Treatment of Malignant Pleural Mesothelioma

Clinicians should perform an initial thoracentesis when patients present with symptomatic pleural effusions and send pleural fluid for cytologic examination for initial assessment for possible mesothelioma.

In patients for whom antineoplastic treatment is planned, it is strongly recommended that a thoracoscopic biopsy should be performed. This will: (a) enhance the information available for clinical staging; (b) allow for histologic confirmation of diagnosis; (c) enable more accurate determination of the pathologic subtype of mesothelioma (epithelial, sarcomatoid, biphasic); and (d) make material available for additional studies (e.g. molecular profiling).

When performing a thoracoscopic biopsy, the minimal number of incisions (two or fewer) is recommended and should ideally be placed in areas that would be used for subsequent definitive resection to avoid tumor implantation into the chest wall.

In patients with suspected mesothelioma in whom treatment is planned, an open pleural biopsy should be performed if the extent of tumor prevents a thoracoscopic approach. The smallest incision possible is encouraged (generally 6 cm or less is recommended).

In patients who are not candidates for thoracoscopic biopsy or open pleural biopsy, who also have a nondiagnostic thoracentesis or do not have a pleural effusion, clinicians should perform a core needle biopsy of an accessible lesion.

Cytologic evaluation of pleural fluid can be an initial screening test for mesothelioma, but it is not a sufficiently sensitive diagnostic test. Whenever definitive histologic diagnosis is needed, biopsies via thoracoscopy or CT guidance offer a better opportunity to reach a definitive diagnosis.

Histologic examination should be supplemented by immunohistochemistry using selected markers expected to be positive in mesothelioma (e.g. calretinin, keratins 5/6, and nuclear WT1) as well as markers expected to be negative in mesothelioma (e.g. CEA, EPCAM, Claudin 4, TTF-1). These markers should be supplemented with other markers that address the differential diagnosis in that particular situation.

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

In surgical, thoracoscopic, or open pleural biopsies with sufficient tissue, further subtyping and quantification of epithelial versus sarcomatoid components of mesothelioma may be undertaken.

The non-tissue-based biomarkers that are under evaluation at this time do not have the sensitivity or specificity to predict outcome or monitor tumor response and are therefore not recommended.

While tumor genomic sequencing is currently done on a research basis in mesothelioma and it may become clinically applicable in the near future, it is not recommended at this time.

A CT scan of the chest and upper abdomen with IV contrast is recommended as the initial staging in patients with mesothelioma.

An FDG PET/CT should usually be obtained for initial staging of patients with mesothelioma. This may be omitted in patients who are not being considered for definitive surgical resection.

If abnormalities that suggest metastatic disease in the abdomen are observed on a chest and upper abdomen CT or on a PET/CT then consideration should be given to perform a dedicated abdominal (+/− pelvic) CT scan, preferably with IV and oral contrast.

An MRI (preferably with IV contrast) may be obtained to further assess invasion of the tumor into the diaphragm, chest wall, mediastinum, and other areas.

For patients being considered for maximal surgical cytoreduction, a mediastinoscopy and/or endobronchial ultrasound should be considered if enlarged and/or PET-avid mediastinal nodes are present.

In the presence of contralateral pleural abnormalities detected on initial PET/CT or chest CT scan, a contralateral thoracoscopy may be performed to exclude contralateral disease.

In patients with suspicious findings for intra-abdominal disease on imaging and no other contraindications to surgery, it is strongly recommended that a laparoscopy be performed.

The current AJCC/UICC staging classification remains difficult to apply to clinical staging with respect to both T and N components and thus may be imprecise in predicting prognosis. Physicians should recognize that in patients with clinical stage I/II disease, upstaging may occur at surgery.

The optimal approach to mesothelioma measurement requires the expertise of a radiologist to identify measurement sites on CT as per modified RECIST for mesothelioma. This approach requires calculating the sum of up to six measurement sites with at least 1 cm thickness measured perpendicular to the chest wall or mediastinum with no more than two sites on each of three CT sections separated by at least 1 cm axially.

Assessment of tumor volume by CT scan may enhance clinical staging and provide prognostic information but remains investigational and thus is not recommended.

It is recommended that tumor response classification be determined based on RECIST criteria from the comparisons of these sums across serial CT scans.

Chemotherapy should be offered to patients with mesothelioma because it improves survival and quality of life.

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.

Selected patients with a poor performance status (PS 2) may be offered single-agent chemotherapy or palliative care alone. Patients with a PS of 3 or greater should receive palliative care.

The recommended first-line chemotherapy for patients with mesothelioma is pemetrexed plus platinum. However, patients should also be offered the option of enrolling in a clinical trial.

The addition of bevacizumab to pemetrexed-based chemotherapy improves survival in select patients and therefore may be offered to patients with no contraindications to bevacizumab. The randomized clinical trial demonstrating benefit with bevacizumab used cisplatin/pemetrexed; data with carboplatin/pemetrexed plus bevacizumab are insufficient for a clear recommendation.

Bevacizumab is not recommended for patients with PS 2, substantial cardiovascular comorbidity, uncontrolled hypertension, age >75, bleeding or clotting risk, or other contraindications to bevacizumab.

In patients who may not be able to tolerate cisplatin, carboplatin may be offered as a substitute for cisplatin.

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 in patients with mesothelioma, participation in clinical trials is recommended.

In patients for whom clinical trials are not an option, vinorelbine may be offered as second-line therapy.

In asymptomatic patients with epithelial mesothelioma and a low disease burden who are not surgical candidates, a trial of expectant observation may be offered before initiation of systemic therapy.

Front-line pemetrexed-based chemotherapy should be given for four to six cycles. For patients with stable or responding disease, a break from chemotherapy is recommended at that point.

There is insufficient evidence to support the use of pemetrexed maintenance in mesothelioma patients, and thus it is not recommended.

In selected patients with early-stage disease, it is strongly recommended that a maximal surgical cytoreduction should be performed.

Maximal surgical cytoreduction as a single modality treatment is generally insufficient; additional antineoplastic treatment (chemotherapy and/or radiation therapy) should be administered. It is recommended that this treatment decision should be made with multidisciplinary input involving thoracic surgeons, pulmonologists, and medical and radiation oncologists.

Patients with transdiaphragmatic disease, multifocal chest wall invasion, or histologically confirmed contralateral mediastinal or supraclavicular lymph node involvement should undergo neoadjuvant treatment before consideration of maximal surgical cytoreduction. Contralateral (N3) or supraclavicular (N3) disease should be a contraindication to maximal surgical cytoreduction.

Patients with histologically confirmed sarcomatoid mesothelioma should not be offered maximal surgical cytoreduction.

Patients with ipsilateral histologically confirmed mediastinal lymph node involvement should only undergo maximal surgical cytoreduction in the context of multimodality therapy (neoadjuvant or adjuvant chemotherapy). Optimally, these patients should be enrolled in clinical trials.

Maximal surgical cytoreduction involves either extrapleural pneumonectomy (EPP) or lung-sparing options (pleurectomy/decortication [P/D], extended P/D). When offering maximal surgical cytoreduction, lung-sparing options should be the first choice, due to decreased operative and long-term risk. EPP may be offered in highly selected patients when performed in centers of excellence.

A maximal cytoreduction (either lung sparing or non–lung sparing) should only be considered in patients who meet specific preoperative cardiopulmonary functional criteria, have no evidence of extrathoracic disease, and are able to receive multimodality treatment (adjuvant or neoadjuvant).

In patients who have a symptomatic pleural effusion, who are PS 2 or greater, or in whom a maximal cytoreduction cannot be performed (due to disease extent or comorbid conditions), palliative approaches such as a tunneled permanent catheter placement or thoracoscopic exploration with partial resection and/or pleurodesis should be offered. In the latter case, additional biopsy to confirm pathologic diagnosis should be performed during the procedure. If the patient is being evaluated for investigational therapy, material for additional studies (e.g. molecular and/or immunologic profiling) should be obtained.

In patients who have a symptomatic pericardial effusion, percutaneous catheter drainage or pericardial window may be performed.

Since surgical cytoreduction is not expected to yield an R0 resection, it is strongly recommended that multimodality therapy with chemotherapy and/or radiation therapy should be administered.

Chemotherapy may be given pre- or postoperatively in the context of multimodality treatment.

Adjuvant radiation therapy may be associated with a decreased risk of local recurrence and may be offered to patients who have undergone maximal cytoreduction. Treatment is complex, and it is recommended that it should be delivered at experienced centers of excellence.

In the context of multimodality treatment, four to six cycles of pemetrexed/platin-based chemotherapy may be administered pre- or postoperatively.

Intracavitary therapies (chemotherapy or photodynamic therapy) may be administered safely in experienced centers of excellence, preferably in the context of a clinical trial. Their role in improving outcome is indeterminate.

Tunneled pleural catheters are not recommended in patients who are candidates for maximal surgical cytoreduction, because of the risk of tumor implantation into the chest wall.

In patients who are not candidates for maximal surgical cytoreduction, tunneled pleural catheters or pleurodesis (performed via chest tube or thoracoscopy) may be offered. As noted above, these procedures should be performed using the minimal number and size incisions. Multidisciplinary input including surgical consultation with a center of excellence should be sought to optimize management of a pleural effusion and for consideration of investigational intracavitary therapies.

Prophylactic irradiation of intervention tracts should generally not be offered patients to prevent tract recurrences.

It is recommended that adjuvant radiation should be offered to patients who have resection of intervention tracts found to be histologically positive.

Radiation therapy should be offered as an effective treatment modality to palliate patients with symptomatic disease.

It is recommended that standard dosing regimens used in other diseases be offered to patients with mesothelioma (8 Gy × one fraction, 4 Gy × five fractions, or 3 Gy × 10 fractions).

Radiation therapy may be offered to patients with localized asymptomatic recurrence. The dosing fractionation is dependent on the site and extent of disease and should be determined by the radiation oncologist in consultation with the patient.

Hemithoracic adjuvant radiation therapy may be offered to patients who undergo non–lung-sparing cytoreductive surgery (extrapleural pneumonectomy), preferably in centers of excellence with experience in this modality for mesothelioma.

Hemithoracic neo-adjuvant radiation therapy may be offered to patients who undergo non–lung-sparing cytoreductive surgery. This potentially toxic regimen remains experimental and should only be performed in highly experienced centers within the context of a clinical trial.

Hemithoracic adjuvant intensity-modulated radiation therapy may be offered to patients who undergo lung-sparing cytoreductive surgery (pleurectomy/decortication or extended pleurectomy/decortication). This potentially toxic regimen should only be performed in highly experienced centers, preferably in the context of a clinical trial.

Due to the potential for severe pulmonary toxicity, neoadjuvant radiation therapy is not recommended for patients who undergo lung-sparing surgical cytoreductive surgery.

For palliative radiation therapy, electrons, 2D, 3D, and intensity-modulated radiation therapy may be considered appropriate techniques depending on location of the treatment target and organs at risk.

For adjuvant or neoadjuvant hemithoracic radiation therapy, 3D or intensity-modulated radiation therapy may be offered, respecting guidelines of organs at risk. Proton therapy may be considered in centers with significant experience, preferably in the context of a clinical trial.

It is recommended that standard dosimetric guidelines for organs at risk be used as established predictors of radiation toxicity.