The surgeon: new surgical aproaches

The surgeon: new surgical aproaches Paul Van Schil, MD Department of Thoracic and Vascular Surgery Antwerp University, Belgium no disclosures, no conflict of interest Malignant pleural mesothelioma: clinical, pathological and legal features. Padua, November 8, 2012

Malignant pleural mesothelioma surgical treatment surgical techniques, definitions pleurectomy/decortication extrapleural pneumonectomy recent surgical studies EORTC 08031 MARS 1 pilot trial surgery: quo vadis?

Surgical techniques Pleurectomy / decortication removal involved parietal + visceral pleura + resection diaphragm, pericardium if necessary preservation of lung parenchyma

Surgical techniques Pleurectomy / decortication advantages disadvantages low mortality morbidity preservation of lung parenchyma good palliation subsequent therapy rapidly possible - adjuvant chemoradiotherapy reduced radiation dose only radical for early stages Maggi G. Trimodality management of malignant pleural mesothelioma. EJCTS 2001; 19:346-50

Surgical techniques EPP : extrapleural pneumonectomy removal parietal pleura ipsilateral lung pericardium if necessary diaphragm if necessary reconstruction diaphragm, pericardium : PTFE soft tissue patch Sugarbaker D. J Thorac Cardiovasc Surg 2004; 128:138-46

Surgical techniques EPP : extrapleural pneumonectomy advantages maximal debulking procedure postop. radiation dose good palliation disadvantages major operation mortality morbidity survival advantage?

Technique of extrapleural pneumonectomy

Technique of extrapleural pneumonectomy pericardial patch diaphragm patch

Technique of extrapleural pneumonectomy intercostal muscle flap pericardial patch

Recommendations for uniform definitions of surgical techniques MPM

EORTC Phase II feasibility trial 08031 registration pathologically proven MPM ct3n1m0 or less (UICC TNM) induction chemotherapy 3 cycles cisplatin 75 mg/m 2 Q 21 days + pemetrexed 500 mg/ m 2 Response evaluation preferably at the end of induction chemotherapy or after at least 2 cycles

EORTC Phase II feasibility trial 08031 if - no progressive disease - no unacceptable toxicity extrapleural pneumonectomy (EPP) within 21 to 56 days after last dose of chemotherapy postoperative radiotherapy (54 Gy) 30 days after surgery but within 84 days 3D planning/total dose of 54 Gy (30 once daily fractions) if - no progressive disease - recovery from surgery - performance status WHO 0-2

Mesothelioma 08031 trial 1ary endpoint : success of teatment : full protocol, alive after 90 days no progression, no G3 - G4 toxicity 2ary endpoints : overall and progression-free survival, toxicity

Mesothelioma 08031 trial - results Surgery 46 pts (79.3%) operated; 42 (73.7%) had EPP R0 30 R1 10 R2 3 6 reoperations bleeding hematoma bronchopleural fistula diaphragmatic eventration

Mesothelioma 08031 trial - results Surgery pt0 2 pt1 5 pt2 19 pt3 15 pt4 4 pn0 34 pn1 2 pn2 6 pnx 2 30 and 90-day 3 pts (6.5%): pulmonary embolism lung edema, pneumonia progressive disease

Mesothelioma 08031 trial - results Follow-up persisting G3-4 toxicity 90 days after end of protocol treatment: 3 pts (5.3%) radiation pneumonitis 1 bronchopleural fistula 2

Mesothelioma 08031 trial - results Survival data median follow-up time 19.3 mos (95% CI 17.4-25.0) overall MST 18.4 mos (95% CI 14.8-NR) progression-free MST 13.9 mos (95% CI 10.9-17.2) Van Schil P et al. Eur Resp J 2010; 36:1362-9

Ov erall surv iv al All eligible patients who started their treatment 100 90 80 70 overall MST 18.4 mos 60 50 40 30 20 10 0 (months) 0 4 8 12 16 20 24 28 32 36 O N Number of patients at risk : All Patients 27 57 54 49 38 22 13 9 5 2 N b Patie nts

Progression free surv iv al All eligible patients who started their treatment 100 90 80 70 progression-free MST 13.9 mos 60 50 40 30 20 10 0 (months) 0 4 8 12 16 20 24 28 32 36 O N Number of patie nts at risk : All Patients 39 57 48 40 29 16 8 6 3 1 Nb Patie nts

Mesothelioma 08031 trial results Primary endpoint only 24 pts (42.1%) met definition of success (onesided 90% CI for proportion of success 0.33-1.00) reasons for failure at least 2 cycles of ICT not given 1 no EPP 15 no 54 Gy PORT 21 not within time frame 27 mortality 7 persisting G3/4 toxicity 3 progressive disease 16 1ary endpoint not met Van Schil P et al. Eur Resp J 2010; 36:1362-9

MARS trial (UK) Mesothelioma And Radical Surgery trial 3 cycles of induction chemotherapy, repeat staging eligibility : reviewed by MARS multidisciplinary team randomization : no EPP surgery 670 patients T1-3, N0-1, M0 EPP primary endpoint : survival secondary endpoint : QOL

MARS trial (UK) randomized pilot feasibility study : aims : feasibility of randomizing 50 pts. feasibility of undertaking this surgery as a multi-center trial feasibility of surgery 11 centres; 112 pts evaluated and induction therapy 50 pts (45%) randomized randomization feasible between surgical and non-surgical treatment Treasure T. J Thor Oncol 2009; 4:1254-8

MARS: trial design Fit for surgery (BTS guidelines) Patient consent and registration Staging: PET & mediastinoscopy 3 cycles of platinum-chemotherapy Repeat staging by CT scan N = 112 Eligibility reviewed by virtual multidisciplinary team N = 57 Patient consent R EPP No EPP N = 24 N = 26 Post-operative radical hemithoracic radiotherapy Treasure et al. Lancet Oncol 2011; 12: 763-772 Snee et al. J Thoracic Oncol 2011; 6 suppl 2: O 30.07

MARS 1 pilot It took 3 years to randomize 50 patients to EPP or no EPP! 3/16 = 18.8% Treasure et al. Lancet Oncol 2011; 12: 763-772 Snee et al. J Thoracic Oncol 2011; 6 suppl 2: O 30.07

MARS: OS No EPP= 13 deaths Median OS: 14m EPP vs 19m no EPP 1-yr OS: 52% EPP vs 73% no EPP adjusted HR: 2.75 ; p 0.016 EPP= 17 deaths Treasure et al. Lancet Oncol 2011; 12: 763-772 Snee et al. J Thoracic Oncol 2011; 6 suppl 2: O 30.07

MARS: Quality of Life Treasure et al. Lancet Oncol 2011; 12: 763-772 Snee et al. J Thoracic Oncol 2011; 6 suppl 2: O 30.07

MARS: authors conclusions In view of the high morbidity associated with EPP in this trial and in other non-randomized studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. Thus EPP can no longer be recommended as an option for patients with mesothelioma Treasure et al. Lancet Oncol 2011; 12: 763-772 Snee et al. J Thoracic Oncol 2011; 6 suppl 2: O 30.07

P/D is superior to EPP in multimodality management of pts with MPM prospective, non-randomized study 7- year period 2 groups: EPP 25 pts induction CT: cisplatin-gemcitabine or cisplatin-pemetrexed 22 pts EPP (3 abandoned due to extent of disease) 17 pts adj. RT 54 Gy (68% full protocol) P/D 61 pts P/D + hyperthermic pleural lavage (povidone-iodine) 57% macroscopic complete resection 54 pts+ prophylactic RT 21 Gy + adjuvant CT 4-6 cycles Lang-Lazdunski L et al. J Thor Oncol 2012; 7:737-43

P/D is superior to EPP in multimodality management of pts with MPM 30-day EPP 4.5% P/D 0% morbidity 68% 28% survival MST EPP 12.8 mos P/D 23 mos 5-year 9% 30.1% p =.004 multivariable analysis: P/D epitheloid histology completeness of resection multimodality setting: P/D superior to EPP Lang-Lazdunski L et al. J Thor Oncol 2012; 7:737-43

Is it time to consider P/D as the only surgical treatment for MPM? EPP gold standard until now MARS trial: EPP morbidity - is P/D now standard therapy? to be abandoned «it is too early based on this data to completely abandon EPP altogether» Weyant MJ. Editorial. J Thor Oncol 2012; 7:629-30 options: macroscopic complete resection P/D EPP EORTC: randomized phase II of induction versus adjuvant CT + extended P/D in early stage MPM

Surgical studies in mesothelioma Conclusions MPM highly lethal disease surgery: role diagnosis, staging, palliation, treatment combined modality treatment indicated in early stages role of induction versus adjuvant chemotherapy? role of maximal debulking by EPP versus P/D? survival advantage of trimodality treatment? further phase II/III multicenter trials necessary

Surgical studies in mesothelioma Staging - restaging pleura lung surrounding organs precise estimation tumor volume difficult correct staging : comparative studies treatment and prognosis

IMIG 1995 International Mesothelioma Interest Group no classical T N M descriptors until 1995 similar to other solid tumors (NSCLC) : TNM, stage grouping reconciles previous staging systems, mainly surgically based prospective IASLC database, new proposal Rusch VW (IMIG). Chest 1995; 108:1122-28 Pleural mesothelioma. AJCC cancer staging handbook, Springer, 2002

Restaging MPM how to evaluate response after chemo-, chemoradiotherapy? neoadjuvant therapy: surgery assessment of response non-invasive: subsequent CT scans role of PET? WHO, RECIST criteria inadequate for MPM WHO: perpendicular diameters of tumor nodules RECIST: unidimensional, longest diameter of tumor - applies for spherical tumors Van Klaveren R. Lung Cancer 2004; 43:63-69 Monetti F. Lung Cancer 2004; 43:71-74

MPM response evaluation modified RECIST RECIST longest diameter : stable disease modified RECIST perpendicular diameter : partial response Byrne M. Ann Oncol 2004; 15:257-60

Surgical studies in mesothelioma landmark trials combined modality therapy 183 pts trimodality : EPP + adjuvant chemotherapy and radiotherapy till 30 Gy mortality : 3.8 % morbidity 50 % MST 19 mos. 5-year survival : 15 % prognostic factors : epithelial cell type, resection margins, extrapleural nodes Sugarbaker DJ. J Thorac Cardiovasc Surg 1999; 117:54

Surgical results in mesothelioma total series 496 pts EPP analysis 328 consecutive pts 1980-2000 3.4 % morbidity 60 % complications: % atrial fibrillation 44.2 prolonged intubation 7.9 vocal cord paralysis 6.7 DVT 6.4 technical complications 6.1 patch dehiscence, hemorrhage, or both Sugarbaker DJ. J Thorac Cardiovasc Surg 2004; 128:138

Surgical studies in mesothelioma landmark trials SAKK : Swiss Group for Clinical Cancer Research neoadjuvant chemotherapy 3 cycles cisplatin + gemcitabine 61 pts. T2N2M0 MPM 45/58 patients completing chemotherapy EPP ± radiotherapy (incomplete resection or areas at risk) 37 complete resection (61 %); 36 postop. radiotherapy Opitz I. Eur J Cardiothorac Surg 2006; 29:5744 Weder W. Ann Oncol 2007; 18:1196

Surgical studies in mesothelioma landmark trials 90-day 2 pts. (3.2 %) 1 or more complic. in 62 % empyema 16 % bronchopleural fistula 9.5 % 1-year survival : 69 % MST EPP 25.9 mos. Opitz I. Eur J Cardiothorac Surg 2006; 29:5744 Weder W. Ann Oncol 2007; 18:1196 phase II trial : induction chemotherapy + EPP ± PORT