Mesothelioma. Malignant Pleural Mesothelioma

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1 Mesothelioma William G. Richards, PhD Brigham and Women s Hospital Malignant Pleural Mesothelioma 2,000-3,000 cases per year (USA) Increasing incidence Asbestos (50-80%, decreasing) year latency Simian Virus 40 (SV 40) 1

2 Presentation Median age 60, M:F = 4-5:1 Dyspnea / Pleural effusion ( 80% ) Cough ( 60% ) Chest Pain ( 40-60% ) Bilateral Disease ( 5% ) Diagnosis often difficult differential versus lung adenocarcinoma Local progression Clinical Course lung, chest wall, mediastinum, diaphragm Distant metastases rare Rapidly fatal median survival 7 months with palliation 12 months with best chemotherapy 2

3 Histologic subtypes Epithelial (50%) Sarcomatoid (15%) Mixed (35%) Sarcomatoid / mixed have poor prognosis Staging Butchart (1976, EPP) surgical extent of disease Brigham (Trimodality, 1993, revised 1999) surgical margins, pn2 status UICC, IMIG 1994 pathologic TNM CALGB, EORTC (non-surgical, 1998) histology, PS, chest pain, WBC, platelets 3

4 Chemotherapy Radiation therapy Therapy Surgery Combined approaches Targeted Strategies Chemotherapy CALGB trials (Vogelzang, Kindler) 8435, 8638, 8833, 8933, 9031, 9131, 9234 N = 347; response rates 7-26%; MST mo gemcitabine - no CR, PR MST 4.7 mo high-dose doxorubicin - no responses 9733 Irinotecan - no CR, PR MST 9.3 months Capecitabine - 1 PR 4.9 mo. med. surv Gefitinib 1 CR, 1 PR 6.8 mo. med. surv. 4

5 Cisplatin Single agent 13-14% response rate Cisplatin in combinations 13-48% response rate Gemcitabine / cisplatin phase II 47.6% RR, 10 mo MST Pemetrexed / cisplatin phase III 12 mo MST vs 9 mo cisplatin alone Phase III Pemetrexed + cisplatin versus cisplatin Pemetrexed + Cisplatin Cisplatin P value # of patients Response rate 41.3% 16.7% < Time to 5.7 months 3.9 months progression Survival 12.1 months 9.3 months 0.02 Vogelzang, J Clin Oncol 21: ,

6 Radiation Therapy Need > 40 Gy even for palliation Dose limiting toxicity - Lung 20 Gy spinal chord, heart, esophagus 45 Gy Biopsy site to prevent seeding Boutin Chest 108:754-8, 1995 High dose Memorial Rusch J Thorac Cardiovsc Surg 122: , 2001 Surgery Thoracoscopy / sclerosis palliation of effusion, 80-90% effective Pleurectomy / decortication low morbidity, mortality (1-5%) complete resection uncommon Extrapleural pneumonectomy higher morbidity (25%) and mortality (4-15%) more complete tumor cytoreduction empty thorax permits high-dose radiotherapy 6

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9 Extrapleural Pneumonectomy Complications after 328 consecutive cases 30-Day Mortality 11 patients (3.4%) Major or minor morbidity 198 (60%) Management issues: atrial fibrillation 145 (44%) vocal chord paralysis 22 (6.7%) early ambulation, aspiration precautions Deep vein thrombosis 21 (6.4%) perioperative diagnosis and management Technical (patch dehiscence, hemorrhage) 20 (6.1%) immediate re-operation Infection (empyema, broncho-pleural fistula) thoracoscopic or open drainage Sugarbaker, J Thorac Cardiovasc Surg 128:138-46,

10 Multimodality Therapy Trimodality therapy EPP, chemotherapy and radiation sandwich adjuvant protocol: Extrapleural Pneumonectomy Taxol Carboplatin 2 cycles XRT Gy Weekly Taxol Taxol Carboplatin 2 cycles Trimodality Therapy 183 Patients enrolled males and 43 females Mean age 57 yrs. ( range ) Asbestos exposure - n = 132 (72%) Symptoms - dyspnea 73% - chest pain 56% - cough 36% Sugarbaker J Thorac Cardiovasc Surg 117:54-63,

11 Perioperative Results 30-day Mortality- 7 patients (3.8%) - pulmonary embolus 3 - myocardial infarction 2 - aspiration / sepsis / ARDS 1 - cardiac herniation 1 Morbidity - Major 24.5% - Atrial Fibrillation 37% Median LOS 9 days (range 5 to 101) Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999 Extrapleural Nodal Status 1 Proportion Surviving Extrapleural Nodes Negative (N = 136) Extrapleural Nodes Positive (N = 40) p = Months Sugarbaker J Thorac Cardiovasc Surg 117:54-63,

12 Resection Margins 1 Proportion Surviving Negative Resection Margins (N = 66) Positive Resection Margins (N=110) p < Months Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999 *Revised Brigham Staging System Proportion Surviving Stage I (n = 52, MST 25 mo) Stage II (n = 84, MST 20 mo) Stage III (n = 40, MST 16 mo) p = Months *Sugarbaker et al, JCO 1993 Sugarbaker J Thorac Cardiovasc Surg 117:54-63,

13 Patterns of Failure After Trimodality Therapy The most common sites of failure were: the ipsilateral hemithorax (35%) abdomen (26%) Isolated distant failure were uncommon Future strategies should investigate methods of enhancing local control Baldini Ann Thorac Surg 63:334-8, 1997 Potential Sources of Local Recurrence Free intrathoracic tumor cells shed from the pleural surface prior to surgery Disseminated tumor cells during surgical manipulation, spillage Residual tumor at resection margins 13

14 Multimodality Tx Current goals Improve local recurrence rate High-dose adjuvant radiation therapy Intensity modulated radiotherapy (IMRT) Intracavitary chemotherapy Improve resectability rate neoadjuvant chemotherapy High-dose XRT Memorial Sloan Kettering CC 88 patients (66 EPP) median 54 Gy 8% mortality stage I, II 33.8 mo MST stage III, IV 10 mo MST Excellent local control Relapse primarily distant Rusch J Thorac Cardiovsc Surg 122: ,

15 MD Anderson CC 28 Patients IMRT EPP (surgical clips to delineate CTV) Gy with 60 Gy boost areas Respiratory motion minimal 100% local control at 9 months median f/u Ahamad Int J Radiat Oncol Biol Phys 52:1381-8, 2002 Intracavitary Chemotherapy Malignant Pleural Mesothelioma Extrapleural Pneumonectomy or Pleurectomy / Decortication Intrathoracic/Intraperitoneal Hyperthermic Cisplatin (42 C x 1hr) with IV Sodium Thiosulfate or Amifostine Recommended Adjuvant Tx: Concurrent Cisplatin/Gemcitabine and Radiation (6-8 weeks postop) Surveillance (every 3 months) 15

16 Lilly Sponsored phase II Trial Multi-institutional participation Neoadjuvant pemetrexed + cisplatin Extrapleural pneumonectomy High-dose hemithoracic radiation 54 GY Primary endpoint - pathologic CR rate Secondary endpoints - survival, clinical response, toxicity, pattern of relapse, parmacogenomic markers 16

17 Future Directions CALGB Trimodality concept Targeted Therapy gene discovery small molecule inhibitors vs cytotoxics preselect the right patients likely to respond to particular treatment strategies CALGB Concept A phase II trial of EPP followed by radiation therapy and chemotherapy in MPM PI: Raphael Bueno, MD EPP Pemetrexed 500 mg/m 2 +Cisplatin 75 mg/m 2 w/ Folic acid, B12 q 21d x 3 Cycles IMRT Trimodality therapy with state of the art chemotherapy, radiation therapy Specimen Collection through CALGB Lung Cancer Tissue Bank (140202) Comprehensive cutting edge correlative science 17

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