Mesothelioma Guidelines

The following organizations have released guidelines on the diagnosis and treatment of malignant pleural mesothelioma (MPM):

• American Society of Clinical Oncology (ASCO)
• National Comprehensive Cancer Network (NCCN)
• The European Respiratory Society/European Society of Thoracic Surgeons/European Association for Cardio-Thoracic Surgery/European Society for Radiotherapy and Oncology (ERS/ESTS/EACTS/ESTRO)
• European Society for Medical Oncology (ESMO)
• British Thoracic Society (BTS)

NCCN guidelines recommend that patients be managed by a multidisciplinary team with experience in MPM. ^[52]  Treatment options include surgery, radiation therapy (RT), and/or chemotherapy. Select patients may be candidates for multimodality treatment.

Diagnosis

All the guidelines recommend the following tests be performed in the initial evaluation and diagnosis of MPM ^{[52, 50, 51]} :

• Chest CT with contrast
• Thoracentesis for cytologic assessment
• Pleural biopsy (thoracoscopic biopsy is preferred)

In addition, NCCN guidelines suggest that soluble mesothelin-related peptide (SMRP) measurement may be considered and may correlate with disease status, according to NCCN guidelines. ^[52] In contrast, ESMO guidelines state that circulating tumor markers cannot adequately distinguish MPM. ^[56]

ASCO and BTS guidelines concur on the following recommendations for the pathological diagnosis of MPM ^{[50, 51]} :

• Do not rely on cytology alone to make a diagnosis of MPM. If effusion cytology is frankly malignant, the diagnosis may be strongly suggested but confirmation by biopsy, if possible, is recommended. 

• Immunohistochemistry (IHC) is recommended for the differential diagnosis of MPM in both biopsy and cytology-type specimens.

• A combination of at least two positive mesothelial (calretinin, cytokeratin 5/6, Wilms tumor 1, D-240) and at least two negative adenocarcinoma immunohistochemical markers (TTF1, CEA, Ber-EP4) should be used in the differential diagnosis of MPM. 

• MPM should be reported as epithelial, sarcomatoid, or biphasic, because these subtypes have a clear prognostic significance 

Chemotherapy

NCCN and ASCO concur on the following recommendations for first-line chemotherapy ^{[51, 52]} :

• Chemotherapy should be offered either alone for medically inoperable patients or as part of a multimodality regimen for patients with medically operable disease
• In asymptomatic patients with epithelial histology and minimal pleural disease who are not surgical candidates, a trial of close observation may be offered prior to the initiation of chemotherapy.
• First-line chemotherapy of pemetrexed-cisplatin (category 1) or pemetrexed-carboplatin (category 2A)
• Addition of bevacizumab (Avastin) to pemetrexed-cisplatin in selected patients 
• Bevacizumab not recommend for patients with significant cardiovascular comorbidity, uncontrolled hypertension, or bleeding/clotting risk.

According to NCCN guidelines, nivolumab plus ipilimumab is also a category 1 option (preferred in non-epithelioid mesothelioma). Other acceptable first-line chemotherapy options include gemcitabine-cisplatin for patients who cannot take pemetrexed. For patients who are not candidates for platinum-based combination therapy, pemetrexed or vinorelbine are first-line treatment options. ^[52]

The BTS guidelines recommend first-line therapy with cisplatin and pemetrexed in patients with good performance status. Raltitrexed is an alternative to pemetrexed. ^[50]

ESMO recommendations for first-line therapy are as follows ^[56]

• Pemetrexed combined with cisplatin (or alternatively carboplatin), and vitamin supplementation, for up to six cycles
• Combination of bevacizumab with platinum–pemetrexed
• Nivolumab plus ipilimumab, given up to 2 years equivalent dosing, regardless of histologies or PD-L1 status for unresectable MPM
• Maintenance gemcitabine is not routinely recommended in patients with non-progressive MPM but may prolong progression-free survival and can be considered when the benefits of deferring progression outweigh the inconveniences and toxicities of ongoing treatment
• Maintenance pemetrexed is not recommended in patients with non-progressive MPM after first-line platinum–pemetrexed

Second-line therapy

NCCN recommendations for second-line therapy are as follows ^[52] :

• Pemetrexed, if not administered as first-line therapy (category 1); consider rechallenge if the patient had a good sustained response at the time initial chemotherapy was interrupted
• Nivolumab ± ipilimumab, if not administered in first-line therapy
• Pembrolizumab

ASCO guidelines offer the following recommendations for second-line chemotherapy ^[51] :

• Retreatment with pemetrexed-based chemotherapy may be offered in pleural mesothelioma patients who achieved durable (> 6 months) disease control with first-line pemetrexed-based chemotherapy 
• Given the very limited activity of second-line chemotherapy, participation in clinical trials is recommended
• In patients for whom clinical trials are not an option, vinorelbine may be offered 

The BTS guidelines advise that pemetrexed or vorinostat should not be offered as second-line treatment for patients with MPM. ^[50]

ESMO recommendations for second-line MSM therapy are as follows ^[56] :

• Single-agent pembrolizumab in immunotherapy-naïve patients as second-line therapy has similar outcomes to single-agent chemotherapy.
• Single-agent nivolumab is superior to best supportive care in pretreated immunotherapy-naïve patients.
• Combination nivolumab–ipilimumab can be considered in immunotherapy-naïve patients as a second- or third-line treatment option.
• Reintroduction of platinum–pemetrexed or pemetrexed chemotherapy has second-line activity in selected circumstances, as suggested by objective response rates (ORRs).
• Single-agent gemcitabine or vinorelbine has limited second-line activity, as suggested by ORRs or overall survival rates
• Initial evidence shows encouraging activity of gemcitabine combined with ramucirumab.

Surgery

NCCN and ASCO concur on the following recommendations for surgical treatment of MPM ^{[51, 52]} :

• In selected patients with early-stage disease, pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) are reasonable surgical options to achieve complete gross cytoreduction.
• Mediastinal node dissection of at least three nodal stations is recommended in patients undergoing either P/D or EPP. 
• Maximal surgical cytoreduction as a single modality treatment is generally insufficient; additional antineoplastic treatment (chemotherapy and/or radiation therapy) should be administered.
• Surgery is not recommended for patients with stage IV disease, saracomatoid or mixed histology. 
• Surgery is not recommended for patients with N2 disease unless performed at a center of expertise or in a clinical trial

However, the ERS/ESTS/EACTS/ESTRO joint guidelines published in 2020 declined to issue a recommendation on the use of P/D or EPP because of the large variability and conflicting results of reported outcomes for morbidity, mortality, quality of life and overall and disease-free survival. ERS/ESTS/EACTS/ESTRO guidelines acknowledge that surgery may be appropriate in select patients. In those cases, P/D is preferred over EPP due to its lower comparative respiratory postoperative morbidity and quality of life. Patients considered for radical surgery should be included in prospective randomized controlled clinical trials or in national/international surgical registries. ^[53]

ERS/ESTS/EACTS/ESTRO guidelines for the surgical treatment of MPM include the following recommendations ^[53] :

• The first choice to control a recurrent MPM effusion and achieve pleurodesis in patients with expanded lungs is talc poudrage via thoracoscopy.
• Palliative video-assisted thoracic surgery–partial pleurectomy (VATS-PP) to obtain pleural effusion control in symptomatic patients may be considered for patients fit enough to undergo surgery who cannot or did not benefit from chemical pleurodesis or indwelling catheter.

ESMO surgical recommendations are as follows ^[56]

• Surgery is recommended for obtaining diagnostic samples of tumor tissue, for staging, and for palliation of pleural effusions when chest tube drainage is not successful.
• Talc poudrage via thoracoscopy remains the first surgical procedure of choice for pleurodesis over VATS partial pleurectomy.
• Macroscopic complete resection, in combination with other modalities, is recommended in selected MPM patients, to be carried out at experienced centers and to be discussed with a multidisciplinary team involving thoracic surgeons, pulmonologists, medical and radiation oncologists.
• Extended pleural decortication is a lung-preserving procedure and is preferred over EPP.

Radiation Therapy

NCCN guidelines recommend the use of radiation therapy (RT) as part of a multimodality regimen, but do not recommend RT alone for treatment, and do not routinely recommend prophylactic RT to prevent instrument-tract recurrence after pleural intervention. ^[52] ASCO guidelines recommend against prophylactic RT but recommend adjuvant RT for resection of intervention tracts found to be histologically positive. ^[51]

The BTS recommends against preoperative or postoperative RT, prophylactic radiotherapy to chest wall procedure tracts, and hemithorax RT. ^[50]  Similarly, the ERS/ESTS/EACTS/ESTRO guidelines strongly recommend against using RT to prevent procedure-tract metastases, and recommend considering postoperative RT only in the context of clinical trials and/or including it in national/international surgical registries. ^[53]

All four guidelines recommend RT for palliative therapy to relieve chest pain, bronchial or esophageal obstruction, or symptomatic relief of metastases in the bone or brain. ^{[50, 51, 52, 53]}

In 2019, the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation issued an expert opinion recommending the use of RT for MPM in the following scenarios ^[57] :

• Before or after extrapleural pneumonectomy
• As an adjuvant to lung-sparing procedures (ie, without pneumonectomy)
• As palliative therapy for focal symptoms caused by the disease

ESMO recommendations regarding RT for MPM are as follows ^[56] :

• RT can be considered for palliation of pain related to local infiltration of thoracic structures
• •The use of prophylactic RT of tracts after diagnostic or therapeutic pleural procedures to prevent chest wall metastases is not recommended.
• RT can be considered in an adjuvant setting after macroscopic complete resection to reduce the local failure rate; however, no evidence is available for its use as a standard treatment.
• When postoperative RT is applied, strict dose constraints for thoracic critical organs must be adhered to in order to avoid toxicity to organs at risk.

Palliative and supportive care and surveillance

ESMO recommendations are as follows ^[56] :

• Early access to specialist palliative care at the time of diagnosis does not improve quality of life
• Pleurodesis is useful in preventing recurrent effusions
• For recurrent pleural effusions, an indwelling pleural catheter  can provide good clinical benefit.
• For patients with indwelling pleural catheters, aggressive draining is not superior to symptomatic drainage for controlling breathlessness.
• For surveillance, imaging to evaluate response is best carried out with contrast-enhanced computed tomography scanning.