Radiation Oncology/Mesothelioma/Overview

Mesothelioma Overview Epidemiology 3000 patients diagnosed yearly. 70-80% related to asbestos exposure Not related specifically to smoking; however, smoking + asbestos dramatically increase risk M>F Peak incidence in 5th to 7th decade. 96% occurs after 20+ years latency period after asbestos exposure Pathology Sarcomatous Epithelial (best prognosis of 3 subtypes) Mixed Prognostic Factors CALGB Prognostic Index - Based on a trial of 337 patients treated for malignant mesothelioma in 7 phase II CALGB trials. Pleural Involvement LDH>500 IU/L Poor KPS Non-epithelial histology Age>75 Resectable disease Surgical resection possible in minority of patients Trimodality therapy is treatment of choice for non-metastatic mesothelioma Extrapleural pneumonectomy is surgical procedure of choice: Removes ipsilateral lung, parietal pleura, pericardium, diaphragm and mediastinal nodal dissection with reconstruction of the diaphragm. Adjuvant radiotherapy includes hemithorax irradiation ~10% patients fail at biopsy tract, but prophylactic tract RT is probably not beneficial Prophylactic RT After Biopsy Glasgow, 2007 (1998-2004) 17588698 -- "A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma." (O'Rourke N, Radiother Oncol. 2007 Jul;84(1):18-22.) Randomized. 61 patients. Chest drain or pleural biopsy + RT 21/3 vs. observation Tract mets: RT arm 13% vs. supportive care 10% (NS) Conclusion: Prophylactic drain site RT does not reduce tumor seeding Marseille, France, 1995 7656629 -- "Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy." (Boutin C, Chest. 1995 Sep;108(3):754-8.) 40 pts w/ histologically proven malignant mesothelioma. Xrt arm received 7 Gy in 3 fractions to the thoracic wall via electrons. Xrt was 10-15 days after thoroscopy. 40% in the observation arm developed metastases at the entry tract. None of the patients in the xrt arm developed entry tract mets. Trimodality Therapy EORTC 08031, 2011 (2005-2007) 20525721. Van Schil PE, et al. "Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial," European Respiratory Journal. 2010 Dec;36(6):1362-9. 57pts tx'd from 2005-2007 with induction cisplatin (75mg/m2) + pemetrexed (500mg/m2) for three cycles followed by extrapleural pneumonectomy (42pts) followed by hemithorax RT to 54Gy in 30fx (37pts completed RT). Local recurrence occurred in 16% of patients completing all trimodality therapy. Median OS was 18.4 months. MSKCC, 2001 (1995-1998) 11581615. Rusch, V. et al. "A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma," Journal of Thoracic Cardiovascular Surgery. 2001 Oct;122(4):788-95 88 patients tx'd from 1995-1998 with 54 Gy hemithoracic xrt after complete resection. 70% extrapleural pneumonectomies. Xrt reduced local recurrence; pts treated w/ extrapleural pneumonectomy w/ adjuvant chemoxrt failed at distant sites. Harvard, 1999 9869758. Sugarbaker, D. et al. "Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma," Journal of Thoracic Cardiovascular Sugery. 1999 Jan;117(1):54-63 183 patients, resectable mesothelioma with KPS>70. Patients treated with extrapleural pneumonectomy, adjuvant chemoxrt (30 Gy in 1.5 Gy fx to hemithorax w/ boost to 50.4 Gy, concurrent taxol), adjuvant taxol. Peri-operative mortality 3.8%, subgroup w/ extended survival were epithelial type, negative extrapleural nodes, negative margins. 5 yr OS 46% w/ all 3 positive prognostic factors. MSKCC, 1982 (1939-1981) 7144218. McCormack, P. et al. "Surgical treatment of pleural mesothelioma." Journal of Thoracic Cardiovascular Surgery. 1982 Dec;84(6):834-42 170 pts at MSKCC tx'd from 1939 to 1981 for pleural mesothelioma. Variation in tx regimens, but after 1972, pts tx'd w/ pleurectomy (w/o lung resection) w/ adjuvant ext beam xrt or brachy. Median survival for surg + xrt cohort was 21 months w/ better local control than surg alone. Conclusion: multi-modality approach including surgery, xrt and chemo led to better overall survival. Intensity Modulated Radiation Therapy Early studies showed improved local control over historical controls. Recent publication from BWH shows a significant mortality from radiation induced pneumonitis when fail to use more stringent dose constraints. MD Anderson (2000-2005) 2007 17954086 -- "Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma." (Rice DC, Ann Thorac Surg. 2007 Nov;84(5):1685-92; discussion 1692-3.) Retrospective. 100 patients, who underwent extrapleural pneumonectomy. 63 IMRT (median 45 Gy). Right side 66%, left side 34%. Stage I 6%, Stage II 7%, Stage III 72%, Stage IV 15%; 54% ipsilateral LN+. Perioperative mortality 8% Outcome: median OS 10.2 months; if IMRT 14.2 months; if LN- and epithelioid 28 months. Recurrence LR 13%, DM 54% Conclusion: IMRT excellent local control, need systemic therapy 2007 17467922 -- "Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma." (Rice DC, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):350-7. Epub 2007 Apr 30.) Retrospective. 63 patients treated with IMRT after extrapleural pneumonectomy. Dose 45-50 Gy Outcome: 37% died within 6 months (43% recurrence, 17% pneumonia, 9% pneumonitis, 31% non-cancer and non-pulmonary causes) Predictors of pulmonary-related death: only contralateral V20. If >7%, 42X risk of death. Also, if absolute lung volume receiving 10 Gy >1200 cm3 and 5 Gy >300 cm3 had better outcome Conclusion: Fatal pulmonary toxicity (9%) associated with V20 Harvard, 2006 16751058. Allen, AM. et al. "Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma," Int J Radiat Oncol, Biol, Phys. 2006 Jul 1;65(3):640-5. Pts treated to 54 Gy in 1.8 Gy fractions. Contralateral lung limited to V20 of 20%. 6 of 13 patients developed fatal radiation pneumonitis. Conclusion: metrics such as V5 and MLD should be used in addition to V20 to determine patient tolerance to xrt. Unresectable disease One randomized trial suggests that chemotherapy (MVP) may not be superior to active symptomatic control alone; there may be benefit to vinorelbine alone Two randomized trials suggest that cisplatin + antifolate (pemetrexed or raltitrexed) should be used over cisplatin alone The role of cisplatin itself is not clear, but it has been used historically British MS01 (2001 - 2006) - Active Symptom Control vs. ACS + MVP vs. ACS + vinorelbine Randomized, 3 arms. 409 patients with malignant pleural mesothelioma. Arm 1) Active symptom control (steroids, analgesics, bronchodilators, palliative RT) vs. Arm 2) ASC + MVP (mitomycin 6 mg/m2, vinblastine 6mg/m2, cisplatin 50mg/m2) vs. Arm 3) ASC + vinorelbine 20 mg/m2 2008 18486741 -- "Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial." (Muers MF, Lancet. 2008 May 17;371(9625):1685-94.) Outcome: median OS ASC 7.6 months vs. ASC + chemo 8.5 months (NS); subset trend benefit for vinorelbine 9.5 months (p=0.08) Toxicity: No difference Conclusion: Addition of MVP or vinorelbine to active symptom control offered no significant benefit EORTC-NCIC 08983 (2000-2003) - Cisplatin vs. Cisplatin + Raltitrexed Randomized. 250 patients with advanced malignant pleural mesothelioma. Arm 1) cisplatin 80 mg/m2 vs. Arm 2) cisplatin 80 mg/m2 + raltitrexed 3 mg/m2 2005 16192580 -- "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." (van Meerbeeck JP, J Clin Oncol. 2005 Oct 1;23(28):6881-9.) Outcome: median OS cisplatin 9 months vs. cisplatin + raltitrexed 11 months (SS); 1-year OS 40% vs. 46% (SS) Conclusion: Raltitrexed and cisplatin improves survival compared with cisplatin alone Pemetrexed Trial (1999-2001) - Cisplatin vs. Cisplatin + Pemetrexed Randomized. 456 patients with chemo-naive and inoperable mesothelioma. Arm 1) cisplatin 75 mg/m2 vs. Arm 2 cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 2003 12860938 -- "Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma." (Vogelzang NJ, J Clin Oncol. 2003 Jul 15;21(14):2636-44.) Outcome: median OS cisplatin 9 months vs cisplatin/pemetrexed 12 months (SS); time-to-progression 3.9 months vs. 5.7 months (SS) Conclusion: Pemetrexed + cisplatin + vitamin supplements resulted in superior outcome compared with cisplatin alone