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the Lebanese Society of Medical Oncology
commitment to cure cancer
november 13-15, 2008
Beirut
adjuvant therapy in
non-small cell lung cancer
Dominique H. Grunenwald, MD
Professor in Thoracic and Cardiovascular Surgery
Hopital Tenon, University of Paris. France
IS NATURAL HISTORY OF NON-SMALL CELL LUNG CANCER IN
ACCORDANCE TO TNM STAGING SYSTEM ?
Grunenwald DH, et al. J Thorac Oncol 2007;2 Suppl.4:S574-S575
TN staging for 392 M1 nsclc
T1
T2
T3
T4
total
%
N0
12
40
18
16
86
22
N1
2
25
3
16
46
12
N2
14
75
34
39
162
41
N3
3
49
11
35
98
25
total
31
189
66
106
392
%
8
48
17
27
100
among patients with stage IV
metastatic nsclc :
%
no.
N0-1
34
N status 132
T1-2
56
T status 220
%
no.
N2-3
260
T3-4
172
66
44
T1-2N0 = 13%
metastatic spreading is not the privilege of
locally advanced disease in nsclc
let's remember year 1995 !
the only curative treatment is surgery
post-operative radiotherapy is a paradigm
ct is something for metastatic disease
"new" drugs are emerging … for stage IV
vinorelbine
taxanes
gemcitabine
induction ct is coming out … in stage IIIA
remember year 1995 !
Non-Small Cell Lung Cancer Collaborative
Group
Chemotherapy in non-small cell lung cancer: a
meta-analysis using updated data on individual
patients from 52 randomized clinical trials
Br Med J 1995;311:899-909
postoperative cisplatin regimen could improve
the overall survival of patients resected for nonsmall cell cancer
adjuvant ct in nsclc
NSCLC Collaborative Group BMJ 311:899,1995
Surgery vs Surgery + CT
(cisplatin-based trials)
1.0
S
U
0.9
Surgery+CT
Surgery
0.8
R
0.7
V
0.6
I
0.5
V
0.4
A
0.3
L
0.2
 5%
0.1
Patients at risk
Surgery+CT
Surgery
0.0
Events Total
298
706
688
316
0
12
24
706
688
590
548
462
433
Months
36
48
60
371
353
295
258
206
177
phase III trials
management of early stage nsclc
Trial
Stage
CT
IB, IIA
vinorelbine - CDDP
I, II, IIIA, complete
resection
Platinum based,  RT
II, IIIA
EPx4 + RT vs. RT
I-IV
Various, vs. BSC
ALPI
I, II, IIA
Cisplatin, MMC,
vindesine x 3
ANITA
I, II, IIIA
vinorelbine - CDDP
T2N0
Paclitaxel-CBDCA
NCIC CTG BR.10
IALT
ECOG
BIG Lung Trial
CALGB 9633
remember year 1998 !
paradigm explodes
PORT meta-analysis published in
the Lancet
post-operative radiotherapy is detrimental
… in early stages
questionable in stage IIIA
remember year 2002 !
Adjuvant Lung Project Italy (ALPI)
presented at ASCO
"negative"
"death of adjuvant therapy!!!"
Dr. Scagliotti is disappointed…
results of ialt
and anita are
about to come ...
others are smiling ...
remember year 2003 !
ALPI is published
"negative"
Scagliotti GV, et al. J Natl Cancer Inst 2003
International Adjuvant Lung cancer Trial (IALT)
presented at ASCO
"positive"
Japan Lung Cancer Research Group (UFT)
presented at ASCO
"positive"
IALT
cisplatin combined with
a "new" drug in 30% of cases
Japanese study
adjuvant ct without
platinum salts
IALT outcomes
N patients
Events
MST
Median DFS
5-year survival*
5-year DFS**
Chemo
Control
P value
932
469
50.8 mos
40.2 mos
44.5%
39.4%
935
504
44.4 mos
30.5 mos
40.4%
34.3%
0.03
0.003
* HR = 0.86 (95% CI 0.76-0.98) ** HR = 0.83 (95% CI 0.74-0.94)
planned 3.300 patients; enrolled 1867
IALT Collaborative Group NEJM 2004; 350: 351-360
Overall survival
Probability of survival (%)
100
90
80
70
60
50
40
30
20
10
0
0
No. at risk
Control 488
UFT
491
UFT
Control
No.
of
cases
5 YS
(%)
Control
488
85.4
UFT
491
87.9
H.R.=0.709 [0.515-0.978]
1
2
3
4
Logrank
test
0.0350
5
6
7
8
Years after resection
481
482
469
471
445
442
423
416
378
368
219
96
221 105
T1N0
T2N0
UFT
Control
UFT
Control
despite smaller subset of pT2 (130 vs 360),
all benefit comes from pT2 patients
acceptance of CT according to tumor size is
unavailable
overall compliance relatively poor (53%)
IALT & ALPI
common features
large scale randomised clinical trials
across all resectable stages (I-IIIA)
cisplatin-based ct
sequential adjuvant rt allowed
sample size calculation around the
survival advantage indicated by 1995
nsclc meta-analysis
ALPI - Overall Survival
Eve nts/Total
CT
Control
278/548
288/540
HR=0.96 (0.81 - 1.13)
P<0.03
100
80
p=0.585
60
survival (%)
P
R
O
B
A
B
I
L
I
T
Y
ialt overall survival
40
adjuvant ct
20
0
control
0
•
•
1
775
774
2
624
450
308
602
432
286
3
4
5
years
181
164
N Engl J med 2004;350:351-60
YEARS
Scagliotti
GV et al. JNCI 2003; 95 (19) : 1453-61
initial toxicity affects the results
ALPI - Overall Survival
P
R
O
B
A
B
I
L
I
T
Y
Events/Total
CT
278/548
Control
288/540
HR=0.96 (0.81 - 1.13)
p=0.585
Scagliotti
GV et al. JNCI 2003; 95 (19) : 1453-61
YEARS
ialt overall survival
P<0.03
100
survival (%)
80
60
adjuvant ct
40
control
20
0
0
1
932
2
775
933
3
624
774
602
4
450
432
5
years
308
286
181
164
N Engl J med 2004;350:351-60
remember year 2004 !
IALT1 and JLCRG2 (UFT) published
1. IALT collaborative group. N Engl J Med 2004;350(4):351-60
2. Kato H, et al. N Engl J Med 2004;350(17):1713-21
NCI Canada JBR.10 (cisplatin + vinorelbine)
presented at ASCO
"positive"
CALGB 9633 (carboplatin + paclitaxel)
presented at ASCO
"positive"
JBR.10 stage IB & II
cisplatin combined with
a "new" drug
CALGB 9633
stage IB
"new" combination
Intergroup JBR.10
National Cancer Institute of Canada
SWOG JBR10; ECOG JBR10; CALGB 9795
Vin/Cis
Observation
phase III randomised trial of adjuvant
VINORELBINE and CISPLATIN
in completely resected stage IB and II nsclc
Winton T, et al., ASCO 2004
summary
• overall survival
vinorelbine-cisplatin
= 15 % improvement of 5-yr OS (p = 0.0022)
= 30 % reduction in risk of death (p = 0.012)
• 5-yr recurrence-free survival
NVB-CDDP control
61 %
48 %
(p = 0.012)
• tolerability
NVB-CDDP well tolerated (59 % > 3 cycles)
negligeable negative impact on qol
CALGB 9633
only stage I B (approx. 1/3 of early nsclc)
median follow up time : 34 months only!!
a lot of censored patients!!!
trial stopped early
CALGB 9633
(stage IB only)
0.8
0.6
0.4
0.2
----Chemotherapy
---chemotherapy
----Observation
---observation
p=0.028
0.0
Probability
1.0
OVERALL SURVIVAL
0
20
40
60
Survival Time (Months)
80
Review by ASCO*
adjuvant chemotherapy trials
from ASCO 2003-2004
IALT
CALGB
n
JBR 10
1867
344
482
5-yr rfs
I, II and III
different CDDPbased CT ± RT
39.4% vs 34.3%
IB and II
NVB + CDDP
without RT
61% vs 48%
5-yr surv.
44.5% vs 40.4%
IB
PCT+CBDCA
without RT
61% vs 50%
(4 yrs f.-up)
71% vs 59%
(4 yrs f.-up)
stages
adj. ct
69% vs 54%
*from review by K. Pisters, ASCO 2004
what about year 2005?
NCI C JBR.10 : cddp + vinorelbine published
Winton TL, al. N Engl J Med 2005;352:2589-97
Adjuvant Navelbine International Trialists
Association (ANITA) : cddp + vinorelbine
presented at ASCO
"positive"
ANITA: Phase III Adjuvant
Vinorelbine and Cisplatin versus
Observation in Completely Resected
Non-Small-Cell Lung Cancer Patients
JY. Douillard, et al.
on behalf of the Adjuvant
Navelbine International Trialists
Association
type of surgery, pTNM, histology
Type of surgery
Pneumonectomy
Lobectomy
Stage
I (pT2 N0)
II
IIIA
Histology
Squamous
Non Squamous
PORT
Chemotherapy at relapse
OBS
n= 433
35.8%
58.4%
n= 433
34.2%
30.5%
35.3%
n= 433
58.9%
41.1%
33.3%
48%
NVB+CDDP
n= 407
38.1%
57.2%
n= 407
35.4%
29.2%
35.4%
n= 407
60.0%
40.0%
21.6%
39.2%
ANITA
overall survival
Median months
1.00
Survival Distribution Function
P-value
OBS.
NVB + CDDP
43.8
65.8
0.013
Hazard Ratio
0.79 [0.66 - 0.95]
0.75
0.50
Obs
0.25
NVB + CDDP
0
0
20
40
60
80
100
120
months
ANITA
survival: Cox univariate analysis
covariates
univariate
P value
age
> 55 years
< 55 years
WHO ps 0
1-2
surg. pneumonectomy
other
radiotherapy no
yes
stage
IIIA
IB-II
N status
N+
N0
histology
adk
other
ANITA
HR [95% CI]
0.04
0.81
0.012
1.27
0.001
0.73
0.003
1.34
< 0.001
0.54
< 0.001
0.53
0.733
0.97
1
[0.67 - 0.99]
1
[1.05 - 1.52]
1
[0.60 - 0.88]
1
[1.10 - 1.63]
1
[0.45 - 0.65]
1
[0.44 - 0.65]
1
[0.80 - 1.17]
survival: Cox univariate analysis
covariates
univariate
P value
age
> 55 years
< 55 years
WHO ps 0
1-2
surg. pneumonectomy
other
radiotherapy no
yes
stage
IIIA
IB-II
N status
N+
N0
histology
adk
other
ANITA
HR [95% CI]
0.04
0.81
0.012
1.27
0.001
0.73
0.003
1.34
< 0.001
0.54
< 0.001
0.53
0.733
0.97
1
[0.67 - 0.99]
1
[1.05 - 1.52]
1
[0.60 - 0.88]
1
[1.10 - 1.63]
1
[0.45 - 0.65]
1
[0.44 - 0.65]
1
[0.80 - 1.17]
what about year 2006?
Adjuvant Navelbine International Trialists
Association (ANITA) : cddp + vinorelbine
published
Douillard JY, et al. Lancet Oncol 2006;7:719-27
Update of CALGB 9633 (stage IB, PCT-CBDCA)
presented at ASCO
negative!!!!
LACE adjuvant meta-analysis presented
adjuvant ct as a standard ?
issues :
1. which drug combination ?
2. which patients (stages) ?
3. role of PostOperativeRT
4. perspectives
Probability
Lung Adjuvant Cisplatin Evaluation
(LACE)
1,0
0,8
0,6
0,4
HR translates into an absolute benefit
of 5.4% at 5 years
0,2
Time (years)
0
0
1
2
3
4
5
6
7
8
Patients at risk
Surg alone
4068
3585
3043
2539
2034
1548
779
358
103
Surg+CT
4079
3607
3074
2584
2137
1665
835
389
108
individual patient data from 5 trials (4,584 patients)
postoperative cisplatin-based ct significantly improves
survival in patients with nsclc
Pignon JP, et al. J Clin Oncol 2008;26:3552-9
which drug combination ?
Lung Adjuvant Cisplatin Evaluation (LACE)
5 randomized clinical trials including 4,584 patients
Pignon JP, et al. J Clin Oncol 2006;24:18S 7008
vinorelbine associated with 320 to 400 mg/m2 of cisplatin
appears the most promising drug combination
Pignon JP, et al. J Clin Oncol 2006;24:18S 7008
Rx
N
5yr surv. (%)
Absolute
benefit
JBR.10
IB-II
(ASCO 04)
Surgery
vinorelbine-CDDP
241
241
54
69
+ 15%
ANITA
IB, II, IIIA
(ASCO 05)
Surgery
vinorelbine-CDDP
433
407
43
51
+ 8%
LACE NVB
Meta-analysis
(ESMO 06)
Surgery
vinorelbine-CDDP
1888
46.1
55
+ 8.9%
Study
which patients (stages) ?
uft
survival: Cox univariate analysis
covariates
univariate
P value
age
> 55 years
< 55 years
WHO ps 0
1-2
surg. pneumonectomy
other
radiotherapy no
yes
stage
IIIA
IB-II
N status
N+
N0
histology
adk
other
ANITA
HR [95% CI]
0.04
0.81
0.012
1.27
0.001
0.73
0.003
1.34
< 0.001
0.54
< 0.001
0.53
0.733
0.97
1
[0.67 - 0.99]
1
[1.05 - 1.52]
1
[0.60 - 0.88]
1
[1.10 - 1.63]
1
[0.45 - 0.65]
1
[0.44 - 0.65]
1
[0.80 - 1.17]
"cisplatin-based ct is certainly
effective for stages II and III"
Pignon JP, et al. J Clin Oncol 2006;24:18S 7008
adjuvant paclitaxel plus carboplatin vs. observation in
stage IB non-small-cell lung cancer (CALGB 9633)
344 patients randomly assigned
median follow-up
74 months
predominant toxicity = gr. 3 to 4 neutropenia
no treatment-related deaths
survival not different
(p = .12)
significant survival difference in favor of
adjuvant ct for tumors  4 cm (p = .043)
Strauss GM, et al. J Clin Oncol 2008;26:5043-51
Goldstraw P, et al. J Thorac Oncol 2007;2:706-14
Goldstraw P, et al. J Thorac Oncol 2007;2:706-14
Mountain CF
Goldstraw P, et al. J Thorac Oncol 2007;2:706-14
Vancouver 2002
impact of postoperative radiation therapy
(ANITA)
adjuvant cisplatin and vinorelbine ct vs. observation
completely resected nsclc stages IB to IIIA
PORT recommended for pN+ disease
unplanned subgroup analysis
observation
33%
PORT
impact on surv.
overall
deleterious
pN1
improved
pN2
improved
chemotherapy
22%
deleterious
detrimental
improved
Douillard JY, et al. Int J Rad Oncol Biol Phys 2008
Role of PORT:
ANITA subset analysis
PORT
232 pts
Overall Survival in N2 patients
Med. survival OVERALL:
47.4 m.
1.00
N1
37%
N2
50%
Survival Distribution Function
N0
13%
32.6 m. CT
20 m. OBS
0.75
23.8 m.
22.7 m.
12.7 m.
CT + PORT
CT
PORT
OBS
0.50
Chemotherapy
Control
0.25
5YS
(%)
PORT
noRT
PORT
noRT
0.00
0
20
40
60
80
100
120
DURATION OF SURVIVAL (MONTHS)
N1
40%
56%
43%
31%
N2
47%
34%
21%
17%
Douillard J, et al. (ANITA), Lancet Oncology, 2006;7(9):719-27
Rosell, IASLC 2005
Possible benefit for PORT in N2 patients to be confirmed by a phase III trial
don't forget to join
LungART trial
(all resected N2 nsclc)
http://www.ifct.fr
perspectives in adjuvant strategy
for resected nsclc
better convenience (oral ct?)
non studied drugs (gemcit., pemetr., taxanes, …)
combinations without cisplatine
adjuvant immunotherapy (Mage A3)
tailored therapies (ERCC1, BCRA1, RRM1,
EGFR, p53, RAS mutations)
targeted therapies (tki, mc ab, …)
convenience
• age
• quality of life
• administration
effect of age on adjuvant cisplatin-based ct
for completely resected nsclc (LACE)
individual patient data from 4,584 patients
5 trials of cisplatin-based ct
group
age
no.
%
young
< 65
3,269
71
midcategory
65 to 69 901
20
elderly
 70
414
9
survival & event-free survival
ns
Früh M, et al. J clin Oncol 2008;26:3573-81
quality-of-life outcomes for adjuvant ct (JBR.10)
adjuvant cisplatin + vinorelbine vs. observation
completely resected stages IB to II nsclc (n=482)
QOL assessments:
- 173 patients in observation arm
- 186 in ct arm
effects of adjuvant ct on QOL temporary
return to baseline in most patients
Beziak A, et al. J Clin Oncol 2008;26:5052-9
vinorelbine D1, D8 + cddp every 3 weeks
optimises with respect of planned dose intensity
Similar efficacy
Improved Tolerance
“The combination of VNR on day 1,8 plus CDDP every 3
weeks may be considered as a reference regimen”
Gebbia et al, Lung Cancer 2008
better convenience ?
oral ct?
adjuvant
immunotherapy ?
immunotherapy MAGE A3
nsclc express MAGE-A3 antigen in 35% of cases
MAGE-A3 expression has poor prognosis
randomized phase II in Stage IB/II MAGE-A3+ (n=182)
postop.
MAGE-A3 (5 x q3w, then 8 x q3 mo.)
vs. Placebo
good tolerance and treatment compliance
27% relative improvement of DFI & DFS
in the MAGE-A3 arm (ns)
ongoing phase III (MAGRIT)
Vansteenkiste, ASCO 2007 – Abs 7554
post-surgical adjuvant chemo-immunotherapy
using autologous dendritic cells and activated
killer cells from tissue culture of tumor-draining
lymph nodes in primary lung cancer
N2 lung cancer
no. of patients = 28
immunotherapy
no. of courses = 313
4 x ct + immunotherapy / 2 mo. for 2 years
fever/chill on the day of cell transfer #
80%
5-yr survival
53%
CONCLUSION
adoptive transfer is feasible and safe
Kimura H, et al. Anticancer Res 2008;28:1229-38
biomarkers ?
DNA repair by ERCC1 in non-small-cell
lung cancer and cisplatin-based adjuvant
chemotherapy
patients with completely resected nsclc and
ERCC1-negative tumors appear to benefit from
adjuvant cisplatin-based ct, whereas patients
with ERCC1-positive tumors do not
Olaussen KA, et al. N Engl J Med 2006;355:983-91
prognostic and predictive importance of p53
and RAS for adjuvant chemotherapy in non
small-cell lung cancer (JBR. 10)
stage IB and II nsclc
adjuvant cisplatin plus vinorelbine or observation
p53 expression (IHC)
predictive and prognostic
p53 mutations (sequencing)
ns
RAS mutations (hybridization)
ns
p53 overexpression
52%
obs. arm: p53-positive < p53-negative (P = .03) progn.
ct arm: p53-positive > p53-negative (P = .02) predict.
Tsao MS, et al. J Clin Oncol 2007;25:5240-7
targeted therapies ?
ongoing studies
bevacizumab
cetuximab
pazopanib ...
Cancer Care Ontario and ASCO guideline
adjuvant cisplatin-based ct
- recommended in stages IIA, IIB, and IIIA
- not currently recommended in stage IB disease
- not recommended in stage IA
adjuvant radiation therapy
- appears detrimental to survival in stage IB and II
- may possibly confer a modest benefit in stage IIIA
Pisters KM, et al. J Clin Oncol 2007;25:5506-18
long-term results of the IALT
ialt was positive after a median follow-up
of 56 months, but the significant effect was
no longer present after a median follow-up
of 90 months
significant difference between the results of overall
survival before and after 5 years
(p-value for interaction 0.006)
possible late adjuvant ct-related over-mortality
need for long-term follow-up of adjuvant lung
cancer trials
Le Chevalier T, et al. 2008 ASCO Annual Meeting
overall survival
Median months
OBS.
NVB + CDDP
43.8
65.8
1-year survival
+ 3.1%
80.4%
83.5%
2-year survival
+ 5.1%
62.8%
67.9%
5-year survival
+ 8.6%
42.6%
51.2%
7-year survival
+ 8.4%
36.8%
45.2%
logrank p value = 0.013
ANITA
take home messages
• the adjuvant debate is not closed down
• however adjuvant cisplatin-based ct is
recommended for stages II and IIIA
• adjuvant ct can be proposed to stage IB
patients with resected T2 > 4 cms
• the only evidence-based "new drug"
doublet is cisplatin-vinorelbine
•better convenience could be obtained
with oral ct
there is still no evidence for...
• any other drug combination
• the assimilation of ct for advanced
disease to adjuvant ct for early stages
• the role of PORT in resected N2 disease
• the role of biomarkers
• the role of immune or targeted therapies
thank you ...