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. ( EB , I , S )
614
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)
d) make material available for additional studies (e.g. molecular profiling). ( EB , H , S )
614
When performing a thoracoscopic biopsy, the minimal number of incisions (≤2) is recommended and should ideally be placed in areas that would be used for subsequent definitive resection in order to avoid tumor implantation into the chest wall. ( EB , H , S )
614
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 is recommended). ( EB , I , M )
614
In patients who are not candidates for thoracoscopic biopsy or open pleural biopsy, who also have a non-diagnostic thoracentesis or do not have a pleural effusion, clinicians should perform a core needle biopsy of an accessible lesion. ( EB , I , S )
614
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. ( EB , I , S )
614
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. ( EB , I , S )
614
Mesothelioma should be reported as epithelial, sarcomatoid or biphasic, because these subtypes have a clear prognostic significance. ( EB , H , S )
614
In surgical, thoracoscopic, or open pleural biopsies with sufficient tissue, further subtyping and quantification of epithelial vs. sarcomatoid components of mesothelioma may be undertaken. ( IC , , M )
614
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. ( EB , I , M )
614
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. ( EB , I , M )
614
Staging
A CT scan of the chest and upper abdomen with IV contrast is recommended as the initial staging in patients with mesothelioma. ( EB , I , S )
614
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. ( EB , I , S )
614
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. ( EB , I , S )
614
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. ( EB , I , M )
614
For patients being considered for maximal surgical cytoreduction, a mediastinoscopy and/or endobronchial US should be considered if enlarged and/or PET-avid mediastinal nodes are present. ( EB , I , S )
614
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. ( EB , I , M )
614
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. ( EB , I , S )
614
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. ( EB , H , S )
614
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 ≤6 measurement sites with ≥1 cm thickness measured perpendicular to the chest wall or mediastinum with ≤2 sites on each of 3 CT sections separated by ≥1 cm axially. ( EB , I , S )
614
Assessment of tumor volume by CT scan may enhance clinical staging and provide prognostic information but remains investigational and thus is NOT recommended. ( EB , I , S )
614
It is recommended that tumor response classification be determined based on RECIST criteria from the comparisons of these sums across serial CT scans. ( EB , I , S )
614
Treatment
Chemotherapy
Chemotherapy should be offered to patients with mesothelioma because it improves survival and quality of life. ( EB , I , S )
614
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. ( IC , , M )
614
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 should receive palliative care. ( EB , L , M )
614
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. ( EB , H , S )
614
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 utilized cisplatin/pemetrexed. Data with carboplatin/pemetrexed plus bevacizumab is insufficient for a clear recommendation. ( EB , H , M )
614
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. ( EB , I , M )
614
In patients who may not be able to tolerate cisplatin, carboplatin may be offered as a substitute for cisplatin. ( EB , I , S )
614
Re-treatment with pemetrexed-based chemotherapy may be offered in pleural mesothelioma patients who achieved durable (>6 months) disease control with first-line pemetrexed-based chemotherapy. ( EB , L , M )
614
Given the very limited activity of 2nd line chemotherapy in patients with mesothelioma, participation in clinical trials is recommended. ( EB , I , S )
614
In patients for whom clinical trials are not an option, vinorelbine may be offered as second line therapy. ( EB , L , M )
614
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. ( EB , L , M )
614
Frontline pemetrexed-based chemotherapy should be given for 4–6 cycles. For patients with stable or responding disease, a break from chemotherapy is recommended at that point. ( EB , L , M )
614
There is insufficient evidence to support the use of pemetrexed maintenance in mesothelioma patients and thus it is NOT recommended. ( EB , L , S )
614
Surgical Cytoreduction
In selected patients with early stage disease, it is strongly recommended that a maximal surgical cytoreduction should be performed. ( EB , I , S )
614
Maximal surgical cytoreduction as a single modality treatment is generally insufficient; additional anti-neoplastic 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, medical and radiation oncologists. ( EB , I , S )
614
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 disease (N3) disease should be a contraindication to maximal surgical cytoreduction. ( EB , I , S )
614
Patients with histologically confirmed sarcomatoid mesothelioma should NOT be offered maximal surgical cytoreduction. ( EB , I , S )
614
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. ( EB , I , S )
614
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. ( EB , I , S )
614
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). ( EB , I , S )
614
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 co-morbid 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 pathological 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 immunological profiling) should be obtained. ( EB , I , S )
614
In patients who have a symptomatic pericardial effusion, percutaneous catheter drainage or pericardial window may be performed. ( EB , H , S )
614
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. ( EB , I , S )
614
Chemotherapy may be given pre- or post-operatively in the context of multimodality treatment. ( EB , L , M )
614
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. ( EB , I , M )
614
In the context of multimodality treatment, four to six cycles of pemetrexed/platin based chemotherapy may be administered pre- or post-operatively. ( EB , I , M )
614
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. ( EB , L , W )
614
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. ( EB , I , S )
614
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. ( EB , I , S )
614
Radiation Therapy
Prophylactic irradiation of intervention tracts should generally NOT be offered patients to prevent tract recurrences. ( EB , H , M )
614
It is recommended that adjuvant radiation should be offered to patients who have resection of intervention tracts found to be histologically positive. ( EB , I , M )
614
Radiation therapy should be offered as an effective treatment modality to palliate patients with symptomatic disease. ( EB , I , S )
614
It is recommended that standard dosing regimens used in other diseases be offered to patients with mesothelioma (8 Gy x 1 fraction, 4 Gy x 5 fractions or 3 Gy x 10 fractions). ( EB , I , S )
614
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. ( IC , , M )
614
Hemithoracic adjuvant radiation therapy may be offered to patients who undergo non-lung sparing cytoreductive surgery (EPP), preferably in centers of excellence with experience in this modality for mesothelioma. ( EB , I , S )
614
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 be performed only in highly experienced centers within the context of a clinical trial. ( EB , I , M )
614
Hemithoracic adjuvant intensity-modulated radiation therapy may be offered to patients who undergo lung sparing cytoreductive surgery (P/D or EPD). This potentially toxic regimen should be performed only in highly experienced centers, preferably in the context of a clinical trial. ( EB , I , M )
614
Due to the potential for severe pulmonary toxicity, neoadjuvant radiation therapy is NOT recommended for patients who undergo lung sparing surgical cytoreductive surgery. ( IC , , S )
614
For palliative radiation therapy, electrons, 2D, 3D, and IMRT may be considered appropriate techniques depending on location of the treatment target and organs at risk. ( EB , I , S )
614
For adjuvant or neoadjuvant hemithoracic radiation therapy, 3D or IMRT 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. ( EB , I , S )
614
It is recommended that standard dosimetric guidelines for organs at risk be used as established predictors of radiation toxicity. (EB, I, S)
The purpose of this guideline is to provide recommendations for the management of patients with malignant pleural mesothelioma (MPM), an aggressive tumor with a poor prognosis.
This clinical practice guideline also aims to outline the management of patients with MPM, including diagnosis, pathologic confirmation, and surgical and medical management.
Target Patient Population
Patients with malignant pleural mesothelioma
Target Provider Population
Medical, surgical, and radiation oncologists; oncology nurses and physician assistants; pulmonologists; radiologists; pathologists
The ASCO Clinical Practice Guidelines Committee (CPGC) convened an Expert Panel with multidisciplinary representation in medical oncology, nuclear and radiation oncology, surgical oncology, pulmonology, pathology, community oncology, patient/advocacy representation, and guideline implementation. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review and submitted to Journal of Clinical Oncology for editorial review and consideration for publication. No date mentioned.
Specialties Involved
Family Medicine, Internal Medicine General, Oncology, Pathology, Pulmonology, Radiology, Medical Oncology, Surgical Oncology, Radiation Oncology, Oncology, Oncology, Oncology
Description of Systematic Review
The recommendations were developed by an Expert Panel with multidisciplinary representation using a systematic review (1990 to 2016), which included systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective and retrospective comparative observational studies, and clinical experience.
List of Questions
This clinical practice guideline addresses five overarching clinical questions: (1) What is the optimal approach to obtain an accurate diagnosis of mesothelioma? (2) What initial assessment is recommended before initiating any therapy for mesothelioma? (3) What is the appropriate first- and second-line systemic treatment of patients with mesothelioma? (4) What is the appropriate role of surgical cytoreduction in the management of mesothelioma? (5) When should radiation be recommended for mesothelioma?
Description of Study Criteria
Articles were selected for inclusion in the systematic review of the evidence based on the following criteria:
•Population: Patients diagnosed with MPM.
•Interventions that focused on diagnosis, staging, imaging, chemotherapy, radiation, and surgical cytoreduction of patients with MPM.
•Study designs included were systematic reviews, meta-analyses, RCTs, and prospective and retrospective comparative observational studies. Some phase II studies were included to address some of the clinical questions for chemotherapy management.
•A minimum sample size of 20.
Articles were excluded from the systematic review if they were meeting abstracts not subsequently published in peer-reviewed journals; editorials, commentaries, letters, news articles, case reports, or narrative reviews; or published in a non-English language.
Description of Search Strategy
PubMed and the Cochrane Collaboration Library electronic databases (± meeting abstracts) were searched for evidence reporting on outcomes of interest. Refer to the Data Supplement for details.
Description of Study Selection
Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplements 1.
Description of Evidence Analysis Methods
The guideline recommendations were crafted, in part, using the principles of the GuideLines Into DEcision Support (GLIDES) methodology.
Description of Evidence Grading
High: High confidence that the available evidence reflects the true magnitude and direction of the net effect (i.e., balance of benefits v harms) and that further research is very unlikely to change either the magnitude or direction of this net effect.
Intermediate: Moderate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect.
Low: Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect.
Insufficient: Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. The use of the consensus opinion of experts is reasonable to inform outcomes related to the topic.
Description of Recommendation Grading
Evidence Based: There was sufficient evidence from published studies to inform a recommendation to guide clinical practice.
Formal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. Therefore, the Expert Panel used a formal consensus process to reach this recommendation, which is considered the best current guidance for practice. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). The results of the formal consensus process are summarized in the guideline and reported in the Data Supplement (see the Supporting Documents" field).
Informal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the Expert Panel. The Panel agreed that a formal consensus process was not necessary for reasons described in the literature review and discussion. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak").
No recommendation: There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time. The Panel deemed the available evidence as insufficient and concluded it was unlikely that a formal consensus process would achieve the level of agreement needed for a recommendation.
Description of Funding Source
ASCO provides funding for Guideline Development.
Company/Author Disclosures
Author Disclosures of Potential Conflicts of Interest are documented in the Guideline.
Percentage of Authors Reporting COI
100
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