1 Lung Cancer (2005) 49S1, S123 S127 Consensus report: Pretreatment minimal staging and treatment of potentially resectable malignant pleural mesothelioma Jan P. van Meerbeeck a,,michael Boyer b a University Hospital,De Pintelaan 185, B-9000 Ghent, Belgium b Sydney Cancer Centre, Missenden Road,2050 Camperdown, NSW, Australia 1. Introduction The panel decided to discuss successivelythe issues of staging classification, pretreatment assessment and treatment of potentiallyresectable malignant pleural mesothelioma (MPM). Whenever possible a consensus was agreed and areas of further research were identified based on issues on which no agreement could be obtained. Recommendations were formulated based on the areas of consensus and disagreement. 2. Staging classification Earlier staging systems of MPM reflect the experiences of individual investigators or institutions in their respective patient populations. There is considerable discrepancybetween the various staging systems, resulting in non-uniformity of results reporting. Moreover, these earlier * Corresponding author. addresses: (J.P. van Meerbeeck), (M. Boyer). systems tend to concentrate either on resectable (Butchart, Brigham) or on advanced MPM [1 8]. A new staging system was devised by members of the International Mesothelioma Interest Group (IMIG) and approved byconsensus at the Tri-Annual Meeting of the International Association for the Studyof Lung Cancer (IASLC, Colorado Springs, 1997). This staging system is quite complex reflecting the complex presentation and modes of spread of this unique neoplasm [9,10]. The two most important purposes of the classification were to: 1. Separate out that relativelysmall group of patients with earlympm who maybe potentially curable byaggressive surgical means. 2. Distinguish between later stage presentation of MPM, which is still at a resectable stage, and late MPM, which is unresectable. This classification is hence mainlya surgical pathological one. In view of the limited therapeutic alternatives to surgery, there was little need for further refinement at that time. About 10 years later, with active chemotherapeutic /$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi: /j.lungcan
2 S124 J.P. van Meerbeeck, M. Boyer drugs available and multimodal protocols being activated, the classification is not anymore being considered adequate based on the following arguments: 1. The data base on which it is based is unknown. 2. Its validation has been limited and in a retrospective fashion only [11,16]. 3. The system is not designed to take into account the realityof cross-sectional imaging methodology. Many of the distinctions which the staging system makes: for example, distinguishing visceral from parietal pleural involvement, involvement of endothoracic fascia, transmural versus non-transmural pericardial involvement, cannot be distinguished with the resolution of computed tomography(ct)/ magnetic resonance imaging (MRI) . 4. The complex anatomic presentation of this neoplasm with frequent diffuse, bulkytumour masses involving the pleural surfaces prevents visualization of regional nodal spread. In fact the accuracyof CT/MRI in predicting surgical findings is 55 75% . 5. The regional lymphatic drainage of MPM was thought to mirror the lung cancer one but is in realitymore complex and hence is not reflected in the regional nodal spread (N1, N2 and N3) . With the advent of multislice spiral CT and PET- CT scan, intrathoracic spatial resolution and the qualityof the coronal and sagittal image reconstruction byvoxel isotropism have improved. The application of these techniques in mesothelioma might result in more adequate clinical staging but has insufficientlybeen validated yet . In view of the abovementioned, the consensus panel could not agree on a common staging classification in MPM. 3. Pretreatment minimal assessment 3.1. Assumptions: in reaching its consensus,the panel members made the following assumptions 1. The optimal pretreatment assessment protocol should: a. Be simple and widelyapplicable, without being limited to the lowest denominator. b. Be sequential and logical, unnecessaryinvasive and/or expensive tests should be avoided. c. Identifycandidates for radical locoregional, combined modalitytreatment and palliative treatment. d. Be applicable to good clinical practice with all forms of therapy. There should be no restriction on institutional preference for additional investigations, nor additional requirements for trial purposes. If physical signs or laboratoryinvestigations indicate metastasis and/or invasion, further investigations are indicated onlyif clinicallyrelevant. e. Refer to patients with MPM only. 2. The diagnosis of MPM is alreadyestablished or, at least, the clinical presentation is highlysuspicious for the presence of MPM. 3. Everypatient is fit for all forms of therapy: the suitabilityof individual patients for different forms of therapyshould be separatelyassessed (i.e. cardiac and/or pulmonaryfunction) Pretreatment workup: the pretreatment assessment is ideally split into three steps,which are to some degree overlapping Whether a patient goes through all three steps depends stronglyon the results of the procedures and the consequences for the choice of treatment with radical or palliative intent only Step I,to be considered in all patients at presentation or diagnosis Investigations Including Confirmatory tests Demographics Gender and age Clinical historyperformance As appropriate status, presence/absence of chest pain, dyspnea, change in bodyweight or BMI* Physical examination Presence or absence of shrinking As appropriate Radiological investigations Blood tests hemithorax Chest X-ray: PA/lateral in-/expiration, pre-/post drainage of pleural fluid Hemoglobin, leucocytes, platelets, basic biochemistry *BMI, bodymass index.
3 Consensus report S Step II,to be considered in patients being candidate for any kind of active treatment Investigations Including Confirmatorytests CT scan of chest and upper abdomen Spiral technique, with iv contrast, including lowest costophrenic angles, after drainage of pleural fluid Pulmonaryfunction tests Forced vital capacity(fvc), forced expiratoryvolume 1 sec (FEV1) Bone scan Not routine, to be considered on clinical suspicion onlystandard X-rayor CT/MRI to confirm dubious findings Brain CT/MRI Not routine, to be considered on clinical suspicion only After having gone through the investigations of step I and II, it is usuallyclear if further tests are necessaryto finalize the process of patient selection for combined modalityor radical locoregional treatment. It was the opinion of the panel that this would be onlythe case in a minority( 10%) of patients with MPM. This is reflected in the paucity of data, reflecting different institutional practice. Among the investigations to be considered are mediastinoscopy, MRI of the chest, Video Assisted Thoracoscopy(VATS) and laparoscopy. To some degree these investigations are complementaryto each other and in the absence of comparative trials no formal advice regarding their respective efficacy can be given. Esophageal Ultrasound with fine needle aspiration (EUS-FNA) and PET-CT scan are new techniques that are not uniformlyavailable and need further confirmation of their validityin the pretreatment evaluation. 3. Further research is done with regard to the comparative efficacyof the different intrathoracic techniques (mediastinoscopy, VATS, EUS- FNA) and the value of the newer ones (PET-CT, EUS-FNA). 4. Treatment of potentially resectable disease In considering the management of patients with potentiallyresectable disease, there was acknowledgement bythe panel that the lack of data from adequatelyperformed, prospective, clinical trials limited the conclusions, which could be drawn. Notwithstanding this fact, the panel considered which patients were candidates for surgical resection, and what form the resection and associated management should take. Area Investigation Patient group Confirmatorytests Diaphragm Chest X-ray, in-/expiration Every patient considered Fluoroscopy for radical treatment Extrathoracic, excluding occult M1 Full ring FDG-PET scan Everypatient considered for radical treatment Biopsyof suspected extrathoracic lesions LaparoscopyAccording to institutional practice Mediastinum, excluding T4, N2/3 involvement Cervical mediastinoscopy, VATS, contralateral VATS According to institutional practice MRI of the chest, Gadolinium enhanced EUS-FNA Investigational PET-CT Investigational Step III: to be considered only in patients being candidate for radical treatment The consensus panel further agrees on that: 1. The interval within which the assessment has to be finalized should be as short as possible. 2. Recent (<1-month-old) imaging studies should be available prior to invasive procedures Patient selection Patients were divided into three groups based on the extent of their disease: 1. Patients with distant metastatic disease, those with involvement of mediastinal structures, and those with diffuse chest wall invasion are not considered to be candidates for resection.
4 S126 J.P. van Meerbeeck, M. Boyer 2. Patients with focal chest wall invasion are considered to be potential candidates for resection. 3. Patients with localized disease are considered to be candidates for resection. No agreement could be reached bythe panel on the implications of N2 nodal involvement on resectability. Although technically resectable, the outcomes for patients with involved N2 nodes have been verypoor in the experience of some groups [11,16], leading these groups to exclude such patients from initial resection. Other groups continue to resect tumors, which are associated with involved nodes. Consideration was also given to the impact of histological sub-type on the potential for resection. There was agreement that outcomes seemed to be best for patients with epithelioid tumours [11,16]. However, it was also felt there was insufficient evidence to exclude patients with bi-phasic or sarcomatoid tumor types from consideration for surgical resection Surgical treatment There was general agreement amongst the panel that the goal of surgeryin the management of potentiallyresectable mesothelioma was to improve local control bymaximallydebulking the disease. There was no agreement about the optimal type of surgery (pleuro-pneumonectomy, pleurectomy, or pleurodesis), the need for radiation therapy, or the need for combined modalitytreatment incorporating chemotherapy. Several centres have extensive experience with pleuropneumonectomy, radiation therapyand the addition of chemotherapyto these other modalities [15 18]. However, the lack of appropriatelydesigned prospective trials means that it is difficult to be certain how much patient selection contributes to the results seen after treatment. There was general agreement that prospective trials are needed urgentlyin order to assess different treatment approaches. A necessaryprerequisite for these trials is the development of a generallyagreed-upon staging system, to ensure that patients included in different trials are comparable. Although multimodal therapy, incorporating surgery, radiation therapyand chemotherapyhas become widelyused there was also no agreement as to whether this improved outcomes, and if so, what the optimal sequence and types of treatment were. Further trials are required to evaluate these questions. 5. Recommendations The panel members formulated the following recommendations: 1. A new robust and uniform clinical staging system has to be developed and validated. This new staging classification: a. Should preferentiallybe TNM-compatible. b. Encompass the existing surgical pathologic staging systems (IMIG, Brigham), that should be preferentiallytelescoped. c. Be based on a large database, consisting of a registryof retrospective surgical data (e.g. The International Registryof Lung Metastases ), added with prospective collection of clinical and pathological data of new cases. The IASLC was regarded as the organization of choice to develop this new classification as it has a current similar effort being conducted regarding the staging classification of lung cancer . 2. Further research, ideallycomprising multicentre randomized controlled trials, is required to define preciselythe optimal surgical management of mesothelioma. In addition, trials are also required to evaluate the other components of therapyincluding radiation therapyand chemotherapy. 3. Extrapleural pneumonectomyshould onlybe carried out as part of a prospective clinical trial, in centres with experience in the procedure, and with the support of a multidisciplinaryteam. 4. Credentialing processes should be developed for the surgical and radiation management of malignant pleural mesothelioma, in order to maximize the effectiveness and minimize the toxicity of treatment. Appendix A. Members of consensus group Name Country Dienemann, Hendrik Kestenholz, Peter Steele, JeremyUK Stevens, Craig Schmitt-Opitz, Isabelle Müller, Michael Austria Gaafar, Rabab Egypt Waller, David UK Facciolo Francesco Sorensen, Jens Benn Denmark Van Schil, Paul Belgium Pinto, Carmine
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