Malignant Mesothelioma Treatment (Adult) (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Malignant Mesothelioma Treatment

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, the following were found to be important prognostic factors:[1,2][Level of evidence: 3iiiA]

• Stage.
• Age.
• Performance status (PS).
• Histology.

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 Organisation for the Research and Treatment of Cancer (EORTC) index.

CALGB 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.[3][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] PS = 0, age <49 years; or PS = 0, age ≥49 years and hemoglobin ≥14.6 g/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.[4][Level of evidence: 3iii] Median survival in this study for patients in the best CALGB 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.

EORTC index

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.[5][Level of evidence: 3iiiA] In a multivariate analysis, the following characteristics were associated with poorer survival:

• WBC count >8.3 × 10⁹ /L.
• ECOG PS ≥1.
• Unconfirmed histology on central review.
• Nonepithelioid histology.
• Male gender.

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 or lower (0–2 risk factors) and high-risk patients with a prognostic score higher than 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.[6][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]

• Epithelioid histology.
• Negative lymph nodes.
• Negative surgical margins.

For patients treated with aggressive surgical approaches, nodal status is an important prognostic factor.[7] 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.)

Carcinogenesis

A history of asbestos exposure is reported in about 70% to 80% of all cases of mesothelioma.[1,9,10]

References:

1. Ruffie P, Feld R, Minkin S, et al.: Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 7 (8): 1157-68, 1989.
2. Tammilehto L, Maasilta P, Kostiainen S, et al.: Diagnosis and prognostic factors in malignant pleural mesothelioma: a retrospective analysis of sixty-five patients. Respiration 59 (3): 129-35, 1992.
3. Herndon JE, Green MR, Chahinian AP, et al.: Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 113 (3): 723-31, 1998.
4. Mikulski SM, Costanzi JJ, Vogelzang NJ, et al.: Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J Clin Oncol 20 (1): 274-81, 2002.
5. Curran D, Sahmoud T, Therasse P, et al.: Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 16 (1): 145-52, 1998.
6. Flores RM, Pass HI, Seshan VE, et al.: Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 135 (3): 620-6, 626.e1-3, 2008.
7. Sugarbaker DJ, Strauss GM, Lynch TJ, et al.: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11 (6): 1172-8, 1993.
8. de Perrot M, Feld R, Cho BC, et al.: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27 (9): 1413-8, 2009.
9. Chailleux E, Dabouis G, Pioche D, et al.: Prognostic factors in diffuse malignant pleural mesothelioma. A study of 167 patients. Chest 93 (1): 159-62, 1988.
10. Adams VI, Unni KK, Muhm JR, et al.: Diffuse malignant mesothelioma of pleura. Diagnosis and survival in 92 cases. Cancer 58 (7): 1540-51, 1986.

Cellular Classification of Malignant Mesothelioma

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.[1] Attempts to diagnose by cytology or needle biopsy of the pleura are often unsuccessful. It can be especially difficult to differentiate mesothelioma from adenocarcinoma in small tissue specimens. Thoracoscopy can be valuable in obtaining adequate tissue specimens for diagnostic purposes.[2]

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.[1] 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.[1] Histologic appearance seems to be of prognostic value, and most clinical studies show that patients with epithelial mesotheliomas have a better prognosis than patients do with sarcomatoid or biphasic mesotheliomas.[3,4,5]

References:

1. Travis W, Brambilla E, Müller-Hermelink H, et al., eds.: Pathology and Genetics of Tumours of the Lung, Pleura, and Thymus. IARC Press, 2004. World Health Organization Classification of Tumours.
2. Boutin C, Rey F: Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: Diagnosis. Cancer 72 (2): 389-93, 1993.
3. Chahinian AP, Pass HI: Malignant mesothelioma. In: Holland JC, Frei E, eds.: Cancer Medicine e.5. 5th ed. B.C. Decker Inc, 2000, pp 1293-1312.
4. Nauta RJ, Osteen RT, Antman KH, et al.: Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized. Ann Thorac Surg 34 (1): 66-70, 1982.
5. Sugarbaker DJ, Strauss GM, Lynch TJ, et al.: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11 (6): 1172-8, 1993.

Stage Information for Malignant Mesothelioma

American Joint Committee on Cancer (AJCC) Stage Groupings and Definitions of TNM

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define malignant mesothelioma.[1]

Cancers staged using the AJCC cancer staging system include classifications for diffuse malignant pleural mesotheliomas but do not include localized malignant pleural mesotheliomas or other primary tumors of the pleura.[1]

Patients with stage I disease have a significantly better prognosis than patients do with advanced stages. Because of the relative rarity of this disease, exact survival information based on stage is limited.[2]

Table 1. Definitions of TNM Stages IA and IB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = metastasis.
a Reprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IA	T1, N0, M0	T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
		–visceral pleura.
		–mediastinal pleura.
		–diaphragmatic pleura.
		N0 = No regional lymph node metastases.
		M0 = No distant metastasis.
IB	T2 or T3, N0, M0	T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of diaphragmatic muscle.
		–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
		T3 = Describes locally advanced butpotentially resectable tumor.
		Tumor involving all the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of the endothoracic fascia.
		–extension into the mediastinal fat.
		–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
		–nontransmural involvement of the pericardium.
		N0 = No regional lymph node metastases.
		M0 = No distant metastasis.

Table 2. Definitions of TNM Stage II^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = metastasis.
a Reprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
II	T1, N1, M0	T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
		–visceral pleura.
		–mediastinal pleura.
		–diaphragmatic pleura.
		N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
		M0 = No distant metastasis.
	T2, N1, M0	T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of diaphragmatic muscle.
		–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
		N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
		M0 = No distant metastasis.

Table 3. Definitions of TNM Stages IIIA and IIIB^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = metastasis.
a Reprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IIIA	T3, N1, M0	T3 = Describes locally advanced butpotentially resectable tumor.
		Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of the endothoracic fascia.
		–extension into the mediastinal fat.
		–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
		–nontransmural involvement of the pericardium.
		N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
		M0 = No distant metastasis.
IIIB	T1–3, N2, M0	T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
		–visceral pleura.
		–mediastinal pleura.
		–diaphragmatic pleura.
		T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of diaphragmatic muscle.
		–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
		T3 = Describes locally advanced butpotentially resectable tumor.
		Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of the endothoracic fascia.
		–extension into the mediastinal fat.
		–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
		–nontransmural involvement of the pericardium.
		N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
		M0 = No distant metastasis.
	T4, Any N, M0	T4 = Describes locally advancedtechnically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–diffuse extension or multifocal masses of the tumor in the chest wall, with or without associated rib destruction.
		–direct transdiaphragmatic extension of the tumor to the peritoneum.
		–direct extension of the tumor to the contralateral pleura.
		–direct extension of the tumor to the mediastinal organs.
		–direct extension of the tumor into the spine.
		–tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium.
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastases.
		N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
		N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
		M0 = No distant metastasis.

Table 4. Definitions of TNM Stage IV^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = metastasis.
a Reprinted with permission from AJCC: Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 457–68.
IV	Any T, Any N, M1	TX = Primary tumor cannot be assessed.
		T0 = No evidence of primary tumor.
		T1 = Tumor limited to the ipsilateral parietal pleura with or without involvement of:
		–visceral pleura.
		–mediastinal pleura.
		–diaphragmatic pleura.
		T2 = Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of diaphragmatic muscle.
		–extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
		T3 = Describes locally advanced butpotentially resectable tumor.
		Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–involvement of the endothoracic fascia.
		–extension into the mediastinal fat.
		–solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall.
		–nontransmural involvement of the pericardium.
		T4 = Describes locally advancedtechnically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features:
		–diffuse extension or multifocal masses of the tumor in the chest wall, with or without associated rib destruction.
		–direct transdiaphragmatic extension of the tumor to the peritoneum.
		–direct extension of the tumor to the contralateral pleura.
		–direct extension of the tumor to the mediastinal organs.
		–direct extension of the tumor into the spine.
		–tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or tumor involving the myocardium.
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastases.
		N1 = Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes.
		N2 = Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes.
		M1 = Distant metastasis present.

References:

1. Malignant Pleural Mesothelioma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 457–68.
2. Chahinian AP, Pass HI: Malignant mesothelioma. In: Holland JC, Frei E, eds.: Cancer Medicine e.5. 5th ed. B.C. Decker Inc, 2000, pp 1293-1312.

Treatment Option Overview

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.[1] 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 Cancer 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%,[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 most 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 therapy.[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.

References:

1. Rusch VW, Piantadosi S, Holmes EC: The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 102 (1): 1-9, 1991.
2. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994.
3. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993.
4. Rusch VW, Rosenzweig K, Venkatraman E, et al.: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122 (4): 788-95, 2001.
5. Batirel HF, Metintas M, Caglar HB, et al.: Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 3 (5): 499-504, 2008.
6. Bissett D, Macbeth FR, Cram I: The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 3 (6): 315-7, 1991.
7. Ball DL, Cruickshank DG: The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 13 (1): 4-9, 1990.
8. Krug LM, Pass HI, Rusch VW, et al.: Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 27 (18): 3007-13, 2009.
9. Flores RM, Krug LM, Rosenzweig KE, et al.: Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 1 (4): 289-95, 2006.
10. Weder W, Kestenholz P, Taverna C, et al.: Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22 (17): 3451-7, 2004.

Localized Malignant Mesothelioma (Stage I) Treatment

Standard Treatment Options for Localized Malignant Mesothelioma (Stage I)

Standard treatment options for localized malignant mesothelioma (stage I) include the following:[1]

1. Solitary mesotheliomas: Surgical resection en bloc including contiguous structures to ensure wide disease-free margins. Sessile polypoid lesions are treated with surgical resection to ensure maximal potential for cure.[2]
2. Intracavitary mesothelioma:
   • Palliative surgery (i.e., pleurectomy and decortication) with or without postoperative radiation therapy.
   • Extrapleural pneumonectomy.
   • Palliative radiation therapy.

Treatment Options Under Clinical Evaluation for Localized Malignant Mesothelioma (Stage I)

Treatment options under clinical evaluation for localized malignant mesothelioma (stage I) include the following:

1. Intracavitary chemotherapy after resection.[3,4]
2. Multimodality therapy.[4,5,6]
3. Other clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Antman KH, Li FP, Osteen R, et al.: Mesothelioma. Cancer: Principles and Practice of Oncology Updates 3(1): 1-16, 1989.
2. Martini N, McCormack PM, Bains MS, et al.: Pleural mesothelioma. Ann Thorac Surg 43 (1): 113-20, 1987.
3. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992.
4. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994.
5. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993.
6. Vogelzang NJ: Malignant mesothelioma: diagnostic and management strategies for 1992. Semin Oncol 19 (4 Suppl 11): 64-71, 1992.

Advanced Malignant Mesothelioma (Stages II, III, and IV) Treatment

Standard Treatment Options for Advanced Malignant Mesothelioma (Stages II, III, and IV)

Standard treatment options for advanced malignant mesothelioma (stages II, III, and IV) include the following:

1. Symptomatic treatment to include drainage of effusions, chest tube pleurodesis, or thoracoscopic pleurodesis.[1] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)
2. Palliative surgical resection in selected patients.[2,3]
3. For patients with pain related to their cancer, palliative radiation therapy is a consideration.[4,5]
4. First-line nivolumab and ipilimumab.[6]
5. First-line combination chemotherapy with cisplatin plus pemetrexed, with or without bevacizumab.[7,8]
6. Multimodality clinical trials.[9,10,11,12]
7. Intracavitary therapy. Intrapleural or intraperitoneal administration of chemotherapeutic agents (e.g., cisplatin, mitomycin, and cytarabine) has been reported to produce transient reduction in the size of tumor masses and temporary control of effusions in small clinical studies.[13,14,15] Additional studies are needed to define the role of intracavitary therapy.

Information about ongoing clinical trials is available from the NCI website.

Treatment Options Under Clinical Evaluation for Advanced Malignant Mesothelioma (Stages II, III, and IV)

Treatment options under clinical evaluation for advanced malignant mesothelioma (stages II, III, and IV) include the following trials:

1. A randomized phase III trial demonstrated the safety and efficacy of pemetrexed, an antifolate, and cisplatin in chemotherapy-naive patients with malignant mesothelioma who were not eligible for curative surgery.[16][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 [IV] every 21 days). With 456 patients enrolled 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 PO) 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 months in the pemetrexed-plus-cisplatin arm compared with 9.3 months in the cisplatin-alone arm (P = .020).
     • The hazard ratio (HR) for death of patients in the pemetrexed-plus-cisplatin arm compared with 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 months 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.
2. A randomized phase III trial of 250 patients was performed by the European Organisation for Research and Treatment of Cancer (EORTC-08983 [NCT00004920]) 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.[17] 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 for cisplatin alone was 13.6%, while the response rate in the combination arm was 23.6% (P = .056). No difference in quality of life was observed.
   • The combination arm was associated with increased survival. Median overall survival (OS) was 8.8 months for single-agent cisplatin compared with 11.4 months in the combination arm, and the 1-year survival rate was 40% versus 46% (P = .048).[17][Level of evidence: 1iiA]
3. In an open-label, randomized, phase III study (CheckMate743 [NCT02899299]), 605 patients with advanced treatment-naive pleural mesothelioma were randomly assigned to receive either nivolumab and ipilimumab (n = 303) or chemotherapy (n = 302).[6]
   • At the prespecified interim analysis, patients who received nivolumab plus ipilimumab had significantly extended OS when compared with patients who received chemotherapy (median OS, 18.1 months [95% confidence interval (CI), 16.8–21.4] vs. 14.1 months [12.4–16.2]; HR, 0.74 [96.6% CI, 0.60–0.91]; P = .0020).[6][Level of evidence: 1iiA]
   • Median progression-free survival and objective response rates were not significantly different.
   • Grade 3 to 4 treatment-related adverse events were reported in 91 of 300 patients (30%) who received nivolumab plus ipilimumab and 91 of 284 patients (32%) who received chemotherapy.
   • Three (1%) treatment-related deaths occurred among patients who received nivolumab plus ipilimumab (pneumonitis, encephalitis, and heart failure) and one (<1%) among patients who received chemotherapy (myelosuppression).
4. A randomized, controlled, open-label, phase III trial (IFCT-GFPC-0701 [NCT00651456]) evaluated the addition of bevacizumab to chemotherapy and showed an improved OS with the three-drug regimen.[8] The trial included 448 patients with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and had no contraindications to bevacizumab, including the use of antiplatelet agents, anticoagulants, and nonsteroidal anti-inflammatory agents. Patients were randomly allocated to receive IV pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) (PC) with or without bevacizumab (15 mg/kg) (PCB) in 21-day cycles for up to six cycles, until progression or toxic effects were seen.
   • The primary outcome was OS in the intention-to-treat population.
   • OS was significantly longer with PCB (median, 18.8 months; 95% CI, 15.9–22.6) than with PC (median, 16.1 months; 95% CI, 14.0–17.9; HR, 0.77; 0.62–0.95; P = .0167).
   • Overall, 158 of 222 patients (71%) given PCB and 139 of 224 patients (62%) given PC had grade 3 to 4 adverse events.
     • Patients treated with PCB had more grade 3 or higher hypertension (51 of 222 [23%] vs. 0) and thrombotic events (13 of 222 [6%] vs. 2 of 224 [1%]) than did patients treated with PC.[8][Level of evidence: 1iiA]

   Combination immune checkpoint inhibitor therapy may be considered as an alternative to combination chemotherapy.

Malignant Peritoneal Mesothelioma

Malignant peritoneal mesothelioma arises from the mesothelial cells of the peritoneum and spreads within the confines of the abdominal cavity. There have been few prospective clinical trials conducted in this patient population. Most clinical evidence arises from single-center retrospective studies. Male sex and sarcomatoid or biphasic subtype disease are correlated with poor prognosis.[18,19]

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are offered to patients with diffuse malignant peritoneal mesothelioma, no extraperitoneal disease spread, a good performance status, and those predicted to achieve complete surgical cytoreduction. Among centers with expertise in this form of therapy, reported median survival for appropriately selected patients approaches 3 to 4 years.[18,19]

1. A large multi-institutional registry study evaluated cytoreductive surgery combined with HIPEC in patients with diffuse, malignant, peritoneal mesothelioma.[18] 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 of the 401 patients (31%), and 9 patients (2%) died perioperatively.
   • The median actuarial OS was 53 months, with survival rates of 81% at 1 year, 60% at 3 years, and 47% at 5 years.
   • Prognostic factors associated with improved survival on multivariate analysis were epithelioid histologic subtype, absence of lymph node metastases, complete or near complete resection, and the use of HIPEC.
2. A second multi-institutional report included 211 patients treated at three centers in the United States (who were not part of the previous study).[19] All patients underwent cytoreductive surgery and HIPEC using either cisplatin or mitomycin C.
   • The actuarial OS was 38 months. The survival rates were 41% at 5 years and 26% at 10 years.
   • Prognostic factors associated with improved survival were age younger than 60 years, complete or near-complete gross resection, low versus high histologic grade, and the use of cisplatin versus mitomycin C.

   In patients with malignant peritoneal mesothelioma, efficacy of pemetrexed plus cisplatin appeared comparable to that seen in pleural mesothelioma, and was been well tolerated. Prospective phase II or III clinical trials of this regimen have not been conducted in patients with peritoneal mesothelioma.

3. In the U.S. Pemetrexed Expanded Access Program, 98 patients (9.3%) had peritoneal mesothelioma, 57 patients were previously treated, and 38 patients were chemotherapy-naive.[20] Of the 73 patients with malignant peritoneal mesothelioma and measurable disease, 28 patients were chemotherapy-naive and 43 patients were previously treated. Twenty-six patients received single-agent pemetrexed and 47 patients received pemetrexed and cisplatin.
   • The overall response rate was 26% and similar objective response rates were achieved in previously treated and chemotherapy-naive patients.
   • Median OS for previously treated patients was 13.1 months; it had not been reached at the time of the analysis for chemotherapy-naive patients.
   • As expected, both response rate (29% vs. 19%) and median survival (13.1 vs. 8.7 months) were higher for patients who received the pemetrexed doublet than for those who received pemetrexed alone in this nonrandomized study.
   • These results were comparable to those seen in pleural mesothelioma.

   Carboplatin may be substituted for cisplatin.

4. In the International Pemetrexed Expanded Access Program, 29 evaluable patients with peritoneal mesothelioma received pemetrexed 500 mg/m² and carboplatin, dosed at an area under the curve of 5.[21]
   • Seven patients (24%) had objective responses (one complete), and 52% had stable disease.
   • These results were comparable to those achieved with pemetrexed and cisplatin.

The pemetrexed/cisplatin/bevacizumab and nivolumab/ipilimumab regimens that improved OS were conducted exclusively in patients with malignant pleural mesothelioma, and data to support the efficacy and safety of these regimens in patients with malignant peritoneal mesothelioma are required.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Boutin C, Viallat JR, Rey R: Thoracoscopy in Diagnosis, Prognosis and Treatment of Mesothelioma. In: Antman K, Aisner J, eds.: Asbestos-Related Malignancy. Grune & Stratton, 1987, pp 301-21.
2. Butchart EG, Ashcroft T, Barnsley WC, et al.: The role of surgery in diffuse malignant mesothelioma of the pleura. Semin Oncol 8 (3): 321-8, 1981.
3. Martini N, McCormack PM, Bains MS, et al.: Pleural mesothelioma. Ann Thorac Surg 43 (1): 113-20, 1987.
4. Bissett D, Macbeth FR, Cram I: The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 3 (6): 315-7, 1991.
5. Ball DL, Cruickshank DG: The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 13 (1): 4-9, 1990.
6. Baas P, Scherpereel A, Nowak AK, et al.: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 397 (10272): 375-386, 2021.
7. Chahinian AP, Antman K, Goutsou M, et al.: Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 11 (8): 1559-65, 1993.
8. Zalcman G, Mazieres J, Margery J, et al.: Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387 (10026): 1405-14, 2016.
9. Mattson K, Holsti LR, Tammilehto L, et al.: Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 24 (4): 643-50, 1992.
10. Weissmann LB, Antman KH: Incidence, presentation and promising new treatments for malignant mesothelioma. Oncology (Huntingt) 3 (1): 67-72; discussion 73-4, 77, 1989.
11. de Perrot M, Feld R, Cho BC, et al.: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27 (9): 1413-8, 2009.
12. Sugarbaker DJ, Mentzer SJ, DeCamp M, et al.: Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma. Chest 103 (4 Suppl): 377S-381S, 1993.
13. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992.
14. Markman M, Cleary S, Pfeifle C, et al.: Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma. Cancer 58 (1): 18-21, 1986.
15. Rusch VW, Figlin R, Godwin D, et al.: Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial. J Clin Oncol 9 (2): 313-9, 1991.
16. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al.: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 (14): 2636-44, 2003.
17. van Meerbeeck JP, Gaafar R, Manegold C, et al.: Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 23 (28): 6881-9, 2005.
18. Yan TD, Deraco M, Baratti D, et al.: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol 27 (36): 6237-42, 2009.
19. Alexander HR, Bartlett DL, Pingpank JF, et al.: Treatment factors associated with long-term survival after cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma. Surgery 153 (6): 779-86, 2013.
20. Jänne PA, Wozniak AJ, Belani CP, et al.: Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer 7 (1): 40-6, 2005.
21. Carteni G, Manegold C, Garcia GM, et al.: Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer 64 (2): 211-8, 2009.

Recurrent Malignant Mesothelioma Treatment

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 improved survival or controlled symptoms for a prolonged period. Selected patients with localized disease recurrence may be candidates for additional chest wall resection. One trial of 47 carefully selected patients at a single institution indicated that chest wall resection could be safely performed; time-to-recurrence from initial resection appeared to be predictive of expected survival benefit and was factored into decision-making.[1][Level of evidence: 3iiiA]

Patients with recurrence are candidates for phase I and II clinical trials evaluating new targeted therapies, biologicals, chemotherapeutic agents, or physical approaches.[2,3,4,5,6,7,8,9] Patients who undergo surgery or who have not received chemotherapy are candidates for first-line chemotherapy, which may include cisplatin and pemetrexed or cisplatin and raltitrexed. (Refer to the Advanced Malignant Mesothelioma [Stages II, III, and IV] Treatment section of this summary for more information.)

Treatment Options for Recurrent Malignant Mesothelioma

1. In a multicenter, randomized, double-blind, placebo-controlled, phase II trial (RAMES [NCT03560973]), 161 patients with malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum were randomly assigned (1:1) to receive either gemcitabine plus ramucirumab, an anti-VEGFR-2 antibody (n = 80), or gemcitabine plus placebo (n = 81). The primary endpoint was overall survival (OS).[10] Of note, patients enrolled in the RAMES trial had no previous exposure to bevacizumab or immune checkpoint inhibitors.
   • Patients in the gemcitabine plus ramucirumab group had longer OS when compared with patients who received gemcitabine plus placebo (median OS, 13.8 months; 70% confidence interval [CI], 12.7–14.4 for the gemcitabine plus ramucirumab group vs. 7.5 months [6.9–8.9] for the gemcitabine plus placebo group; hazard ratio [HR], 0.71; 70% CI, 0.59–0.85; P = .028).[10][Level of evidence: 1iA]
   • Median progression-free survival, although longer in the gemcitabine plus ramucirumab group, was not significantly different (HR, 0.79; 70% CI, 0.66–0.94; P = .082).
   • Disease control was achieved in a greater proportion of patients who received gemcitabine plus ramucirumab compared with patients who received gemcitabine plus placebo (73% [70% CI, 66%–78%] vs. 52% [70% CI, 46%–58%]).
   • Grade 3 to 4 treatment-related adverse events were reported in 35 of 80 patients (44%) who received gemcitabine plus ramucirumab and 24 of 81 patients (30%) who received gemcitabine plus placebo.
   • There were no treatment-related deaths in either study group.
2. 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.[11][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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Burt BM, Ali SO, DaSilva MC, et al.: Clinical indications and results after chest wall resection for recurrent mesothelioma. J Thorac Cardiovasc Surg 146 (6): 1373-9; discussion 1379-80, 2013.
2. Rusch V, Saltz L, Venkatraman E, et al.: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12 (6): 1156-63, 1994.
3. Markman M, Kelsen D: Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 118 (7): 547-50, 1992.
4. Zucali PA, Ceresoli GL, Garassino I, et al.: Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Cancer 112 (7): 1555-61, 2008.
5. Boutin C, Viallat JR, Van Zandwijk N, et al.: Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma. Cancer 67 (8): 2033-7, 1991.
6. Ong ST, Vogelzang NJ: Chemotherapy in malignant pleural mesothelioma. A review. J Clin Oncol 14 (3): 1007-17, 1996.
7. Gregorc V, Zucali PA, Santoro A, et al.: Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol 28 (15): 2604-11, 2010.
8. Papa S, Popat S, Shah R, et al.: Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy. J Thorac Oncol 8 (6): 783-7, 2013.
9. Calabrò L, Morra A, Fonsatti E, et al.: Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14 (11): 1104-11, 2013.
10. Pinto C, Zucali PA, Pagano M, et al.: Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 22 (10): 1438-1447, 2021.
11. Jassem J, Ramlau R, Santoro A, et al.: Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol 26 (10): 1698-704, 2008.

Changes to This Summary (01 / 14 / 2022)

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.

Recurrent Malignant Mesothelioma Treatment

Added Treatment Options for Recurrent Malignant Mesothelioma as a new subsection.

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.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult malignant mesothelioma. It is intended as a resource to inform and assist clinicians in the care of their 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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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 (Adult) are:

• Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
• Arun Rajan, MD (National Cancer Institute)
• Eva Szabo, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. 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.

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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:

PDQ® Adult Treatment Editorial Board. PDQ Malignant Mesothelioma Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/mesothelioma/hp/mesothelioma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389420]

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Last Revised: 2022-01-14