, upon the recent establishment of the combination of pemetrexed plus cisplatin (PC) as the new standard in systemic therapy for advanced MPM (6), a multi-institutional single-arm study of the combination of induction PC, EPP and postoperative RT is currently underway in the USA (7). This study will provide initial data on trimodality therapy for MPM using induction PC. An interim report of the study has indicated that 67% of enrolled subjects (50 out of 75) completed surgery and 57% proceeded to RT, although the proportion of patients who completed RT is still unknown.
At the present stage, a trimodality strategy with induction chemotherapy is considered to be a best promising therapeutic option for potentially resectable MPM. However, its feasibility in a multi-institutional setting remains uncertain. In addition, to date, there have been no clinical trials in Asia on multi-modality therapy or even on EPP alone to treat MPM. There is an urgent need of available prospective data for this approach in Asian MPM patients in a multi-institutional setting. In view of this, we have launched a feasibility study of induction PC, EPP and postoperative RT for resectable MPM. Our study is basically similar to the US study but has key differences as follows: (i) we define two primary endpoints, complete resection rate by EPP and treatment-related mortality, while the US study determines pathological complete resection (pCR) rate as the primary outcome measure; (ii) two studies use different doses of cisplatin (60 and 75 mg/m2) and (iii) intensity modulated radiation therapy (IMRT) is not allowed in our study although the US study permits.
The study protocol was approved by the protocol review committee and activated on 15 May 2008. The study has been registered at the UMIN Clinical Trials Registry as UMIN000001154 (http://www.umin.ac.jp/ctr/index.htm).
|
PROTOCOL DIGEST OF THE STUDY |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
Purpose
The aim of this study is to evaluate the feasibility of multi-modality therapy for resectable MPM, comprised induction PC followed by EPP and postoperative RT, in terms of treatment compliance and safety.
Study Setting
A multi-institutional, single-arm study.
Endpoints
The primary endpoints are (i) macroscopic complete resection (MCR) rate by EPP and (ii) treatment-related mortality. MCR is defined as the surgical removal of all tumor tissue visible to surgeons who conduct the EPP procedure (8). Treatment-related death is defined as any death occurring within 30 days after cessation or completion of the trimodality treatment, not related to disease progression. Secondary endpoints are (i) proportion of patients with completion of trimodality therapy, (ii) incidence of adverse reactions during trimodality therapy, (iii) response rate for induction chemotherapy evaluated by a modified version of the Response Evaluation Criteria in Solid Tumors [modified RECIST (9)], (iv) 2-year overall survival rate in all eligible patients and (v) 2-year relapse-free survival rate in patients with MCR.
Eligibility Criteria
Inclusion Criteria
Patients are eligible for the trial if they have a histologically confirmed diagnosis of MPM, including all subtypes and clinical T0–3, N0–2, M0 disease considered to be completely resectable. Other requirements are as follows: no prior treatment with chemotherapy, surgery or RT for the disease; age between 20 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; a predicted postoperative forced expiratory volume in 1 s of >1000 ml; adequate bone marrow, hepatic, renal, cardiac and respiratory functions; a life expectancy of >12 weeks; and written informed consent.
Exclusion Criteria
Patients are excluded if they meet any of the following criteria: serious systemic complications including poorly controlled diabetes or hypertension, active infectious diseases, interstitial pneumonia or lung fibrosis; simultaneous or metachronous (within 5 years) double cancers; serious drug allergy or hypersensitivity to any drugs; pregnancy or breast-feeding; Grade 2 or greater peripheral neuropathy at registration; and considered as clinically inappropriate for registration.
Treatment Methods
Induction Chemotherapy
Induction chemotherapy consists of three cycles of pemetrexed at 500 mg/m2 followed by cisplatin 60 mg/m2 on Day 1, given every 21 days. Folic acid (0.5 mg per oral daily) and vitamin B12 (1 mg intramuscularly every 9 weeks) are administered beginning 1–3 weeks before the first dose of chemotherapy and continued throughout the induction chemotherapy. Dose adjustments of chemotherapy are required for renal and nonhematologic toxicity as well as hematologic effects. Dose delays up to 42 days are permitted for recovery from drug toxicity.
Tumor response is assessed by computed tomography (CT) after completion of neoadjuvant therapy using unidimensional measurement of the pleural thickness perpendicular to the chest wall or mediastinum and modified RECIST criteria (9).
Extrapleural Pneumonectomy
All patients undergo EPP within 42 days after the last dose of induction chemotherapy unless there is progression of disease or deterioration of organ functions that would make the surgery intolerable. EPP is defined as an en-bloc resection of the entire pleura, lung, ipsilateral diaphragm and pericardium (10). A systematic hilar and mediastinal lymphadenectomy is preferred. Patients found to have a multi-level invasion of the chest wall or mediastinal structures at thoracotomy will not be resected and treated off the protocol.
Postoperative RT
Adjuvant hemithoracic RT is performed within 12 weeks after surgery. Patients receive three-dimensional conformal RT by using a linear accelerator for 6–20 MV photon energies. A total dose of 54 Gy in 30 fractions of 1.8 Gy/day is delivered. The target volume includes the hemithorax and chest wall incisions. Cerrobend blocks limit the dose to the liver, heart and stomach, and electrons are used in blocked regions to dose the diaphragm and chest wall adequately. The spinal cord is protected after 41.4 Gy.
Study Design and Statistical Methods
Sample size was determined according to exact binominal test for MCR rate (%MCR), which is one of the primary endpoints. The target size of 40 eligible patients assures a statistical power of 0.885 for the test when expected and acceptable lowest %MCRs are 70% and 50%, respectively, with a one-sided 
level of <0.10. For treatment-related mortality (TRM), the other primary endpoint, we consider that 10% is an acceptable upper limit. The study will be terminated if the total number of treatment-related death reaches five, indicating that a point estimate for TRM exceeds 10% of the planned sample size. Interim monitoring based on Bayesian predictive probability for %MCR is conducted twice during the trial, where such the probability will estimate how likely a final result of the study would reject the null hypothesis that %MCR is less than 50%. The planned accrual period is 3 years. Follow-up will extend 3 years after the completion of patient accrual.
Study Monitoring
The Data and Safety Monitoring Committee (DSMC) independently reviews interim analysis reports and makes recommendations to investigators regarding continuation, termination or modification of the trial. Protocol compliance, safety and study progress will also be monitored by the DSMC.
|
PARTICIPATING INSTITUTIONS |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
A total of 18 institutions in Japan with certified specialists in oncology, surgery and radiation therapy will be participated in this trial.
|
Funding |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
This study is supported by the Special Coordination Funds for Promoting Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
|
Conflict of interest statement |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPROTOCOL DIGEST OF THE...PARTICIPATING INSTITUTIONSFundingConflict of interest statementReferences |
|---|
1 Stewart DJ, Martin-Ucar AE, Edwards JG, West K, Waller DA. Extra-pleural pneumonectomy for malignant pleural mesothelioma: the risks of induction chemotherapy, right-sided procedures and prolonged operations. Eur J Cardiothorac Surg (2005) 27:373–8.
2 Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, et al. Resection margins extrapleural nodal status cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg (1999) 117:54–63.
3 Taverna C, Stahel RA, Bodis S, Russi EW, Weder W. Malignant pleural mesothelioma: trimodality therapy in a single center. Ann Oncol (2000) 11:123.
4 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.
5 Flores RM, Krug LM, Rosenzweig KE, Venkatraman E, Vincent A, Heelan R, et al. Induction chemotherapy extrapleural pneumonectomy postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol (2006) 1:289–95.[CrossRef][Web of Science][Medline]
6 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.
7 Krug LM, Pass H, Rusch VW, Kindler HL, Sugarbaker D, Rosenzweig K, et al. A multicenter U.S. trial of neoadjuvant pemetrexed plus cisplatin (PC) followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT) for stage I-III malignant pleural mesothelioma (MPM). J Clin Oncol (2007) 25. Abstract# 7561.
8 Sugarbaker DJ. Macroscopic complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma. J Thorac Oncol (2006) 1:175–6.[CrossRef][Web of Science][Medline]
9 Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol (2004) 15:257–60.
10 Sugarbaker DJ, Mentzer SJ, Strauss G. Extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. Ann Thorac Surg (1992) 54:941–6.[Abstract]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||