Combined Modality Treatment in Mesothelioma

A Systemic Literature Review With Treatment Recommendations

Charlotte De Bondt; Ioannis Psallidas; Paul E. Y. Van Schil; Jan P. van Meerbeeck

Disclosures

Transl Lung Cancer Res. 2018;7(5) 

In This Article

Abstract and Introduction

Abstract

In spite of recent progress, malignant pleural mesothelioma (MPM) remains synonymous with poor prognosis. A selected minority (<10%) of patients is eligible for a radical treatment with a combination of systemic chemotherapy (CT) and/or surgery and/or radiotherapy (RT), in an effort to maintain locoregional tumor control after achieving a macroscopically complete resection (MCR). However, as of yet there is no standard of care for this so-called multimodality treatment. As its potential gain is still limited (approximately one year added to overall survival), we must balance its efficacy with its cumulative toxicity. Several combined modality treatment trials are currently ongoing using novel techniques in surgery, RT and/or CT in an attempt to reduce the morbidity and mortality associated with older multimodality treatment protocols. Guidelines are following suit and are now including or mentioning this treatment option. In this systematic review, we analyze the available data in order to address the following questions: Is combined modality better than single modality? What is the optimal regimen within each modality? What is the optimal sequence of combined modality?

Introduction

It was first suggested in 1980 that selected patients with malignant pleural mesothelioma (MPM) are to be treated with a combination of different therapeutic modalities, usually surgery, chemotherapy (CT) and radiotherapy (RT), in order to achieve locoregional control and to improve overall outcome.[1] Other types of neoplasms that are treated in this manner include lung,[2] esophageal[3] and colorectal cancer.[4]

As we seem to reach consensus on the necessity of such a multimodality approach or at least on the need for more randomized trials ascertaining its role in the treatment of MPM, there is ongoing debate and research on its individual components and how they should be sequenced. Historically, surgery for MPM consisted of extrapleural pneumonectomy (EPP), which is an en bloc resection of both the parietal and visceral pleurae, the ipsilateral lung as well as pericardium and diaphragm. In the last five years there has been an evolution towards pleurectomy/decortication (P/D), which is a less invasive procedure whereby the parietal and visceral pleurae are removed but lung, pericardium and diaphragm are spared. When diaphragm and pericardium are also resected, this procedure is called an extended P/D (eP/D). Partial pleurectomy is performed to obtain tissue for diagnosis or to relieve symptoms in a palliative setting but is not part of a multimodality treatment for MPM.[5]

In 2003 and 2005, two large scale randomized control trials showed superiority in overall survival time with cisplatin and pemetrexed/raltitrexed over monotherapy with cisplatin, as well as in time to progression and response.[6,7] Since then this combination of cytotoxic agents (platinum based plus antifolate) has become the standard of care, as it is the sole treatment with proven benefit on outcome. In 2015, the French MAPS trial showed that the association of bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor A (VEGF-A), to a cisplatin-pemetrexed backbone improved overall survival in highly selected patients.[8]

Concerning radical RT there is an ongoing effort to find the most effective radiation technique that will improve locoregional disease control but will not result in excess radiation pneumonitis. Because of the large surface area of the pleura, the volume with conventional RT is very high, resulting in damage to the underlying lung (in case of P/D) and/or surrounding tissue and organs. Intensity modulated radiotherapy (IMRT) aims at a better dose distribution and hence less toxicity, which is especially important when RT is administered after lung sparing surgery.[9]

The 2010 European Respiratory Society (ERS)-European Society of Thoracic Surgeons (ESTS) guidelines, recommend that eligible patients (early stage, preferably epithelioid subtype, satisfactory pulmonary and cardiac status) should be included in prospective randomized control trials evaluating multimodality treatment in experienced centers.[10] The 2015 European Society for Medical Oncology (ESMO) guidelines are more restrictive as they conclude that there is insufficient evidence supporting standardized implementation of adjuvant RT in the treatment of MPM, however they do advise against monotherapy with surgery and recommend surgery be part of a multimodality treatment, preferably in a trial setting.[11] The 2018 British Thoracic Society (BTS) advise against EPP in any way and against eP/D outside of clinical trials. Based on the results of the MAPS trial, they suggest association of bevacizumab to a platinum-antifolate doublet to improve survival.[8,12] The 2018 American Society of Clinical Oncology (ASCO) guidelines state that cytoreductive surgery should ideally be supplemented by RT or (neo)adjuvant CT seeing as surgery alone has not shown to provide adequate disease control. For patients with proven N2 status they only recommend surgery when part of a multimodality treatment, preferably in a trial setting.[13] An overview of the most recent guidelines is listed in Table 1.

The purpose of this manuscript is to report the results of a systematic literature search performed on the subject of combined modality treatment in mesothelioma and formulate graded recommendations.

The following clinical questions were raised:

  1. Is multimodality treatment better than CT alone?

  2. What is the optimal regimen within each modality?

  3. What is the optimal sequence of interventions within a combined modality approach?

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