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Malignant Pleural Mesothelioma

Oncology
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Introduction

Malignant pleural mesothelioma (MPM) is an aggressive primary malignancy of the pleural surface. Most cases of MPM are associated with previous asbestos exposure with a reported latency period of approximately 40 years.[1, 2] Within the United States the current incidence of MPM is reported to be between 2,000 and 3,000 cases per year.[3] It is also noted that the global incidence of MPM has steadily risen over the past decade with an estimated 14,000 cases worldwide every year.[4]
Despite surgical adjuncts and medical advances including the incorporation of bicavitary heated chemotherapy and immunotherapy, prognosis in cases of MPM remains poor overall with reported median survival times of 8-14 months from the time of diagnosis.[1, 5]

Symptoms

The most commonly reported presenting symptoms of patients with MPM are shortness of breath and chest pain.[6,7]  Shortness of breath is often the result of malignant pleural effusion from the pleural malignancy, present in approximately 70% of cases.[7] Interestingly, with disease progression, the frequency and amount of pleural effusions tend to decrease secondary to obliteration of the pleural space by tumor progression.[8]  Other associated symptoms of MPM include constitutional symptoms of fatigue, anorexia, malaise, sweats, and weight loss which are resultant of systemic responses to malignancy primarily to upregulation of pro-inflammatory cytokines such as IL-1 and TNF-alpha.[6]

Screening

Given the high mortality and paucity of early symptoms in cases of MPM, there has remained a high level of interest regarding early detection in mesothelioma in efforts to improve outcomes and reduce mortality.  However, given the low incidence of MPM, there currently exists no standard generalized screening guidelines or criteria for mesothelioma.
However, some patients with a personalized history of significant environmental exposure, namely asbestosis exposure, may be considered for screening in a personalized fashion.[9,10]  As early as 1973, the United States Occupational Safety and Health Administration has mandated monitoring and specific screening for high risk individuals with a documented history of occupational airborne asbestosis exposure.[9]
As it relates to environmental exposure risk association with MPM, asbestos exposure and its association with mesothelioma carcinogenesis is derived from epidemiologic studies as well as confirmatory studies.[11]  Carcinogenesis from asbestos fibers is hypothesized to be linked to free radical generation and release as well as the cycle of repeated inflammation and fibrosis that inhaled fibers incite within the pleural space.  Worldwide use and consumption of asbestos and containing products remains surprisingly high despite nationwide banning in many parts of the world.  As such, a decrease in the number of new cases of MPM in Western countries is predicted.[12]

Diagnosis

The diagnosis of MPM can be challenging.  To date, the use of biomarkers has been evaluated in identification of MPM however they remain of limited clinical use without established levels of benefit.  Biomarkers that have been evaluated in the pathogenesis and diagnosis of MPM include mesothelin[13], megakaryocyte potentiating factor[14], and fibulin-3[15].
Elements that are key in the diagnosis of MPM include clinical history and imaging findings that include computed tomography (CT) with or without the adjunct of positron emission tomography (PET).  The characteristic imaging findings of MPM include nodular thickening or a pleural-based mass[8,16]. 
Histopathologic classification of diffuse MPM on microscopic examination and the most widely utilized classification categorizes MPM subtypes as epithelial, sarcomatoid, or mixed.[17]
Accurate histopathologic classification of MPM is necessary as it can assist to predict prognosis as well as aid in delineating treatment pathways for patients.  Currently, patients with epithelial type MPM hare noted to have the best survival with cases demonstrating sarcomatoid features having the worst. Interestingly, cases with sarcomatoid pathology are unlikely to have positive cytology on pleural fluid analysis during staging workup. Part of the investigatory process of MPM will involve video assisted thoracoscopic surgery (VATS) biopsy of the suspected affected pleura for tissue diagnosis.

Staging

Establishment of a universal and generalizable staging system for malignant pleural mesothelioma has been difficult owing to a multitude of factors: low tumor incidence, anatomic complexity, tumor heterogeneity, and limited treatment options.  Additionally, accurate staging of MPM is further complicated due to limitations in current imaging techniques, specifically in accurate tumor characterization and evaluation of lymph nodal involvement[18].
Conceptually, this is manifested as MPM typically spreads in a nodular fashion tangentially along the pleural surfaces and as such, MPM tumors can grow to considerable bulky disease that is not accurately characterized radiographically.  Additionally, lymph node involvement is not accurately assessed using current imaging techniques as nodal size does not necessarily correlate with the presence of metastatic disease.  Also, clinically relevant nodal stations, particularly hilar and internal thoracic stations, are typically located in areas that commonly involve primary MPM tumors.[7,19,20]
Finally, there is a noted lack of correspondence between preoperative clinical stage and final pathologic stage in cases of MPM.  Due to these complexities, pre-treatment clinical staging has been challenging in MPM as related to prognosis stratification or to inform treatment decisions as in other thoracic malignancies, especially evaluation as to whether the treatment modality of surgical resection should be incorporated.  Surgical thoracoscopy with additional mediastinoscopy to assess nodal disease may also be utilized for staging assessment in cases of malignant pleural mesothelioma.[21]
There are a number of staging classifications schema for MPM, all of which have limitations in clinical practice.[4,5]  Currently, modified TNM classification and stage grouping criteria proposed by the International Mesothelioma Interest Group (IMIG) were adopted by The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).[22]  Radiographic imaging is a cornerstone in the staging of patients with MPM and include chest computed topography (CT) scan, and fluorodeoxyglucose positron emission tomography(FDG-PET).
Magnetic resonance imaging (MRI) can be useful to investigate invasion of the local structures including the diaphragm and pericardium. Pathologic mediastinal staging includes cervical mediastinoscopy or endoscopic ultrasound.Pathological staging is obtained for patients undergoing surgery for MPM, and upstaging commonly occurs. As it relates to clinical staging and correspondence to pathologic staging, previous studies have demonstrated only a 46% rate of staging accuracy across 164 patients with resected MPM and completed staging data.[23]
To summarize, apart the identification of overt extra thoracic disease, current clinical staging of MPM is highly variable with very low predictive value for the outcome of patients with MPM under consideration for surgical therapy.
Historically, T classification of malignancies is based primarily on tumor size with associated upstaging when invasion of structures is noted.  By comparison, due to the diffuse and heterogeneous growth pattern of MPM, tumor size is not easily established in mesothelioma.  As such, tumor size is not currently considered when establishing MPM stage.
  • According to current AJCC/UICC criteria, T1 MPM tumors remain confined within the ipsilateral pleural surfaces.[24]
  • T2 tumors extending into the interlobar fissures or showing involvement of the lung parenchyma or diaphragm are classified as T2.
  • Tumors showing extension into the endothoracic fascia or mediastinal adipose tissue but pericardial involvement that is not transmural are classified as  T3.
  • Finally, tumors showing direct extension into the chest wall soft tissue or adjacent mediastinal organs or involvement of the contralateral pleura or pericardium/diaphragm are classified as T4.
Currently, regional lymph node staging of MPM uses the same classification schema as lung cancer which helps to simplify lymph node staging.[25]
  • As such, cases with identified hilar and intraparenchymal lymph nodes are classified as N1.
  • Tumors with associated subcarinal and ipsilateral mediastinal or internal mammary nodal involvement are N2.
  • And finally, contralateral internal mammary/mediastinal nodes or the involvement of supraclavicular nodes are N3
Even though the staging classification for nodal disease in MPM is similar to that of the nodal staging system for lung cancer, the relationship for nodal drainage is more complex as direct lymphatic drainage from the diaphragmatic pleura to the mediastinal nodal chains allows MPM tumors to arrive directly to N2 lymph nodes without first affecting N1 stations.[26] 
It is well established that nodal metastasis is associated poor prognosis in MPM which has been demonstrated in studies on multivariate analysis in patients treated with extrapleural pneumonectomy (EPP) who were able to undergo complete pathologic analysis following surgical resection.[27,28] As related to M status, interestingly, despite the aggressive local growth patterns associated with MPM, rare distant metastases are rare.[29]  Distant organ involvement can be difficult to determine as a result of caused by either direct extension through the diaphragm or hematogenous metastases.[30]

Treatment

Due to the complexity of MPM, treatment of these tumors involves a multidisciplinary approach.  The broad strokes of treatment for primary MPM tumors can be divided into systemic chemotherapy/radiation, targeted therapy, immunotherapy, and surgery.
Systemic chemotherapy
In cases of unresectable disease, systemic chemotherapy should be considered as it has been shown to improve survival and quality of life in select MPM cases.  Standard first line therapy remains a combination of cisplatin and pemetrexed and continues to be the only FDA-labeled treatment option in MPM.
The EMPHACIS trial demonstrated efficacy in terms of response rate, median time to progression of disease, and median overall survival31.  Due to the results of this study, this chemotherapy combination became the standard first line therapy in mesothelioma.  They are delivered intravenously once every 21 days at doses of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 with associated vitamin B12 (1000 ug intramuscularly) and folic acid (400 ug by mouth daily).
Optimum length of therapy for chemotherapy in unresectable MPM has not yet been defined, however current guidelines recommend for four to six cycles of therapy32.  Recently, while not currently FDA approved, vascular endothelial growth factor (VEGF) blockade of receptors VEGFR1 & VEGFR2 utilizing addition of the VEGF inhibitor bevacizumab to platinum and pemetrexed combination therapy, has been included in the NCCN guidelines for consideration in front-line therapy in MPM.[33, 34]
Immunotherapy
Immunotherapy has shown promise in the treatment of MPM.  An early focus on the implementation of immunotherapy in MPM management has involved the use of checkpoint inhibitors such as nivolumab and pembrolizumab.  Programmed cell death protein 1 (PD-1) is expressed in activated T & B lymphocytes as well as natural killer cells.  The binding between PD-1 and its ligands PD-L1/L2 leads to decreased T cell activity.[35]
The results from the recent Checkmate 743 trial demonstrate encouraging results for the use of immunotherapy in the care of malignant pleural mesothelioma.  Checkmate 743 represents an open label randomized phase 3 study evaluating the efficacy and safety of first-line nivolumab with the addition of ipilimumab versus platinum plus pemetrexed chemotherapy in unresectable MPM.[36]  Findings from Checkmate 743 demonstrate clinically and significant meaningful improvement in overall survival in patients treated with immunotherapy versus standard-of-care platinum-based chemotherapy[36] without additional safety profile concerns.  At a follow-up of 29.7 months, nivolumab plus ipilimumab significantly extended overall survival as compared to standard of care chemotherapy (18.1 months vs 14.1 months).[36]  Based on these findings from this landmark study, nivolumab plus ipilimumab has been supported as first line therapy in previously untreated unresectable cases of MPM.[36]
Surgery
Whilst a tenant of the management of the vast majority of solid organ tumors, the benefit and feasibility of surgical resection in the management of MPM has been an area of debate. The two main procedures for resection of MPM can be simplified to include extrapleural pneumonectomy (EPP) and pleurectomy and decortication (P/D).  Currently, as established by the International Association for the Study of Lung Cancer (IASLC), the term P/D is denoted to attempted removal of all macroscopic tumor from the visceral and parietal pleura with the term extended P/D used if the involved diaphragm and pericardium are removed with the aforementioned pleura.[37]  EPP includes resection of the entire lung, visceral pleura, parietal pleura, and involved pericardium and diaphragm.  Original reports of EPP reported improved survival but with prohibitively high rates of associated morbidity and mortality.[38]  In subsequent years with adaptations of multimodality therapy, morbidity rates of EPP improved with resultant mortality reductions.[39]
Given the morbidity associated with EPP, extended P/D has become the most common operation for resection of MPM.  P/D is generally better tolerated and has reported mortality rates of 1% to 2% at high volume tertiary centers.  There currently exists no randomized trial data determining whether P/D extends survival as compared to no surgery however studies such as the multicenter MARS-2 trial is currently evaluating this.[40]
HIPEC (hyperthermic intraperitoneal chemotherapy)
Perioperative adjuncts combined with surgery have also been evaluated in the operative management of MPM.  In cases of MPM treated either with EPP or P/D, the adjunct of heated intraoperative chemotherapy (HIOC) has championed by some groups.  HIOC, which involves intracavitary administration of heated chemotherapy (42oC) with purpose to increase the intracellular uptake of drugs in an effort to decrease systemic side effects while maximizing effect.[41]  Traditionally, thoracic HIOC has been undertaken with platinum-based chemotherapy (cisplatin) with doses of sodium thiosulfate and amifostine to provide added renal protection during heated chemotherapy administration.[42-44]
Certain non-randomized studies in carefully selected patients have reported median survival times of up to 29 months in patients treated with EPP with subsequent HIOC following induction chemotherapy.[45]  HIOC has also been studied in use in patients undergoing P/D with intraoperative chemotherapy with median survival rates of 11.5-13 months.[42, 46] Alternatively, recent groups have evaluated administration of PVP-I (iodine bound to carrier molecule poly-(1-vinyl-2-pyrrolidone)).  Due to its lower side effect profile as compared to HIOC, hyperthermic pleural lavage with PVP-I has been studied as a surgical adjunct during P/D instead of HIOC.  Previous studies evaluating patients treated with P/D and heated intraoperative PVP-I and prophylactic radiotherapy in patients with MPM demonstrated 0% mortality rate with an overall median survival of 24 months.[47]
Targeted therapy
Owing to the increased understanding of biology of MPM disease, targeted therapy has been investigated in combination with systemic chemotherapy for certain cases.  Due to the aforementioned identification of high expression of angiogenic growth factors and receptors in MPM tumors and positive results from the MAPS trial with the utilization of bevacizumab,[33, 34] the implementation of anti-angiogenic agents continue to be an active area of research in mesothelioma.  Results of previous trials have only demonstrated modest results.
Additionally, cediranib and nintedanib are oral small molecule inhibitors of VEGF that have been evaluated in phase I & II clinical trials who experienced MPM disease progression.[48-50]  In addition to angiogenic inhibition, mesothelin, a glycoprotein involved in cell adhesion has been found to have high expression rates in MPM as compared to normal surrounding tissue, and mesothelin inhibitors such as amatuximab have been studied in clinical trials (NCT02357147) with some preliminarily favorable results.[51]
Additional areas of investigation as related to targeted therapy include mammalian target of rapamycin (mTOR) inhibition, oral epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors, histone deacetylase inhibitors (HDACi), and proteosome inhibition are still being evaluated as supplemental therapy in cases of MPM with standard of care systemic chemotherapy.
Management of Malignant Pleural Effusions
The majority of patients diagnosed with MPM will experience a disease related pleural effusion at some point.  Drainage of these effusions improves symptoms and attempts at prevention of re-accumulation can help to improve quality of life in patients diagnosed with MPM.  Simple aspiration and drainage can provide immediate symptomatic relief in cases of malignant effusions, however, fluid will inevitably re-accumulate and as such, a definitive procedure is generally preferable.[52]
Definitive control of recurrent effusions can be accomplished via chemical pleurodesis via a minimally invasive approach, a number of chemical agents have been evaluated and found to be effective that include talc, doxycycline, and bleomycin.  Talc pleurodesis is successful in approximately 60% of patients in providing long term relief from recurrent effusion accumulation.[53]
An alternative to chemical pleurodesis in the management of recurrent pleural effusion from MPM is the placement of a long-term indwelling pleural drainage catheter.  Indwelling pleural catheters have demonstrated efficacy in the management in a number of thoracic malignancies, including MPM.[16, 52]  The decision whether to proceed with either pleurodesis or placement of a pleural drainage catheter should be made with the patient’s input and quality of life in mind.

Surveillance

Due to the low incidence of MPM and the high associated early disease mortality even in patients who have received medical/surgical therapy, there are no currently established post-treatment patient surveillance protocols.  Currently, MPM post-surgery are monitored for disease recurrence with center-specific followup protocols that include regular history and physical exams, monitoring for a decrease in pulmonary function, and interval established radiologic imaging to evaluate for disease recurrence.  Given the high recurrence rates of MPM, oftentimes development of symptoms often precedes radiologic identification of disease recurrence. 

Controversies

Currently, the only reported data from a randomized clinical trial directly comparing MPM cases undergoing surgery vs no surgery are findings from the United Kingdom- based Mesothelioma and Radical Surgery Feasibility Study (MARS) that demonstrated a higher morbidity and in-fact lower overall survival (14.4 vs 19.5 months).[54]
However, these findings should be taken into specific context in that many have argued that this study was not sufficiently powered for survival determination, and that previous studies, albeit lower powered, have exceedingly demonstrated the potential negative impact that EPP can have in the overall outcomes of MPM patients when not performed in high-volume centers or amongst poorly selected candidates.[38, 39]   Conversely, other studies, often limited to single center experiences, have demonstrated more acceptable rates of morbidity and mortality as related to surgical resection.[39, 41]
The balance of literature suggests to maximize the benefit of surgical resection, it should be performed in a multimodal setting with adjuvant and/or adjuvant modalities such as systemic therapy inlcuding chemotherapy, and/or radiotherapy. In our experience and in the experiences of other tertiary high-volume centers, incorporated as a component of multimodal treatment that also includes immunotherapy, systemic chemotherapy, and radiation therapy protocols, surgical resection may provide enhanced survival in appropriately selected mesothelioma patients with acceptable rates of morbidity and complications.
An additional controversy in the surgical management of malignant pleural mesothelioma relates to the selection for cytoreductive surgery technique.  This controversy directly relates to the main crux of criticism of surgery in MPM patients that is often muddied by the morbidity and mortality with which extrapleural pneumonectomy can be associated.[38]  As previously mentioned, providers have begun to evaluate whether extended pleurectomy and decortication can yield comparable oncologic results as the more cardiopulmonary high-risk EPP.  It is well established that EPP can contribute to hazard mortality ratios of greater than 1.4 as compared to P/D.  Because of these issues, the implementation of P/D which is a significantly less radical procedure than EPP, is currently being assessed in conjunction with standard of care chemotherapy in the randomized phase 3 MARS-2 trial.[40]

Summary and recommendations

MPM is an aggressive pleural malignancy that is associated in most cases with exposure to asbestos.
First line systemic therapies for patients with unresectable MPM include platinum-based therapy and pemetrexed (plus/minus bevacizumab) and immune checkpoint blockade
The CheckMate 743 trial was recently published and shows that immumotherapy with nivolumab plus iplimumab increased overall survival in patients with unresectable MPM when compared with chemotherapy
Surgical resection for MPM, in the setting of multimodal therapy, may be associated with extended survival in selected patients. The role of EPP versus P/D is not determined

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