Mesothelioma, a Review of Current Guidelines

*Sonia Maciá*

#### **Abstract**

Mesothelioma is considered as a rare tumor originating in the mesothelial surfaces of pleura or, more rarely, in other sites such as peritoneum, which harbors a very poor prognosis. Despite clinical research efforts, lack of available therapies remains clear. Standard of care treatments and guidelines have not been evolved much along recent years. In this chapter, main guidelines will be reviewed, besides a systematic Pubmed review, with a focus on epidemiology, diagnosis tests, and approved local and systemic treatments, including most important advances. Searched terms included "mesothelioma," "ESMO and NCCN guidelines," "diagnosis," "surgery," "targeted therapy," "clinical trials," "palliative treatment," and "meta-analysis." First-line regimen recommendations have not evolved since the phase III pivotal study of cisplatin-pemetrexed was published, and this combination became the standard of care. Targeted therapies have brought disappointing results. However, recent clinical trial data with immunotherapies are bringing some light and may become a new paradigm in the following years.

**Keywords:** malignant mesothelioma, chemotherapy, pemetrexed, immunotherapy, clinical trials, nivolumab, pembrolizumab, targeted therapy

#### **1. Introduction**

Malignant mesothelioma (MM) is a fatal disease which originates in the mesothelial surfaces of pleura or, more rarely, in other sites such as peritoneum. Most cases have been classically linked to asbestos exposure; however, ionizing radiation may also increase the risk of mesothelioma [1].

Its prognosis is very poor and it is difficult to treat, mainly because most patients are diagnosed with advanced disease [1–3]. Despite clinical research efforts, lack of available therapies remains clear and median overall survival is still approximately 1 year, with only 10% patients alive 5 years after diagnosis. Standard of care treatments and guidelines have not been evolved much along recent years. In this chapter, NCCN and ESMO guidelines have been reviewed, besides an electronic search of the Pubmed database, with a focus on the phase II and III clinical trials, guidelines, meta-analysis, and systematic reviews regarding epidemiology, diagnosis tests, surgical approach, and approved local and systemic treatments, including most important advances. Searched terms included "mesothelioma," "ESMO and NCCN guidelines," "diagnosis," "surgery," "targeted therapy," "clinical trials," "palliative treatment," and "meta-analysis." First-line regimen recommendations have not evolved since the phase III pivotal study of cisplatin-pemetrexed was published, and this combination became the standard of care despite its modest benefit

in survival. Pemetrexed seems to be the most active drug, but its use in the first-line setting limits its administration in further lines. However, a rechallenge may be done in responder patients, who might still get benefit [4].

Only few drugs have demonstrated a mild activity in refractory MM, and targeted therapies have provided disappointing results so far. However, recent clinical trial data with immunotherapies are bringing some light and may become a new paradigm in the following years.

### **2. Epidemiology**

Malignant mesothelioma (MM) is a rare tumor, with an incidence of less than 5 out of 100,000 inhabitants in Europe [1]. Diagnosis is usually done when disease is well advanced, and patients have a high symptom burden [3]. Incidence has decreased along the last decades globally worldwide. Mesothelioma has been typically related to asbestos exposure, which is the most well-known risk factor, although the latency period can be long, with a latency period being approximately 40 years, although in some cases, it may be as long as 60–70 years. Recent reports have suggested that also ionizing radiation may have a role, such as in patients previously treated with radiotherapy (RT). Other studies also suggest that erionite (which may be found in travel roads) increases the risk of MM. Smoking is not a risk factor. There may be a genetic risk in patients with BRCA-1 mutation [5–7].

The most common type of mesothelioma is malignant pleural mesothelioma, being up to 70% cases, followed by peritoneal (30%) and pericardial mesothelioma (1–2%) [2]. According to histology, there are three subtypes: epithelial, sarcomatoid, and biphasic [3], with epithelial subtype having a better prognosis.

Prevalence is highly linked to mortality, and mesothelioma is an unmet medical need due to its very poor prognosis, having a median overall survival of approximately 9–12 months, with only very modest improvements in survival over time [8].

#### **3. Diagnosis**

Most common symptoms include dyspnea, thoracic pain, and weight loss. Usually unilateral effusions are observed. A detailed occupational history is key, checking asbestos exposure among other previously exposed potential risk factors. Patients often present with advanced disease, but without distant metastases, as local implants or effusion cause pain and/or dyspnea. Brain metastases are rare [3].

Diagnosis assessments include chest X-ray, computed tomography (CT) scan of chest and upper abdomen, and thoracentesis, with examination of the pleural effusion and general laboratory blood tests [1]. Citology samples from pleural effusion are frequently negative or inconclusive, hence, histology may bring some further light for a more accurate diagnosis. Some biomarkers may be helpful, including calretinin, WT-1, D2-40, and citokeratyn 5/6, being negative in mesothelioma and positive in lung adenocarcinoma [9]. In order to obtain adequate histology, a thoracoscopy is highly recommended to optimally stage and to allow pleural fluid evacuation (with or without pleurodesis) [9, 10]. Mesothelioma can be difficult to identify and distinguish from benign pleural lesions and from other malignancies; it is therefore recommended to obtain biopsies from the tissue of both abnormal and normal appearance. When a thoracoscopy is not feasible or contraindicated, ultrasound-guided true-cut biopsies are a good alternative [10].

**5**

*Mesothelioma, a Review of Current Guidelines DOI: http://dx.doi.org/10.5772/intechopen.93569*

MM comprises a heterogeneous group of tumors, which are mainly classified as three subtypes (epithelioid, biphasic, and sarcomatoid), despite the numerous

Diagnosis samples may be obtained from pleural effusions, pleural biopsies, and surgical samples [1, 8–10]. Cytological diagnosis from effusion samples may be feasible, but sensitivity is highly variant, with variable atypia (usually low grade). Therefore, usually tissue biopsies with immunohistochemistry analysis are pivotal

Standardly used and most recommended biomarkers for diagnosis include calretinin, cytokeratin 5/6, WT1, and podoplanin (D240). For non-small cell adcenocarcinoma, the most useful markers are TTF1, CEA, and EP4 [8].

Staging procedures are aimed to describe anatomical extent correlating with prognostic features, which is key in order to make treatment decisions. Standard procedures for staging include chest and abdomen CT with contrast and PET/CT (for those patients who may undergo surgery). Video-assisted thoracoscopy (VATS)

Patients should be evaluated by a multidisciplinary committee, including oncologist, radiation oncologist, pathologist, pulmonologist, diagnostic imaging

The limitation of most classifications is their inaccuracy in describing tumor (T-) and node (N-) extent. The most recent staging system was presented by the International Mesothelioma Interest Group (IMIG) [11]. However, it failed to be an independent prognostic factor when analyzed in the clinical setting using multivariate analysis [11–14]. Hence, further workup is needed in order to get an accurate

If a surgical resection is planned, either mediastinoscopy or endobronchial ultrasound of mediastinal lymph nodes are recommended [15]. Besides, two additional tests may be useful if suggested by imaging: laparoscopy in order to rule out any transdiaphragmatic extension and chest MRI to check vascular

Chemotherapy is recommended as the sole therapy for patients with ECOG 0–2 who are not amenable for surgery. For patients with ECOG 3–4, best supportive care

Chemotherapy has a role in the palliative treatment of advanced mesothelioma, getting an improvement of symptoms and modest benefit in survival. Standard first-line treatment is based on platinum doublets, with either pemetrexed or raltitrexed [18, 19], being cisplatin/pemetrexed the only FDA-approved

regimen. This combination was investigated in a phase III trial comparing cisplatin/pemetrexed vs. cisplatin monotherapy, getting a benefit in survival by

variants that are described in the 2004 WHO classification [9].

is recommended if contralateral disease is suspected [3].

**4. Pathology**

**5. Staging**

for confirmatory diagnosis.

specialist, and surgeon.

involvement [14–17].

is strongly recommended.

and prognostic staging system.

**6. Treatment for mesothelioma**

**6.1 First-line therapy for mesothelioma**

2.8 months (12.1 vs. 9.3 months, P = 0.02) [18].
