Chest Medicine Made Easy-Dr Deepu: MESOTHELIOMA

Topics covered

Treatment Option Overview
Treatment of Localized Malignant Mesothelioma (Stage I)

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

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 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 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.[8-10] 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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

5. Batirel HF, Metintas M, Caglar HB, et al.: Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 3 (5): 499-504, 2008. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

Treatment of Localized Malignant Mesothelioma (Stage I)

Standard treatment options:[1]

1. Solitary mesotheliomas: Surgical resection en bloc including contiguous structures to ensure wide disease-free margins. Sessile polypoid lesions should be treated with surgical resection to ensure maximal potential for cure.[2]

2. Intracavitary mesothelioma:

o Palliative surgery (i.e., pleurectomy and decortication) with or without postoperative radiation therapy.

o Extrapleural pneumonectomy.

o Palliative radiation therapy.

Treatment options under clinical evaluation:

1. Intracavitary chemotherapy following resection.[3,4]

2. Multimodality therapy.[4-6]

3. Other clinical trials.

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]
6. Vogelzang NJ: Malignant mesothelioma: diagnostic and management strategies for 1992. Semin Oncol 19 (4 Suppl 11): 64-71, 1992. [PUBMED Abstract]

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

Standard treatment options:

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 combination chemotherapy with cisplatin and pemetrexed showed improved survival compared with single-agent cisplatin.[6][Level of Evidence: 1iiA]

5. Multimodality clinical trials.[7-10]

6. 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.[11-13] Additional studies are needed to define the role of intracavitary therapy.

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.[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 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.[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 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).[17][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.[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 (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:

· Epithelial subtype (P < .001).

· Absence of lymph node metastasis (P < .001).

· Completeness of cytoreduction (CC) scores of CC-0 or CC-1 (P < .001).

· HIPEC (P = .002).

This kind of analysis is subject to the biases of strong patient selection.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withadvanced 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.

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. Orlando,Fla: 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. [PUBMED Abstract]

3. Martini N, McCormack PM, Bains MS, et al.: Pleural mesothelioma. Ann Thorac Surg 43 (1): 113-20, 1987. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]

6. 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. [PUBMED Abstract]

7. 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. [PUBMED Abstract]

8. Weissmann LB, Antman KH: Incidence, presentation and promising new treatments for malignant mesothelioma. Oncology (Huntingt) 3 (1): 67-72; discussion 73-4, 77, 1989. [PUBMED Abstract]

9. 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. [PUBMED Abstract]

10. 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. [PUBMED Abstract]

11. 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. [PUBMED Abstract]

12. 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. [PUBMED Abstract]

13. 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. [PUBMED Abstract]

14. Ong ST, Vogelzang NJ: Chemotherapy in malignant pleural mesothelioma. A review. J Clin Oncol 14 (3): 1007-17, 1996. [PUBMED Abstract]

15. Andreopoulou E, Ross PJ, O'Brien ME, et al.: The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma. Ann Oncol 15 (9): 1406-12, 2004. [PUBMED Abstract]

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. [PUBMED Abstract]

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. [PUBMED Abstract]\
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. [PUBMED Abstract]

Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Pleural mesothelioma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 271-7.
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
T1	Tumor limited to the ipsilateral parietal pleura with or without mediastinal pleura and with or without diaphragmatic pleural involvement.
T1a	No involvement of the visceral pleura.
T1b	Tumor also involving the visceral pleura.
T2	Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: involvement of diaphragmatic muscle; extension of tumor from visceral pleura into the underlying pulmonary parenchyma.
T3	Locally advanced but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: 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	Locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction; direct transdiaphragmatic extension of tumor to the peritoneum; direct extension of tumor to the contralateral pleura; direct extension of tumor to mediastinal organs; direct extension of 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.

Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Pleural mesothelioma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 271-7.
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastases.
N1	Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes.
N2	Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary and peridiaphragmatic nodes.
N3	Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral or contralateral supraclavicular lymph nodes.

Table 3. Distant Metastasis (M)a
aReprinted with permission from AJCC: Pleural mesothelioma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 271-7.
M0	No distant metastasis.
M1	Distant metastasis present.

Table 4. Anatomic Stage/Prognostic Groupsa
Stage	T	N	M
aReprinted with permission from AJCC: Pleural mesothelioma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 271-7.
I	T1	N0	M0
IA	T1a	N0	M0
IB	T1b	N0	M0
II	T2	N0	M0
III	T1, T2	N1	M0
	T1, T2	N2	M0
	T3	N0, N1, N2	M0
IV	T4	Any N	M0
	Any T	N3	M0
	Any T	Any N	M1

TOPICS

MESOTHELIOMA- TREATMENT

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

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

Malignant Peritoneal Mesothelioma

MESOTHELIOMA- STAGING