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 PresentationTRANSCRIPT
1
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
2
7th classificationUICC/AJCC201014 stations (CT)6 zones
3
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
4
N1
5
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
6
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
9
(n=135)
(n=87)
Suzuki JTCS 1999; 118: 145
minimal N2
Post operative survival for « minimal N2 » (normal mediastinum on CT-imaging)
40%
<10%
10
« 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%
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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 ++
14
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
18
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
19
« Clinical N2 »mediastinal adenomegaly on CT-imaging
and/or positive Pet-scan
Initial Staging
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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
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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%
•
23
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%
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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%
25
Since the trials of Roth and Rosell (1994), proven N2 usually leads to induction
chemotherapy
Initial Staging
Induction CH(RT)
26
Meta-analysis of preoperative chemotherapy for stage III
Berghmans: Lung Cancer 2005;49:13-23
Chemotherapy better
27
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%
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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%
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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
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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
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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%
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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%
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Post operative prognostic factor: Down-staging (yN0/N1)?
Betticher JCO 2003;21:1752
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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
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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
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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
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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%
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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
EORTC 08941Non resectable N2
responders after chemotherapy
sequential
3 sessions of chemotherapy
CR/PR
Surgery
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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
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%)
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27% with S
20% without
Intergroup 0139Overall survival
NS
44
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!
Pneumonectomy after chemoradiotherapy
Krasna JTS 2009 138 295-9
GLCCG 45 14%
Intergroup *
*large number of centers involved
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.
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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%
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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…)
51
N3= multistation diffusion!Classical surgical contra-indication
Surgical series are seldom but some have shown satisfactory results
pN3
52
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
53
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%
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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)
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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
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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
59
« 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
60
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%