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Diagnosis and Prognostic Factors
Prognosis in malignant mesothelioma is difficult to assess consistently because there is great variability in the time before diagnosis and the rate of disease progression. In large retrospective series of pleural mesothelioma patients, important prognostic factors were found to be:[1,2][Level of evidence: 3iiiA]
Prognostic Scoring Systems
Two prognostic scoring systems have been developed for advanced unresectable mesothelioma and are used to stratify patients enrolling in clinical trials: the Cancer and Leukemia Group B (CALGB) index and the European Organization for the Research and Treatment of Cancer (EORTC) index.
The CALGB index was developed retrospectively using the clinical characteristics of 337 patients treated on clinical trials of chemotherapy for advanced mesothelioma during a 10-year period.[Level of evidence: 3iiiA] These characteristics were used collectively to define six prognostic groups with median survivals ranging from 13.9 months (Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0, age <49 years; or PS = 0, age ≥49 years and hemoglobin ≥14.6g/dL) to 1.4 months (PS = 1 or 2 and white blood cell [WBC] count ≥15.6 × 109/L).
The prognostic value of the CALGB index was evaluated retrospectively in a phase II clinical trial of 105 patients.[Level of evidence: 3iii] Median survival in this study for patients in the best CALBG prognostic group was 29.9 months compared with 1.8 months for patients in the worst prognostic group. However, the intermediate groups 2 to 4 overlapped in their survival times.
The EORTC index was also developed retrospectively using the characteristics of 181 patients from five phase II clinical trials of chemotherapy during a 9-year period.[Level of evidence: 3iiiA] In a multivariate analysis, the following characteristics were associated with poorer survival:
Patients were allocated a numerical prognostic score based on each of these variables (+0.55 if WBC >8.3 × 109/L, +0.60 if ECOG PS ≥1, +0.52 if unconfirmed histology, and +0.60 if male gender). Subsequently, patients were classified into two prognostic groups that included low-risk patients with a prognostic score of ≤1.27 (0–2 risk factors) and high-risk patients with a prognostic score of >1.27 (3–5 risk factors). High-risk patients had a relative risk of death of 2.9 compared with low-risk patients, P < .001; the 1-year survival rate was 40% for the low-risk group compared with 12% for the high-risk group.
Follow-up and Survivorship
Multimodality therapy incorporating radical surgery (extrapulmonary pneumonectomy or radical pleurectomy with decortication) with or without chemotherapy, administered with or without radiation, may be considered for patients with limited disease and has been associated with a relatively long survival in observational series.[Level of evidence: 3iiiA] For patients treated with aggressive surgical approaches, factors associated with improved long-term survival include the following:[7,8][Level of evidence: 3iiiD]
For those patients treated with aggressive surgical approaches, nodal status is an important prognostic factor. Median survival has been reported as 16 months for patients with malignant pleural disease and 5 months for patients with extensive disease. In some instances, the tumor grows through the diaphragm making the site of origin difficult to assess. Cautious interpretation of treatment results with this disease is imperative because of the selection differences among series. Effusions, both pleural and peritoneal, represent major symptomatic problems for at least 66% of the patients. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)
A history of asbestos exposure is reported in about 70% to 80% of all cases of mesothelioma.[1,9,10]
Histologically, these tumors are composed of spindle cells (sarcomatoid) or epithelial elements or both (biphasic). Desmoplastic mesothelioma, consisting of bland tumor cells between dense bands of stroma, is a subtype of sarcomatoid mesothelioma. The epithelioid form is occasionally confused with lung adenocarcinoma or metastatic carcinomas. Epithelioid tumors account for approximately 60% of mesothelioma diagnoses. Attempts to diagnose by cytology or needle biopsy of the pleura are often unsuccessful. It can be especially difficult to differentiate mesothelioma from adenocarcinoma on small tissue specimens. Thoracoscopy can be valuable in obtaining adequate tissue specimens for diagnostic purposes.
Examination of the gross tumor at surgery and use of special stains or electron microscopy can often help to determine diagnosis. Pancytokeratin stains are positive in nearly all mesotheliomas. Particularly useful immunohistochemical stains for the differential diagnosis of epithelioid mesothelioma include cytokeratin 5 and 6, calretinin, WT-1, and D2-40. Calretinin and D2-40 positivity in combination with pancytokeratin positivity is most useful to distinguish sarcomatoid mesothelioma from sarcoma and other histologies. Histologic appearance seems to be of prognostic value, and most clinical studies show that patients with epithelial mesotheliomas have a better prognosis than those with sarcomatoid or biphasic mesotheliomas.[3,4,5]
Patients with stage I disease have a significantly better prognosis than those with more advanced stages. Because of the relative rarity of this disease, exact survival information based upon stage is limited.
Definitions of TNM
The American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) have designated staging by TNM classification to define malignant mesothelioma.
AJCC and UICC TNM Staging for Diffuse Malignant Pleural Mesothelioma
Standard treatment for all but localized mesothelioma is generally not curative. Although some patients will experience long-term survival with aggressive treatment approaches, it remains unclear if overall survival (OS) has been significantly altered by the different treatment modalities or by combinations of modalities.
Extrapleural pneumonectomy in selected patients with early-stage disease may improve recurrence-free survival, but its impact on OS is unknown. Pleurectomy and decortication can provide palliative relief from symptomatic effusions, discomfort caused by tumor burden, and pain caused by invasive tumor. (Refer to the PDQ summary on Pain for more information.) Trimodality therapy refers to a combination of chemotherapy, definitive surgery, and radiation therapy. Because of the rarity of mesothelioma and the complexities of patient selection, surgical technique, and optimal sequencing of therapy, delivery of such therapy in centers with medical personnel who have established experience and expertise in the management of mesothelioma has shown better results. Operative mortality from pleurectomy with decortication is less than 2%, while mortality from extrapleural pneumonectomy has ranged from 6% to 30%.[1,3]
Several single-arm, phase II studies have demonstrated prolonged survival times (compared with historic controls) for selected patients who received adjuvant radiation therapy after definitive surgery.[2,4,5] The use of radiation therapy in pleural mesothelioma has also been shown to alleviate pain in the majority of patients treated; however, the duration of symptom control is short-lived.[6,7] Other single-arm, phase II studies investigated neoadjuvant chemotherapy (mainly with platinum and pemetrexed or gemcitabine) followed by definitive surgery followed by adjuvant radiation.[8,9,10] These studies have also shown prolonged survival compared with historical controls; however, this advantage has yet to be confirmed in a randomized study.
Standard treatment options:
Treatment options under clinical evaluation:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized malignant mesothelioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Standard treatment options:
Information about ongoing clinical trials is available from the NCI Web site.
Many phase II trials of chemotherapy for the treatment of advanced malignant mesothelioma have been reported.[6,14,15] The safety and efficacy of pemetrexed, an antifolate, and cisplatin in chemotherapy-naive patients with malignant mesothelioma who were not eligible for curative surgery was demonstrated in a randomized, phase III trial.[Level of evidence: 1iiA] This trial compared pemetrexed (500 mg/m2) and cisplatin (75 mg/m2 on day 1) with cisplatin alone (75 mg/m2 on day 1 intravenously every 21 days). With a total of 456 enrolled patients in the trial, 226 patients received pemetrexed plus cisplatin; 222 patients received cisplatin alone, and 8 patients did not receive therapy. After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxic effects. Folic acid (350–1,000 µg orally) was given daily, beginning 1 to 3 weeks before the first chemotherapy dose and continuing daily until 1 to 3 weeks after treatment ended. A vitamin B12 injection (1,000 µg intramuscularly) was administered 1 to 3 weeks before the first chemotherapy dose and was repeated approximately every 9 weeks until treatment ended. Dexamethasone (4 mg) or an equivalent corticosteroid was administered orally twice daily for skin rash prophylaxis to all patients 1 day before, on the day of, and 1 day after each pemetrexed dose.
In an analysis of all patients who were randomly assigned and treated, the combination of pemetrexed and cisplatin was associated with a statistically significant improvement in survival compared with cisplatin alone; the median survival was 12.1 in the pemetrexed plus cisplatin arm versus 9.3 months in the cisplatin alone arm (P = .020). The hazard ratio for death of patients in the pemetrexed plus cisplatin arm versus those in the control arm was 0.77. Median time-to-progression was significantly longer in the pemetrexed plus cisplatin arm (5.7 months vs. 3.9 months, P = .001). This superiority in the combination arm was also demonstrated in the vitamin-supplemented subgroup. The median survival was 13.3 in the combination arm and 10.0 months in the cisplatin alone arm (P = .051). The principal adverse effects of the pemetrexed plus cisplatin regimen were myelosuppression, fatigue, nausea, vomiting, and dyspnea. Most grade 3 to 4 adverse effects were significantly reduced by vitamin supplementation without any decrease in efficacy.
A randomized, phase III trial of 250 patients was performed by the European Organisation for Research and Treatment of Cancer (EORTC-08983) to compare cisplatin alone with the combination of raltitrexed, a thymidine synthase inhibitor, and cisplatin in first-line treatment of patients with malignant pleural mesothelioma. Cisplatin (80 mg/m2 IV) was given on day 1, alone or combined with raltitrexed (3 mg/m2). No toxic deaths resulted, and the main grade 3 or 4 toxicities observed were neutropenia and emesis, which were reported twice as often in the combination arm. Among 213 patients with measurable disease, the response rate was 13.6% versus 23.6%, respectively (P = .056). No difference in quality of life was observed. The combination arm was associated with increased survival. Median overall survival was 8.8 months versus 11.4 months, and the 1-year survival rate was 40% versus 46% (P = .048).[Level of evidence: 1iiA]
Malignant Peritoneal Mesothelioma
A multi-institutional, registry study evaluated cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse, malignant, peritoneal mesothelioma. Among 401 patients, 187 (46%) had complete or near-complete cytoreduction, and 372 (92%) received HIPEC. Of the HIPEC patients, 311 (83%) received cisplatin and doxorubicin. The median follow-up period was 33 months (range, 1–235 months). Grade 3 to 4 complications were seen in 127 (31%) of the 401 patients, and 9 patients (2%) died perioperatively.
The mean length of hospital stay was 22 days (standard deviation, 15 days). The overall median survival was 53 months (1–235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis:
This kind of analysis is subject to the biases of strong patient selection.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with advanced malignant mesothelioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Treatment of patients with recurrent malignant mesothelioma usually utilizes procedures and agents not previously employed in the initial treatment attempt. No standard treatment approaches have been proven to improve survival or control symptoms for a prolonged period of time. These patients are candidates for phase I and II clinical trials evaluating new biologicals, chemotherapeutic agents, or physical approaches.[1,2,3,4,5,6] Patients with recurrent malignant mesothelioma who have not received chemotherapy previously are candidates for first-line chemotherapy with cisplatin pemetrexed or cisplatin raltitrexed. (Refer to the Advanced Malignant Mesothelioma (Stages II, III, and IV) section of this summary.) However, patients with recurrent malignant mesothelioma who undergo surgery, or at least do not receive chemotherapy as part of the primary treatment and recur subsequently, are candidates for chemotherapy.
A large, randomized study compared pemetrexed with best supportive care in 243 patients who received one previous regimen of chemotherapy that did not include pemetrexed.[Level of evidence: 1iiA] No survival benefit was shown in patients who received pemetrexed, although the progression-free survival rate, time-to-progression, and the response rates favored the pemetrexed arm.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent malignant mesothelioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Malignant Mesothelioma Treatment
Added level of evidence 3iiiA.
Added Prognostic Scoring Systems as a new subsection.
Added text to state that multimodality therapy incorporating radical surgery with or without chemotherapy, administered with or without radiation, may be considered for patients with limited disease and has been associated with a relatively long survival in observational series (cited Flores et al. as reference 6 and level of evidence 3iiiA). Also added level of evidence 3iiiD to list of factors associated with improved long-term survival.
Cellular Classification of Malignant Mesothelioma
Revised text to state that histologically, these tumors are composed of spindle cells or epithelial elements or both; also added that desmoplastic mesothelioma, consisting of bland tumor cells between dense bands of stroma, is a subtype of sarcomatoid mesothelioma. Added that the epithelioid form is occasionally confused with lung adenocarcinoma or metastatic carcinomas; epithelioid tumors account for approximately 60% of mesothelioma diagnoses (cited Travis et al. as reference 1).
Revised text to state that examination of the gross tumor at surgery and use of special stains or electron microscopy can often help to determine diagnosis; pancytokeratin stains are positive in nearly all mesotheliomas. Also added that particularly useful immunohistochemical stains for the differential diagnosis of epithelioid mesothelioma include cytokeratin 5 and 6, calretinin, WT-1 and D2-40. Added that calretinin and D2-40 positivity in combination with pancytokeratin positivity is most useful to distinguish sarcomatoid mesothelioma from sarcoma and other histologies (cited Travis et al. as reference 1). Also revised text to state that histologic appearance seems to be of prognostic value, and most clinical studies show that patients with epithelial mesotheliomas have a better prognosis than those with sarcomatoid or biphasic mesotheliomas.
Stage Information for Malignant Mesothelioma
Revised text to state that the American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) have designated staging by TNM classification to define malignant mesothelioma.
Revised text of subheading to state AJCC and UICC TNM Staging for Diffuse Malignant Pleural Mesothelioma.
Treatment Option Overview
Added text to state that trimodality therapy refers to a combination of chemotherapy, definitive surgery, and radiation therapy. Also added that because of the rarity of mesothelioma and the complexities of patient selection, surgical technique, and optimal sequencing of therapy, delivery of such therapy in centers with medical personnel who have established experience and expertise in the management of mesothelioma has shown better results.
Revised text to state that several single-arm, phase II studies have demonstrated prolonged survival times for selected patients who received adjuvant radiation after definitive surgery (cited Rusch et al. as reference 4 and Batirel et al. as reference 5). Also revised text to state that other single-arm, phase II studies investigated neoadjuvant chemotherapy followed by definitive surgery followed by adjuvant radiation (cited Krug et al. as reference 8, Flores et al. as reference 9, and Weder et al. as reference 10). These studies also have shown prolonged survival compared with historical controls; however, this advantage has yet to be confirmed in a randomized study.
Advanced Malignant Mesothelioma (Stages II, III, and IV)
Revised text of standard treatment options to state that for patients with pain related to their cancer, palliative radiation therapy is a consideration. Also added text to state that first-line combination chemotherapy with cisplatin and pemetrexed showed improved survival compared with single-agent cisplatin.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of malignant mesothelioma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Malignant Mesothelioma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Malignant Mesothelioma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/malignantmesothelioma/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-08-15
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