Anish Thomas and Raffit Hassan

INTRODUCTION

Malignant mesothelioma is an aggressive tumor that arises from the serosal surfaces of pleura, pericardium, peritoneum, or the tunica vaginalis. Up to 3,000 patients are affected annually in the United States. The pleura is the most common primary site, accounting for 80% to 90% of cases, and the majority of patients are older adults with a median age at presentation of 74 years (1). Although most cases are attributed to asbestos exposure, roughly 20% of patients have no significant exposure to asbestos. Nonasbestos-related risk factors are not fully understood, but include prior radiation exposure, exposure to nonasbestos mineral fibers, such as erionite, and genetic predisposition. The latter includes germline mutations in the gene encoding BRCA1-associated protein-1 (BAP1) that are linked to susceptibility to mesothelioma, uveal and cutaneous melanoma, renal cell cancer, and possibly other cancers (2,3).

CLINICAL PRESENTATION AND DIAGNOSIS

Mesothelioma is a locally invasive tumor, which usually presents with unilateral involvement of the pleural cavity (Figures 14.1 and 14.2). Early symptoms reflect the pleural origin of the tumor and include dyspnea on exertion and chest discomfort. Invasion of adjacent structures, including the lungs, mediastinum, and chest wall, frequently manifests as pleuritic chest pain, dry, nonproductive cough, chest wall masses, and dysphagia. Constitutional symptoms, such as anorexia, weight loss, fever, and night sweats, are common. Distant metastases are uncommon in the early stages of disease, but do occur in patients with advanced disease. Common findings on physical exam include those indicative of a unilateral pleural effusion.

Diagnostic work-up commonly starts with imaging studies, usually chest CT, and thoracentesis with cytological analysis of pleural fluid in cases with pleural effusion. However, pleural fluid analysis and closed pleural biopsy are inconclusive in the majority of cases. Video-assisted thoracoscopic surgery (VATS) is the preferred method for surgical diagnosis of mesothelioma. This procedure yields sufficient tissue to establish the diagnosis of mesothelioma, characterize the histological subtype, and distinguish mesothelioma from other tumors.

Figure 14.1 CT Showing Pleural Mesothelioma: (A) Involving the Left Hemithorax and Chest Wall (Indicated by the Bold Arrow); (B) Right Hemithorax, Chest Wall, and Mediastinum

Figure 14.2 Positron-Emission Tomography (PET; A and B), CT (C), and PET-CT Fusion (D) Showing Pleural Mesothelioma Involving the Left Hemithorax in a Characteristic Rind-Like Pattern With an Enlarged, Metabolically Active Subcarinal Lymph Node (Indicated by the Bold Arrow)

Three major histologic subtypes have been recognized: epithelioid, sarcomatoid, and a mixture of both, referred to as the biphasic subtype (4). Of the three subtypes, epithelioid tumors are the most common and have a better prognosis than biphasic or sarcomatoid tumors. A panel of immunohistochemical stains can usually differentiate mesothelioma from other malignancies, such as lung adenocarcinoma and sarcoma. Typically, mesothelioma will stain positively for calretinin, WT-1, cytokeratin 5/6, and D2-40, while lung adenocarcinoma will usually stain positively for TTF-1, Napsin A, CEA, BerEP4, and LeuM1.

STAGING AND PROGNOSIS

Staging

The most widely used staging system for mesothelioma is the tumor (T), node (N), metastasis (M) classification that was developed by the International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG), and accepted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) (Tables 14.1 and 14.2) (5). It is challenging to obtain the T and N descriptors using current imaging modalities alone due to the anatomical location and pattern of spread along the pleural surface. Hence, TNM staging is most applicable for patients who have undergone exploratory or cytoreductive surgery. Clinical staging is performed using CT and positron-emission tomography (PET) in patients with potentially resectable disease. However, these techniques have major limitations in assessing the extent of disease and have proven unreliable for staging in some studies (6).

Stage I disease is limited to the ipsilateral parietal pleura with or without mediastinal or diaphragmatic pleural involvement. Stage II involves each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral) with involvement of the diaphragmatic muscle or extension into the underlying pulmonary parenchyma. Stage III involves subcarinal or ipsilateral mediastinal lymph nodes with or without local extension of tumor into the chest wall or mediastinum. Stage IV includes contralateral mediastinal lymph node involvement, direct extension into the peritoneum through the diaphragm, diffuse involvement of the chest wall, and/or distant metastatic disease.

Prognostic Factors

In the absence of a reliable staging system, scoring systems that take into account factors beyond the extent of disease may prove to be useful to determine prognosis. Two major prognostic scoring systems have been developed: the Cancer and Leukemia Group B (CALGB) prognostic index (7) and the European Organization for Research and Treatment of Cancer (EORTC) prognostic system (8). The CALGB prognostic index was derived by examining the effect of various pretreatment clinical characteristics on the survival of patients with pleural and peritoneal mesothelioma who were accrued to various phase II clinical trials conducted by the CALGB. By univariate analyses, poor prognostic factors were poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), chest pain, dyspnea, platelet count greater than 400,000/mcL, weight loss, serum lactate dehydrogenase (LDH) level greater than 500 IU/L, pleural involvement, low hemoglobin level, high white blood cell (WBC) count, and age greater than 75 years. In a multivariate analysis, pleural involvement, serum LDH greater than 500 IU/L, poor ECOG PS, chest pain, platelet count greater than 400,000/mcL, nonepithelioid histologic subtype, and age greater than 75 years predicted poor survival. Median survival ranged from 13.9 months for the best prognostic subgroup (PS 0 and age <49 years; or PS 0, age ≥49 years and hemoglobin ≥14.6) to 1.4 months for the worst subgroup (PS 1–2 and WBC ≥15.6/mcL).

The EORTC prognostic system was derived from previously untreated patients with pleural mesothelioma who were enrolled in EORTC clinical trials. In this system, the following variables predicted a poor outcome: poor PS, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and sarcomatoid histologic subtype. The median survival ranged from 10.8 months for the low-risk group (0–2 poor prognostic factors) to 5.5 months for the high-risk group (3–5 poor prognostic factors).

MANAGEMENT OF PLEURAL MESOTHELIOMA

Pleural mesothelioma remains localized to the hemithorax for most of the disease course. Regardless of the stage at diagnosis, drainage of malignant pleural effusions can effectively palliate effusion-related symptoms, such as dyspnea and pain. Periodic thoracentesis can be used to manage pleural effusions that reaccumulate slowly. Various approaches including pleurodesis and indwelling pleural catheters (which can be drained periodically) may be used to address rapidly reaccumulating pleural effusions. Pleurodesis involves complete drainage of the effusion via a chest tube or thoracoscopy followed by obliteration of the pleural space by forming adhesions between the visceral and parietal pleura. This is achieved by introducing agents, such as talc, which induce an inflammatory response in the pleural space. Video-assisted thoracoscopic partial pleurectomy (VAT-PP) involves thoracoscopic debulking of tumor along the parietal pleura and visceral pleural decortication to release trapped lung. VAT-PP may provide good symptom control in patients with malignant pleural effusions. However, the MesoVATS trial found no improvement in overall survival for patients who underwent VAT-PP compared with talc pleurodesis (1 year, 52% vs. 57%, respectively) (9). Additionally, the surgical complication rate and duration of hospital stay were significantly longer after VAT-PP.

Local control of disease with surgery is an important aspect of the care of patients who present with early stage disease, generally defined as stage I and II and selected patients with stage III, where the goal is macroscopic complete resection. The first step is to determine if the tumor is surgically resectable or not. This determination is based on a number of factors including the extent of disease (denoted by stage), extent of comorbid illnesses, cardiopulmonary status, and PS. Approximately 20% of newly diagnosed patients present with a good PS and stage I to III disease. These patients have potentially resectable disease and are treated with multimodality therapy consisting of surgery, chemotherapy, and radiation therapy (RT), since surgery alone is rarely curative. The majority of patients, however, present with advanced disease and/or comorbidities that preclude surgical resection, and are therefore unresectable or inoperable. These patients are generally treated with systemic chemotherapy or palliative care.

Surgically Resectable Disease

Surgery

There are two main surgical procedures used to achieve macroscopic complete resection in mesothelioma, pleurectomy/decortication (P/D), and extrapleural pneumonectomy (EPP). EPP involves en bloc removal of the ipsilateral parietal and visceral pleura, lung, pericardium, and hemidiaphragm. P/D is a less-invasive procedure involving removal of the parietal pleura from the chest wall, mediastinum, and diaphragm, as well as removal of the visceral pleura from the ipsilateral lung. The key difference between the procedures is that the lung is removed in EPP allowing administration of definitive doses of RT postoperatively with the goal of reducing the risk of local recurrence. However, EPP is associated with substantial postoperative morbidity and mortality, which in most large volume centers is below 8% (10,11). P/D preserves the lung parenchyma and provides good control of malignant pleural effusions with a lower rate of perioperative mortality, typically in the 0% to 5% range.

In a large retrospective series of over 600 patients who underwent resection from 1990 to 2006, Flores et al. reported an operative mortality of 7% for EPP (27/385 patients) and 4% for P/D (13/278 patients) (11). Multivariate analysis demonstrated better overall survival with P/D (HR = 1.4 for EPP; P < .001) when controlling for stage, histology, gender, and multimodality therapy. In another retrospective series of 1,365 patients who underwent resection from 1982 to 2012, the 30-day mortality was similar between patients who underwent EPP and P/D (4.1% vs. 2.6%, respectively; P = .4) (12). Patients with good prognostic factors (age <70 years, epithelioid subtype, received chemotherapy) had a similar overall survival with P/D or EPP.

Although there have been no randomized comparisons of efficacy between EPP and P/D, the Mesothelioma and Radical Surgery (MARS) study did assess the feasibility of a trimodality approach in the context of EPP (13). In this study, 112 patients underwent induction platinum-based chemotherapy and 50 were then randomly assigned to EPP followed by postoperative hemithorax RT or to no EPP. Median survival was 14.4 months (95% CI 5.3–18.7) for the EPP group and 19.5 months (95% CI 13.4—not reached) for the no EPP group. It is difficult to draw definitive conclusions from this trial since it was not adequately powered to detect a survival difference between the groups, but it does reinforce concerns regarding the utility of EPP. Decisions regarding surgery for patients with mesothelioma should be made on a case-by-case basis within a multidisciplinary team consisting of experienced thoracic surgeons, radiation oncologists, medical oncologists, pulmonologists, pathologists, and radiologists.

Adjuvant RT

RT to the ipsilateral chest cavity and chest wall after EPP improves local control (14). While intensity-modulated techniques can minimize the risk of RT-induced toxicity to adjacent organs, the possibility of lethal pulmonary injury exists for patients undergoing extensive pleural RT without having undergone EPP. Therefore, RT to the lung and chest wall is not standard practice after P/D (15). The role of hemithoracic RT after neoadjuvant chemotherapy and EPP was evaluated in the randomized SAKK 17/04 trial, which enrolled patients 18 to 70 years old with resectable stage I to III (T1–3 N0–2 M0) disease and good PS (16). Patients received three cycles of neoadjuvant cisplatin plus pemetrexed followed by EPP, and those with R0-R1 resection were randomly assigned to receive high-dose RT or observation. Overall, 151 patients received neoadjuvant chemotherapy, 113 went on to EPP, and 54 were randomized to RT or observation. Median local-regional relapse-free survival was similar in both arms (9.4 months for RT vs. 7.6 months for no RT).

Adjuvant and Neoadjuvant Chemotherapy

In patients with potentially resectable mesothelioma, chemotherapy can be given preoperatively (17, 18) or postoperatively (19). In the SAKK 17/04 trial, 34% of patients who received neoadjuvant chemotherapy achieved an objective response and 75% underwent EPP, with 64% achieving an R0/R1 resection (16). Chemotherapy agents used in this setting are essentially the same as those used in patients with unresectable disease and are described in more detail in the following.

Unresectable Disease

Role of Chemotherapy

Patients with surgically unresectable disease should be considered for palliative systemic chemotherapy. Although definitive comparisons are lacking, a large body of evidence suggests that chemotherapy offers improvements in symptom control, quality of life, and survival over best supportive care alone. One trial that randomized patients to active symptom control (ASC) with or without vinorelbine or mitomycin C, vinblastine, and cisplatin (MVP) closed prematurely due to poor accrual (20). In this study, the ASC alone arm (n = 136) and the ASC plus chemotherapy arms (vinorelbine, n = 136; MVP, n = 137) had a similar median survival of approximately 8 months when the chemotherapy arms were combined. However, when the chemotherapy arms were analyzed independently versus ASC alone, the vinorelbine arm demonstrated a 2-month survival benefit that approached statistical significance (HR 0.80, P = .08). There was no evidence of a survival benefit with MVP versus ASC alone (HR 0.99, P = .95). Only 140 patients in the chemotherapy arms underwent formal tumor assessment after treatment, with response rates of only 10% for MVP and 16% for vinorelbine. Notably, the chemotherapy agents used in this trial are not as active as the agents currently in use.

First-Line Chemotherapy

In patients with previously untreated, advanced mesothelioma, the pivotal EMPHACIS trial demonstrated that the combination of cisplatin plus pemetrexed provided an overall survival benefit over cisplatin alone (median, 12.1 vs. 9.3 months; HR 0.77, P = .02) (21) (Table 14.3). This trial randomized 456 patients who were not eligible for curative surgery to pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or cisplatin 75 mg/m² alone every 21 days. In addition to improved survival, response rates were also higher with the combination regimen (41.3% vs. 16.7%, P < .0001). Based on this data, the U.S. Food and Drug Administration (FDA) approved pemetrexed plus cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery. A similar survival benefit has been seen with the combination of raltitrexed plus cisplatin versus cisplatin alone, with survival improving from 8.8 to 11.4 months (22).

Role of Bevacizumab

Since its approval in 2003, pemetrexed plus cisplatin was the standard first-line therapy for patients with unresectable mesothelioma. In 2016, a randomized phase III trial (IFCT-GFPC-0701) reported that the addition of bevacizumab 15 mg/kg to pemetrexed plus cisplatin significantly improved overall survival from 16.1 months to 18.8 months (HR 0.77, P =·.167) (23). Patients enrolled in this study were 18 to 75 years old with PS 0 to 2 and no substantial cardiovascular comorbidity. Patients on therapeutic doses of anticoagulants or antiplatelet agents and those with uncontrolled hypertension, hemoptysis, or recent major surgery were excluded. Treatment-related drug discontinuation (24.3% vs. 6%) and bevacizumab-related adverse events, such as hypertension, hemorrhage, arterial and venous thromboembolic events, and proteinuria, were higher in patients receiving bevacizumab. Of note, median overall survival of 16.1 months in the control arm in this trial was much longer than that reported with cisplatin plus pemetrexed in the EMPHACIS trial. Based on these results, the combination of bevacizumab, pemetrexed, and cisplatin may be considered a standard regimen for selected patients with unresectable malignant pleural mesothelioma who are not amenable to curative surgery and have no contraindications to bevacizumab.

Supportive Care

The addition of folic acid and vitamin B₁₂ resulted in a significant reduction in toxicity, particularly grade 3/4 neutropenia and leukopenia, in the pemetrexed plus cisplatin arm of the pivotal EMPHACIS trial. Folic acid 400 to 1,000 mcg daily should be administered orally beginning 7 days prior to treatment with pemetrexed and continued during treatment and for 21 days after the last pemetrexed dose. Vitamin B₁₂ 1,000 mcg should be administered intramuscularly prior to treatment initiation and repeated every three cycles. Dexamethasone 4 mg orally is administered twice a day for 3 days beginning the day before treatment to minimize cutaneous reactions from pemetrexed. Cisplatin is highly emetogenic and nephrotoxic, so the routine use of pretreatment antiemetics and hydration is recommended.

Response Assessment

Response to chemotherapy is assessed using CT scans performed at baseline and then every two to three cycles during treatment. PET scans, although not recommended for routine follow-up, may supplement CT in selected cases by providing an indication of response or progression at an earlier time point. Serum biomarkers such as mesothelin may have a role in noninvasive tumor load assessment, but have not been prospectively validated in the clinical setting (24).

Duration of First-Line Therapy

Although combination chemotherapy improves survival and has a palliative effect on symptom control and quality-of-life, it is not curative. Based on pivotal trials discussed previously (23, 25), four to six cycles is considered the optimal duration of chemotherapy. Continuation of the first-line, combination regimen beyond this point is not thought to offer any benefit in terms of response, symptom relief, quality-of-life, or survival. In addition, cumulative toxicity occurs more frequently in patients who received longer durations of treatment.

Maintenance Therapy

The role of maintenance chemotherapy after four to six cycles of first-line chemotherapy is not known. In the IFCT-GFPC-0701 trial, the group that was randomized to receive bevacizumab, pemetrexed, and cisplatin was allowed maintenance bevacizumab after six cycles of combination chemotherapy until disease progression. A randomized phase II study is addressing the role of maintenance pemetrexed (NCT01085630). In this study, patients with pleural mesothelioma who have a response or stable disease after four cycles of pemetrexed plus cisplatin or carboplatin will be randomized to continue treatment with pemetrexed alone or to observation.

Alternative First-Line Regimens

The combination of pemetrexed plus carboplatin is a reasonable alternative for patients who cannot tolerate or have contraindications to cisplatin, based on results from large phase II trials and the expanded access experience showing comparable response rates and survival times (26–28). In an Italian phase II trial with 76 patients, pemetrexed plus carboplatin resulted in an overall response rate of 25% and median survival of 14 months (27).

Second-Line Chemotherapy

The vast majority of patients who receive first-line chemotherapy for mesothelioma will eventually experience disease progression. A number of agents have shown activity in the second-line setting and beyond, but none have been evaluated in randomized clinical trials. The most studied agent is pemetrexed, although this data was primarily derived when pemetrexed was not widely used as first-line therapy (29). A phase III trial randomized patients who had relapsed after first-line chemotherapy that did not include pemetrexed to receive pemetrexed plus best supportive care or best supportive care alone. Although patients who received pemetrexed had a higher response rate (18.7% vs. 1.7%; P < .0001) and better progression-free survival (median, 3.6 vs. 1.5 months; P = .148), overall survival was not significantly different between the arms (median, 9 months). Data on the utility of retreatment with pemetrexed are not available in patients who have received pemetrexed as part of their first-line regimens. Nevertheless, re-treatment with pemetrexed is considered a reasonable second-line option in patients who had disease control on prior pemetrexed-based therapy. Other second-line chemotherapy options include vinorelbine and gemcitabine. Single-agent vinorelbine resulted in a response rate of 16% and median overall survival of 9.6 months in patients with relapsed disease (30). The reported activity with single-agent gemcitabine monotherapy has been variable, but response rates of approximately 20% have been reported in combination with platinum (31).

Immunotherapy

Immune checkpoint inhibitors remain investigational in mesothelioma, although preliminary results are encouraging. In an open-label, single arm, phase II trial, the anti-CTLA4 monoclonal antibody tremelimumab showed a disease control rate of 31% and a 1-year survival of 48% in 21 patients with progression of disease on first-line platinum plus pemetrexed (32). An updated analysis continued to show clinical benefit with a median overall survival of 11.3 months (33). However, a phase III randomized, placebo-controlled trial failed to show superiority in overall survival for tremelimumab as second- or third-line therapy in 571 patients with pleural or peritoneal mesothelioma who were randomized to tremelimumab versus placebo (median, 7.7 vs. 7.3 months; HR = 0.92, P = .408) (34). In another trial, 25 patients with malignant pleural mesothelioma that was positive for PD-L1 expression received pembrolizumab, an anti-PD-1 antibody, and seven experienced a partial response with 12 having stable disease (35). Avelumab, an anti-PD-L1 antibody, resulted in unconfirmed responses in 9% (5 of 53) of patients in a trial which included patients with both PD-L1-positive and PD-L1-negative pleural or peritoneal mesothelioma (36).

Palliative RT

A short course of RT can effectively control pain in some patients with mesothelioma involving the chest wall. In a single-arm phase II trial of palliative RT (20 Gy in 5 fractions), 14 of 40 (35%) patients had a clinically meaningful improvement in pain 5 weeks after treatment (37). A wide variety of doses and fractionation schemes have been used for palliative RT.

 

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