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P BONNETTE Thoracic surgery and Lung transplantation Hôpital Foch PARIS FRANCE

The role of surgery in non-small-cell lung cancer with lymph node metastases ESCT 53th congress Cairo 27-30 March 2012. P BONNETTE Thoracic surgery and Lung transplantation Hôpital Foch PARIS FRANCE. 7th classification UICC/AJCC2010 14 stations (CT) 6 zones.

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P BONNETTE Thoracic surgery and Lung transplantation Hôpital Foch PARIS FRANCE

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  1. The role of surgery in non-small-cell lung cancer with lymph node metastasesESCT 53th congress Cairo 27-30 March 2012 P BONNETTE Thoracic surgery and Lung transplantation Hôpital Foch PARIS FRANCE

  2. 7th classification UICC/AJCC2010 14 stations (CT) 6 zones

  3. Mediastinal assessment forlung cancerACCP 2007 • CT Imaging: • abnormal if short axis >1cm, St 7>1.5cm • Pet Scan: • more sensitive and specific Chest 2007;132: 178S-201S

  4. N1

  5. Guidelines Surgery is indicated for stage II N1 NSCLC • ACCP 2007 • ESMO 2008 Lobectomy is recommanded + sleeve resection +lymphadenectomy JTO 2007;7:606 N1 IALSC statistics

  6. Prognosis of N1 in relation withnumber numberof involved nodes of involved stations Cerfolio ATS 2007;84:182-90 Ditto Chest 2011 140 433-40

  7. Hilar Interlobar Lobar Segmental Subsegmental Prognosis in relation with the location of N1lymph node metastases 5 stations, 2 zones peripheral Demir ATS 2009;87:1014-22 interlobar Hilar (= N2 unistation) Rusch JTO 2007 2 610

  8. « Minimal N2 »Normal mediastinum on CT-imagingPost operative N2 status

  9. Post operative survival for « minimal N2 » (normal mediastinum on CT-imaging) Suzuki JTCS 1999; 118: 145 minimal N2 (n=135) 40% (n=87) <10%

  10. « Clinical N1 » (hilar adenomegaly without mediastinal adenomegalyon CT-imaging staging) • 135 resectionswith curage • poorpredictive value • pN0 19% • pN1 44% • pN2 37%(« minimal N2 ») Watanabe ATS 2005;79:1682-5

  11. Post operative survival for pN2  with normal mediastinum on CT-imagingand Pet Scan OS >40% pN2 Kim HK JTO 2011, 6:336-42

  12. « Clinical N1 on Pet-Scan staging  » (hilar fixation without mediastinal fixation) • 17 petN1 : 41 % pN2(« minimal N2 ») • 136 petN0 : 11% pN2 Cerfolio (Chest 2006;130:1791-95)

  13. Stage IIIN2Postoperative chemotherapy recommanded Pignon JCO 2008;21:3552-9 Efficacy of Cisplatine-vinorelbine especially demonstrated ++

  14. Long term survival: JBR10 (stage IB-II)JCO 2010, 28, 35-42 CysP + Vinorelbine

  15. Post operative radiotherapy (PORT) for pN2?Meta-analysis 1998 PORT for N2 Old trials with Cobalt++ lancet 1998 352 257-63

  16. PORT (1988-2002)Surveillance, Epidemiology, and End Results DatabaseSEER PORT No PORT Lally JCO 2006 24 2998-3006

  17. PORT (LINAC) in Anita trial: N2 Douillard IJROBP 2008;72:695-701 Ch+Rt Ch Rt No Ch

  18. Loco regional recurrences after surgery for Stage IIIA with or without PORT(LINAC) >40% Scotti Radioth Oncol 2010;96:84-88 N=179 <20% 5

  19. « Clinical N2 »mediastinal adenomegaly on CT-imaging and/or positive Pet-scan

  20. cN2 : is it a pN2? • CT Scan : PPV 0.56 • Pet : PPV 0.79 (Toloza Chest 2003;123:137S-146S) insufficient! • Histological confirmation is important only if it modifies therapy • It is necessary to justify chemotherapy in case of a tumour less than 4cm • Mediastinoscopy: large tissu samples • EBUS-TBNA: sensitivity 0.93

  21. Initial prognostic factors of cN2 patients can be collected!1- tumor size Vansteenkiste Lung cancer 1998;19:3-13

  22. Initial prognostic factors after surgery: 2-uni or multi-station cN2 cN2 V Rusch JTO 2007 2 610 cN2 Riquet ATS 2007 84:1818-24 Uni 28% Multi 17%

  23. Initial prognostic factors after surgery: 3-Bulky (>2cm) or not 386 resected pN2 (1984-2003) Riquet ATS 2007;84:1818-24 Non bulky 207 34% Bulky 126 Micrometastases 53 23%

  24. Initial prognostic factors after surgery: 4-SUV max of the tumour 72 stages IIIA median SUVmax:14.2 SUVmax < 14.2 SUVmax > 14.2 Cerfolio JTCS 2005;130:121-9 64% 16%

  25. Since the trials of Roth and Rosell (1994), proven N2 usually leads to induction chemotherapy

  26. Meta-analysis of preoperative chemotherapy for stage III Chemotherapy better Berghmans: Lung Cancer 2005;49:13-23

  27. Response rate after neoadjuvant chemotherapy (2 to 4 sessions)RECIST: decrease of at least 30% on largest diameters of mesurable tumoral zones % response About 60%

  28. Post operative mortality after neoadjuvant chemotherapy

  29. Induction chemo or chemo-radiotherapy?Randomised trial (GLCCG) • 524 IIIA/IIIB patients  (200 IIIAN2) 296 operated on • Better downstaging with CH-RT (46% vs 29%) • Increased post operative mortality (lobe: 8% vs 2%/ Pn: 14% vs 6%) • Equivalent overall survival A Swiss Trial for IIIA Thomas Lancet Oncol 2008; 9:636-48 All N=520 After resection N=272 CH-RT CH P=0.54

  30. Post induction pronostic factors can then be collected • after restaging • « Response » to induction: CT-imaging, Pet Scan • « Downstaging »: EUS/EBUS/mediastinoscopy

  31. Prognostic factor: Objective response on CT-imaging RECIST F André, JCO2000; 18: 2981 Stages IIIAN2 Response N=69 20% No response N=26 5%

  32. Prognostic factor: Response on Pet-scan with the same machine and protocol to compare SUVmax SUV>60% 62% 13% Dooms JCO2008;26:1128

  33. Post operative prognostic factor:Down-staging (yN0/N1)? Betticher JCO 2003;21:1752

  34. Downstaging (yN0-yN1) and5 year survival *ChemoRT ** at 3 years

  35. How to prove Downstaging (yN0/N1) preoperatively? CT Imaging, Pet Scan, EBUS and EUS are not efficient for proving downstaging! JTO 2010;5:390

  36. Remediastinoscopy? Fibrosis due to previous mediastinoscopy First mediastinoscopy++ Initial staging with EBUS Neoadjuvant chemotherapy Re-staging with mediastinoscopy

  37. Is it useful to prove downstaging?Is it the key to surgical decision? Overall survival after chemotherapy and surgery for persistent yN2? Unistation n=33 37% Decaluwe EJCTV 2009 ditto Takeda multistations

  38. Initial Staging Induction CH(RT) Restaging Radio-chemotherapy Surgery +/-RT Therapeutic choice The different prognostic factors do not indicate the best local treatment for a still confined tumor!

  39. EORTC* Non resectable Responders after chemotherapy P/L 72/58 5 years OS Surg: 15.7% Rt: 14% NS Intergroup** Resectable Non progressing after radio-chemotherapy P/L 54/98 5 years OS Surg: 27,2% Rt: 20,3% NS 2 large randomised published trials of Surgery VS radiotherapy *Van Meerbeeck:J Natl Cancer Inst 2007; 99:442-50 **Albain: Lancet 2009; 374: 379-86

  40. EORTC 08941Non resectable N2responders after chemotherapy 3 sessions of chemotherapy CR/PR Surgery sequential

  41. Mediane survival 5 years survival Radiotherapy N=165 17.5 m 14% Surgerymortality 4% N=167 16.4 m 15.7% 72 pneumonectomies Mortality 7.2% 13.4 m 12% 58 lobectomies Mortality 0% 25.4m 27% EORTC 08941 Overall Survival 100 80 60 Overal Survival (%) 40 Surgery Survival X 2 NS 20 Radiotherapy 0 0 12 24 36 48 60 72 84 96 108 Mois Survival of lobectomy twice as high at 5 years

  42. Intergroup 0139 • T1-3 N2 proven and resectables (T3:12%) • Only one clinically invaded stations in 76% • Randomised: 396 cases without progressive disease (93%)

  43. Intergroup 0139 Overall survival 27% with S NS 20% without

  44. . Survival of lobectomy twice as high! Postoperative mortality 1% Intergroup 0139Survival of patients according to type of resection , compared to those who had radiotherapy and who would have had the same resection if operated on Survival X 2 Surg 36% CH-RT 18% LOBECTOMIES Postoperative mortality 26% CH-RT 24% Surg 22% PNEUMONECTOMIES

  45. Pneumonectomy after chemoradiotherapy Intergroup * GLCCG 45 14% *large number of centers involved Krasna JTS 2009 138 295-9

  46. Synthesis of the 2 trials In both studies, there were good results for patients having had a lobectomy but the operative mortality of the pneumonectomy patients meant that any benefit of surgery was cancelled out.

  47. Resection after radio-chemotherapy >60G • 326 cases (1997-2007), Pet for all • proven N2, non bulky, invasion of 1 station predominently • Radio-chemotherapy >60G • Re-staging after 4 weeks with Pet-CT • 149 thoracotomies (46%) for responders (Day +51) • 36 exploratory thoracotomies • 116 resections (surgical mortality 1.7%): 91 L, 14 Pn, 8 S • 23% histologic sterilisation only • 5 year survival • 17% without resection • 42% with resection but pN2(n=14) • 49% with resection and pT1-3N0N1(n=65) • 53% with resection and pT0N0 (n=34) Cerfolio ATSurg 2008 86 912-20

  48. chemoRT>59G + surgery for N2

  49. Locoregional recurrence for N2 patients • Exclusive chemoradiotherapy 60G: 68% (5yrs)  (7 trials from RTOG) • Machtay JTO 2012:7;716-22 • Surgery: 40% (5yrs) • Scotti Radioth Oncol 2010;96:84-88 • Surgery and PORT: 20% (5yrs) • Scotti Radioth Oncol 2010;96:84-88

  50. In short • Post surgical local control is superior compared with chemo radiotherapy alone, and better with PORT • Post operative risk determines the therapeutic options • If post operative risk is low, surgery is preferable for N2 patients, especially uni-stationN2, even by pneumonectomy, and may be performed directly followed by adjuvant chemotherapy • If operative risk is high, poor prognostic factors lead to chemo-radiotherapy (bulkyN2,or initial multistation N2, high initial SUV max, non responder on CT, persistent multistation N2…)

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