p bonnette thoracic surgery and lung transplantation hôpital foch paris france

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1 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

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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. - PowerPoint PPT Presentation

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Page 1: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

Page 2: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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7th classificationUICC/AJCC201014 stations (CT)6 zones

Page 3: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Mediastinal assessment forlung cancer

ACCP 2007

• CT Imaging:– abnormal if short axis >1cm, St 7>1.5cm

• Pet Scan:– more sensitive and specific

Chest 2007;132: 178S-201S

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N1

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Guidelines Surgery is indicated for stage II N1 NSCLC

– ACCP 2007

– ESMO 2008

Lobectomy

is recommanded+ sleeve resection

+lymphadenectomy

N1

JTO 2007;7:606

IALSC statistics

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Prognosis of N1 in relation with

number numberof involved nodes of involved stations

Cerfolio ATS 2007;84:182-90

Ditto Chest 2011 140 433-40

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Prognosis in relation with the location of N1lymph node

metastases

HilarInterlobar

LobarSegmentalSubsegmental

Hilar (= N2 unistation)

peripheral

interlobar

Demir ATS 2009;87:1014-22

Rusch JTO 2007 2 610

5 stations, 2 zones

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« Minimal N2 »Normal mediastinum on CT-imaging

Post operative N2 status

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(n=135)

(n=87)

Suzuki JTCS 1999; 118: 145

 minimal N2 

Post operative survival for « minimal N2 » (normal mediastinum on CT-imaging)

40%

<10%

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« Clinical N1 » (hilar adenomegaly without mediastinal adenomegaly

on CT-imaging staging) • 135 resections with curage

• poor predictive value– pN0 19%– pN1 44%

– pN2 37% (« minimal N2 »)(« minimal N2 »)

Watanabe ATS 2005;79:1682-5

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Post operative survival for pN2  with normal mediastinum on CT-imaging and Pet Scan

Kim HKJTO 2011, 6:336-42

OS

pN2

>40%

Page 12: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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« 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)

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Stage IIIN2Postoperative chemotherapy recommanded

Pignon JCO 2008;21:3552-9

Efficacy of Cisplatine-vinorelbine especially demonstrated ++

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Long term survival: JBR10 (stage IB-II)

JCO 2010, 28, 35-42CysP + Vinorelbine

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Post operative radiotherapy (PORT) for pN2?

Meta-analysis 1998 PORT for N2

Old trials with Cobalt++

lancet 1998 352 257-63

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PORT (1988-2002)

Surveillance, Epidemiology, and End Results DatabaseSEER

Lally JCO 2006 24 2998-3006

PORT

No PORT

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PORT (LINAC) in Anita trial: N2 Douillard IJROBP 2008;72:695-701

Ch+Rt

Ch

RtNo Ch

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Loco regional recurrences after surgery for Stage IIIA with or without

PORT(LINAC)

Scotti Radioth Oncol 2010;96:84-88

N=179

<20%

>40%

5

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« Clinical N2 »mediastinal adenomegaly on CT-imaging

and/or positive Pet-scan

Initial Staging

Page 20: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

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Initial prognostic factors of cN2 patients can be collected!

1- tumor size

Vansteenkiste Lung cancer 1998;19:3-13

Page 22: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Initial prognostic factors after surgery: 2-uni or multi-station cN2

Riquet ATS 200784:1818-24

V Rusch JTO 2007 2 610cN2 cN2

Uni

Multi

28%

17%

Page 23: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Initial prognostic factors after surgery: 3-Bulky (>2cm) or not

386 resected pN2 (1984-2003)

Non bulky 207

Bulky 126

Micrometastases 53

Riquet ATS 2007;84:1818-24

34%

23%

Page 24: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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%

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

chemotherapy

Initial Staging

Induction CH(RT)

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Meta-analysis of preoperative chemotherapy for stage III

Berghmans: Lung Cancer 2005;49:13-23

Chemotherapy better

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Response rate after neoadjuvant chemotherapy (2 to 4 sessions)

RECIST: decrease of at least 30% on largest diameters of mesurable tumoral zones

0

10

20

30

40

50

60

70

80

R0 Rate- Stage IIIA

LCSG (MVP)

Memorial (MVP)

Toronto (MVP)

Dana Farber (PFl)

CALGB II (VP)

Crino (GP)

Van Zandwijk (GP)

Pisters (TC)

% response

About 60%

Page 28: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Post operative mortality after neoadjuvant chemotherapy

Without chemo With chemo

Nbre DCD Nbre DCD

Pass ATS 92 (Eto+P)X2 14 0 13 0

Roth JNCI 94 (Cyclo+Eto+P)X6 32 2 20 0

Rosell NEJM 94 (MIP)X3 30 2 27 2

Depierre JCO 2002 (MIP)X3 187 8 186 13

Nagai JTS 2002 (P+Vindésine)X3 31 0 31 0

Pisters ASCO 2007 (Carbo+Taxol)X3 174 4 180 7

LU22

Lancet 2009 (Platine based)X3 80PN 3 63PN 3

NATCH JCO 2010 (Carbo+Taxol)X3 401 26 181 9

chEST JCO2012 (P+Gemzar)X3 136 5 110 4

TOTAL 1085 50 4.6%

811 38 4.7%

Page 29: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

AllN=520

After resectionN=272

CH-RT

CH

Thomas Lancet Oncol 2008; 9:636-48

P=0.54

A Swiss Trial for IIIA

Page 30: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Initial Staging

Induction CH(RT)

Restaging

Post induction pronostic factors can then be collectedafter restaging

« Response » to induction: CT-imaging, Pet Scan« Downstaging »: EUS/EBUS/mediastinoscopy

Page 31: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Prognostic factor: Objective response on CT-imaging RECIST F André, JCO2000; 18: 2981

Stages IIIAN2

ResponseN=69

No responseN=26

20%

5%

Page 32: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Prognostic factor: Response on Pet-scan with the same machine and protocol to compare SUVmax

Dooms JCO2008;26:1128

SUV>60%

62%

13%

Page 33: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Post operative prognostic factor: Down-staging (yN0/N1)?

Betticher JCO 2003;21:1752

Page 34: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Downstaging (yN0-yN1) and5 year survival

Downstaging Without

Bueno 2000 36 9Betticher 2003 61** 11**Lorent 2004 44 14EORTC 2005 29 7Mansour 2008 35 32Thomas* 2008 48 13Intergroup 2009 41 24Decaluwe 2009 49 27

*ChemoRT ** at 3 years

Page 35: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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How to prove Downstaging (yN0/N1) preoperatively?

CT Imaging, Pet Scan, EBUS and EUS are not efficient for proving downstaging!

JTO 2010;5:390

Page 36: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Remediastinoscopy?n Sensitivity Specificity Exactness

Stamatis 2005 165 74 100 93

De Leyn 2006 30 29 100 60

DeWaele2008

104 70 100 80

Fibrosis due to previous mediastinoscopy

First mediastinoscopy++

Initial stagingwith EBUS

Neoadjuvantchemotherapy

Re-stagingwith mediastinoscopy

Page 37: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

multistations

Decaluwe EJCTV 2009

ditto Takeda

37%

Page 38: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Therapeutic choice

Initial Staging

Induction CH(RT)

Restaging

Surgery +/-RTRadio-chemotherapy

The different prognostic factors do not indicate the best local treatment for a still confined tumor!

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2 large randomised published trials of Surgery VS radiotherapy

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

*Van Meerbeeck:J Natl Cancer Inst 2007; 99:442-50**Albain: Lancet 2009; 374: 379-86

Page 40: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

EORTC 08941Non resectable N2

responders after chemotherapy

sequential

3 sessions of chemotherapy

CR/PR

Surgery

Page 41: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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EORTC 08941

Overall Survival

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96 108

Mois

Radiotherapy

Surgery

12%13.4 m72 pneumonectomies

Mortality 7.2%

15.7%16.4 mSurgery mortality 4%

N=167

27%25.4m58 lobectomies

Mortality 0%

14%17.5 mRadiotherapy

N=165

5 years survival

Mediane

survival

Ove

ral S

urv

ival

(%

)

Survival

X 2

Survival of lobectomy twice as high at 5 years

NS

Page 42: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Intergroup 0139

• T1-3 N2 proven and resectables (T3:12%)

• Only one clinically invaded stations in 76%

• Randomised: 396 cases without progressive disease (93%)

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27% with S

20% without

Intergroup 0139Overall survival

NS

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Intergroup 0139

Survival of patients according to type of

resection , compared to those who had

radiotherapy and who would have had the

same resection if operated on

Surg 36%

CH-RT 18%

CH-RT 24%

Surg 22%

Postoperative mortality 1%

Postoperativemortality 26%

LOBECTOMIES

PNEUMONECTOMIES

Survival X 2

. Survival of lobectomy twice as high!

Page 45: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

Pneumonectomy after chemoradiotherapy

Krasna JTS 2009 138 295-9

GLCCG 45 14%

Intergroup *

*large number of centers involved

Page 46: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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.

Page 47: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

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chemoRT>59G + surgery for N2

Indication DownStaging

pCR Survival

Sonett ATS 2004 ? 85% 45% OS 5 yrs 46%

Daly ATS 2006 Non progressing

47% 29% OS 5 yrs 33%

Shaikh AJCO 2007 Non progressing

77% 35% OS 3 yrs 46%

Edelman ATS 2008 Down Staging Median 56 months

Cerfolio EJCTS 2009 Down Staging 85% 33% OS 5 yrs 34%

Krasna ATS 2010 Down Staging 91% 55% DFS 5yrs 48%

RTOG 0229 JCO Abs 2010 ? 63%Shumway Lung Cancer

2011Non progressing

77% 40% OS 2 yrs 62%

Page 49: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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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

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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…)

Page 51: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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N3= multistation diffusion!Classical surgical contra-indication

Surgical series are seldom but some have shown satisfactory results

pN3

Page 52: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Chemo-radiotherapy and surgeryfor IIIB

• 45 cases: N3:29%, T4 78%

• Chemo X3 then RT-CT 44G

• Objective Response: 67%

• 31 resections, 17 pneumonectomies

• 2 post-op deaths/ 24 complete resections

Stupp Lancet Oncol 2009;10:785-93

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Survival of cN3 and T4

Months

0.0

0.2

0.4

0.6

0.8

1.0

/ / /

//

// /

/ / /

/

/ / / // / //

12 24 36 48 60

/

/ / /

/ /

/ //

/ /

/ /

/ / // / //

cN3

T4 autres

<30%

Page 54: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Limited N3 diffusion

• The number of invaded lymph nodes is more important than the situation of these nodes!– Lee ATS 2008 85 211-5 (corée)– Wei JTO 2011 6 310-8 (japon) – Saji JTO 2011 6 1865-71(japon)

• 5% skip N 3 (Riquet JCTS 1989;97:623-32)

Page 55: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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Conclusion

• Resected non hilar N1 patients have a good prognosis• Surgery seems useful for N2 patients with low operative

risk, and better with PORT.• If the operative risk is higher (in particular

pneumonectomy in older patients or those with impaired function), surgery is justified for unistation N2 or responders to chemotherapy

• N3 status is a surgical contra -indication (except for young patients without operative risks , with few invaded nodes, an objective response or downstaging proven by mediastinoscopy)

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Thank you for your attention

Hôpital FochFrance2012

Page 57: P BONNETTE       Thoracic surgery and  Lung transplantation Hôpital Foch  PARIS FRANCE

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EORTC 08941• 332 proven IIIAN2, non resectables

– All non epidermoid N2– epidermoid N2 with 2R+/4L+

• objective response (WHO) after 3 courses of chemotherapy with platinum (62%)

• randomised between– Radiotherapy 60G (sequential)– Surgery (+/- RT if incomplete resection): 154

• 72 pneumonectomies• 58 lobectomies• 21exploratory thoracotomies

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N1: ipsilateral peribronchial, ipsilateral hilarN2: ipsilateral mediastinal, subcarinal N3: contralateral mediastinal or hilar, scalene or supraclavicular

N1 N1N2

N2

5-6

10L

JTO 2009; 4:568-77

CT imaging marks

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« Clinical N2 »mediastinal adenomegaly on CT-imaging

and/or positive Pet-scan• IIIA3: preoperative discovery potentially

resectable

• IIIA4: preoperative discovery potentially non resectable– N2 multizones– Bulky on CT-imaging– fixed or with capsular disruption at

mediastinoscopyACCP Chest 2007

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Intergroup 0139CH-RT45G + Surgery: 202 cases

• 81% operated• 71% completely resected• 46% down stagging• mortality 7.9%,• 98 lobectomies: mortality 1%• 54 pneumonectomies: mortality 26%• numerous surgical units

CH-RT 61G: 194 cas,• treatment completed 80% • mortality 2.1%