Assessment of tumor response in malignant pleural mesothelioma

Summary

Most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of their disease. Assessment of the response with conventional criteria based on computed tomography (CT) measurements is challenging, due to the circumferential and axial pattern of growth of MPM. Such difficulties hinder an accurate evaluation of clinical study results and make the clinical management of patients critical. Several radiological response systems have been proposed, but neither WHO criteria nor the more recent RECIST unidimensional criteria nor hybrid uni- and bidimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria for MPM have been published. Although they are already being used in current clinical trials, they have been criticized based on the high grade of inter-observer variability and on theoretical studies of mesothelioma growth according to non-spherical models. Computer-assisted techniques for CT measurement are being developed. The use of FDG-PET for prediction of response and, more importantly, of survival outcomes of MPM patients is promising and warrants validation in large prospective series. New serum markers such as osteopontin and mesothelin-related proteins are under evaluation and in the future might play a role in assessing the response of MPM to treatment.

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive tumor which usually has a poor prognosis. Its incidence is increasing throughout most of the world, and it is predicted that it will rise in the next 10–15 years as a result of widespread exposure to asbestos in past decades.¹ The management of patients with MPM remains controversial. Due to the usually advanced stage at presentation, only a minority of patients are eligible for radical surgery²; most are candidates for chemotherapy during the course of their disease. The relatively low incidence of the disease has made it difficult to conduct randomized controlled studies with adequate numbers of cases. Therefore, a nihilistic attitude has existed for many years regarding treatment of MPM, with retrospective studies reporting median survival of less than one year and 5-year survival rates of 1% or less.³ Several new cytotoxic agents with definite activity in mesothelioma have been evaluated in the last decade, including gemcitabine, vinorelbine and the antifolates pemetrexed and raltitrexed.⁴ Recently, two randomized controlled trials wherein single-agent cisplatin was compared with its combination with an antifolate have established the combination treatment as the reference regimen for first-line chemotherapy.5, 6 More specifically, a large phase III trial testing pemetrexed and cisplatin versus cisplatin alone in 448 chemotherapy-naive patients with MPM showed a significant advantage with the combined regimen in survival, time to progression and response rate.⁵ Several biological agents have been explored or are currently under evaluation.7, 8

Contrast-enhanced computed tomography (CT) is the primary imaging modality for the evaluation of MPM; rind-like extension of the tumor on the pleural surfaces is the most common CT feature, and is seen in up to 70% of cases.9, 10, 11 However, it lacks the ability to depict the extent of disease accurately. For patients being assessed for surgery, magnetic resonance imaging (MRI) can provide additional information in detecting chest wall and diaphragmatic invasion.12, 13 On the other hand, the sensitivity and specificity of CT for mediastinal nodal involvement are very low, due to the unpredictable and not well characterized lymphatic pattern of spread of MPM.¹⁴ The use of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of MPM has been described recently. FDG-PET has proved useful in detecting malignant pleural lesions¹⁵ and partially in assessing the extent of tumor involvement. In one study of 65 MPM patients, this imaging technique correctly detected extrathoracic metastases but failed to reliably identify the locoregional (tumor and mediastinal nodal) status of MPM¹⁶; sensitivity was 19% for locally advanced disease (T4) and 11% for nodal metastases. Integrated CT-PET with coregistration of anatomic and functional imaging data increases the accuracy of MPM staging for T4 disease (sensitivity 67%, specificity 93%), while it remains inaccurate in the evaluation of nodal metastases (sensitivity 38%, specificity 78%), with high rates of false-positive and false-negative results.17, 18 Further studies have demonstrated that FDG uptake, measured at diagnosis by standardized uptake value (SUV), has independent prognostic value in this disease. In a retrospective study of 137 patients with MPM, a SUV > 10 was significantly related to poor prognosis in multivariate analysis; patients with high SUV had a death hazard ratio of 1.9 compared to patients with SUV <10.¹⁹