ReviewResponse evaluation in mesothelioma: Beyond RECIST
Introduction
Malignant pleural mesothelioma (MPM) is a rare and often aggressive neoplasm that originates from mesothelial cells lining the pleura [1], [2], [3]. In the UK, the incidence of MPM is reportedly 41 per million in 2011, of which males are 4.5 times more affected than females [4]. The pathogenesis of malignant pleural mesothelioma is related to asbestos exposure [1], and the use of asbestos in the developing countries may result in further increase in the global incidence of MPM [5]. There are three major histological subtypes of MPM: epithelioid, sarcomatoid, and mixed or biphasic, among which the sarcomatoid type has the worst prognosis [6]. MPM has a relatively poor outlook, with a median survival of 9–17 months [7].
There are a number of potential contributing factors to the poor disease survival in MPM. First, the disease is usually multifocal at diagnosis with multiple tumour nodules along the pleura and lung fissures at presentation, sometimes also involving the diaphragm and pericardium, rendering a complete surgical resection impossible. Second, despite the known association between asbestos and MPM, there is a long latency between asbestos exposure and the onset of MPM, making it challenging for the life-long surveillance of disease within the at-risk population. Third, conventional chemotherapy has not been very effective for the treatment of these cancers, although promising new targeted therapies are now beginning to emerge. Last but not least, there is still a significant challenge for the accurate quantification of disease burden and the assessment of disease response to treatment. This has undoubtedly had an impact on clinical trial designs in MPM, and the robustness of end-points used to defined disease response or progression in research and clinical practice.
In this review, we will survey the existing roles of CT and MRI for the management of MPM, including the currently applied size measurement criteria (e.g., WHO, RECIST and modified RECIST) for the assessment of treatment response. Functional imaging techniques, such as positron emission tomography (PET), diffusion-weighted MRI (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) that may potentially improve the assessment of treatment response will be highlighted and discussed.
Section snippets
Growth pattern of MPM: a challenge for imaging
Malignant pleural mesothelioma grows on the pleural surface by sheet-like extension instead of producing spherical lesions, and this growth pattern leads to an irregular rind-like tumour encasing the lung [8] (Fig. 1). The disease frequently extends to or invades the thoracic wall, the diaphragm, the mediastinum [8], [9], [10]. The tumour can also spread along interlobar fissures across the mediastinum to the opposite pleura, or through the diaphragm into the peritoneum and / or adjacent organs
The roles of conventional CT and MR imaging
Currently, CT is routinely used for the diagnosis, staging, and treatment planning of MPM due to its wide availability and relatively low cost [11], [12]. At diagnosis, the main CT findings include unilateral pleural effusion, nodular pleural thickening and thickening of the interloblar fissure [13]. However, CT is limited for detecting early local tumour extension, including chest wall invasion, transdiaphragmatic spread and small lymph node metastases [14].
MRI has superior soft tissue
Assessing treatment response using size measurement criteria: WHO, RECIST and modified RECIST
In the 1980s, the World Health Organisation (WHO) proposed using the product of the bi-dimensional tumour diameters as the basis for assessing tumour shrinkage after treatment [20]. This was further simplified by the Response Evaluation Criteria in Solid Tumours (RECIST) criteria in the 1990s, when a single maximum axial tumour diameter measurement was proposed [21]. More recently, the RECIST 1.1 criteria, a revision of the original RECIST, are being widely adopted as imaging end-point in
Response assessment using volumetry on CT and MRI
Disease burden before and after treatment has been measured by volumetry on CT or MR images with encouraging results [30], [34], [35], [36], [37]. These studies applied segmentation techniques to the CT or MR images to estimate the total amount of disease present within a hemithorax. In a study of 57 patients with MPM treated with chemotherapy, response assessment was evaluated by CT volumetry, WHO and modified RECIST criteria [34]. The authors found that response defined by CT volumetry
Beyond RECIST: response assessment using functional imaging techniques
Recognizing the inherent limitations of size-based tumour response criteria, particularly in the context of MPM, there is considerable interest in using functional or molecular imaging techniques to assess treatment effectiveness. Functional imaging techniques are applied to derive quantitative measurements of tumours, which reflect particular aspects of the tumour pathophysiology. By quantifying how these measurements change with treatment, it is possible to observe treatment effects.
Conclusions
Despite the known limitations of size measurement response criteria in MPM; WHO, RECIST (1.0 and 1.1) and modified RECIST criteria are still widely used in clinical trials of MPM. This may be because these measurements are relatively simple to undertake, and when performed meticulously, can yield meaningful results that inform on patient outcomes. Nonetheless, current evidence suggests that using the modified RECIST criteria is associated with a lower degree of inter-study and interobserver
Conflict of interests
The authors declare there is no conflict of interests.
Acknowlegements
We acknowledge the CR-UK and EPSRC support to the Cancer Imaging Centre at ICR and RMH in association with MRC & Department of Health C1060/A10334, C1060/A16464, NHS funding to the NIHR Biomedicine Research Centre and the Clinical Research Facility in Imaging.
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