Role of Induction and Adjuvant
Therapy in Regionally Advanced /
Resectable NSCLC
Rodney J. Landreneau M.D.
Professor of Surgery
Department of CardioThoracic Surgery
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Stage IIIA Non Small Cell Lung
Cancer
A “heterogeneous”
anatomic stage
classification with difficult
to interpret responses to
therapy
Stage IIIa Non-Small Cell Lung
Cancer Heterogeneity
• Microscopic mediastinal disease prognosis
compared to macroscopic disease.
• Single station mediastinal node
involvement compared to multiple station
involvement
• Minimal clinical nodal involvement vs.
Bulky mediastinal node involvement
Stage IIIa – “Bulky”
Stage IIIa – “Minimal Involvement”
Single Station IIIa Disease
Induction Chemo-radiotherapy
for Stage III-a non-small cell
lung cancer
Standard of Care ???
Intergroup Trial 0139
Chemo-radiation vs Chemo-radiation
followed by surgical resection of Stage
IIIa NSCLC
Kathy Albain et al.
Lancet. 2009 Aug 1;374:379-86
LUNG INTERGROUP TRIAL 0139 STUDY
DESIGN IIIA(PN2)
STRATIFY
KPS 70-80 vs 90-100
T1 vs T2 vs T3
RANDOMIZE
Induction
CT/RT
Cisplatin, 50 mg/m2 IV d1, 8, 29, 36
Etoposide, 50 mg/m2 IV d1-5, 29-33
Thoracic RT, 45 Gy (1.8 Gy/d), begin d1
RE-EVALUATE
2-4 weeks after
completion of RT
RE-EVALUATE
7 days before
completion of RT
LUNG INTERGROUP TRIAL 0139 STUDY
DESIGN
No progression at
re-evaluation
Surgical
Resection
Continue RT to 61 Gy
without interruption
CONSOLIDATION
cisplatin plus etoposide
X 2 cycles
% Alive without Progression
INTERGROUP 0139/RTOG 9309
PROGRESSION-FREE SURVIVAL BY
TREATMENT
ARMS
100
Failed/Total
75
CT/RT/S
CT/RT
/
50
/ ///
// /
25
Logrank p = 0.017
Hazard ratio = 0.77 (0.62, 0.96)
159/202
172/194
/ // / /
/ // / /
/ //
// / /
0
0
12
24
36
Months from Randomization
48
60
Criteria for Patient
Eligibility for O139
Trial?
“Any mediastinal node positive status by any
means? No systemic sampling/ recording” – Kathy
Albain - personal communication
Adjuvant Chemotherapy
in NSCLC:
A new standard of care?
N Engl J Med 2004;350:351-60
4%
New Engl J Med 2004;350:351-60
Chemotherapy better
NEJM 2004;350:351-60
"Fading" Benefit ?
IALT: 7.5-Year Median Follow-Up
100%
chemotherapy: 578 deaths
- 495 deaths before 5 years
80%
- 83 deaths after 5 years
60%
HR: 0.91 (0.81-1.02, P = 0.10)
40%
control 590 deaths
- 534 deaths before 5 years
- 56 deaths after 5 years
20%
0%
0
1
2
3
4
5
6
7
8 years
935
775
619
520
447
372
282
208
125
932
780
650
550
487
399
300
208
133
Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.
ASCO 2004
CALGB 9633
NCIC BR 10
1.0
100
Chemotherapy
Observation
69%
54%
20
HR 0.7
Observation
71%
59%
0.2
40
0.6
60
0.4
Probability
0.8
Chemotherapy
p=0.012
HR 0.62
p=0.028
0.0
Per cen tage
80
0
0.0
2.0
4.0
6.0
239
243
182
193
94
121
47
51
5yrsTime (years)
# At Risk(Observation)
# At Risk(Vinorelbine)
Observation
SUMMARY STATISTICS:
Vinorelbine
8.0 YRS10.0
13
10
0
0
0
20
40
60
Survival Time (Months)
4yrs
80
ASCO 2006 (137/155 of Total Events)
ABSTR #7007
1.0
CALGB 9633 - OVERALL SURVIVAL
0.6
0.4
0.2
MOS
Chemotherapy
Observation
95 months
78 months
P value
0.10
HR (90% CI)
0.80 (0.60-1.07)
0.0
Probability
0.8
Observation
Chemo
0
1
2
3
4
5
6
Survival Time (Years)
7
8
9
ASCO 2005
ANITA : OS
OBS. NVB + CDDP
Median months
1.00
Survival Distribution Function
P-value
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
months
80
100
120
Review of Adjuvant
Chemotherapy
Adjuvant Platinum-Based
Chemotherapy
Study
Design
Stage
N
Chemo
ALPI
RCT
I-III
1209
Cis / Mito / Vindesine
IALT
RCT
I-III
1867
Cis / Vinca or
Etoposide
BLT
RCT
I-IIIA
488*
Cis regimen (1 of 4)
JBR.10
RCT
IB-II
482
Cis / Vinorelbine
CALGB
RCT
IB
344*
Carbo / Paclitaxel
ANITA
RCT
I-IIIA
840
Cis / Vinorelbine
Negative trial result
*Failed to complete goal enrollment.
Positive trial result
Initial positive result, later follow-up negative
Perception or Reality???
Adjuvant Chemotherapy for NSCLC
Lung Adjuvant Cisplatin Evaluation (LACE)
• Meta-analysis of adjuvant cisplatin trials
performed since 1995
• BLT, ALPI, IALT, JBR.10, ANITA
• Pooled individual patient data
• 4584 resected patients, 5 randomized trials
– 7% Stage IA
– 30% Stage IB
– 36% Stage II
– 27% Stage III
Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.
Adjuvant Chemotherapy for NSCLC
LACE: Overall Survival
Trial
No Deaths
Hazard Ratio
/ No Entered (Chemotherapy / Control) HR (95%
[95% CI)
CI]
ALPI
569 / 1088
0.95 [0.81;1.12]
ANITA
458 / 840
0.82 [0.68;0.98]
BLT
186 / 307
0.95 [0.71;1.27]
IALT
980 / 1867
0.91 [0.80;1.04]
JBR10
197 / 482
0.71 [0.54;0.94]
2390 / 4584
0.89 (0.82;0.96]
[0.82;0.96]
Total
0.0
0.5
1.0
1.5
2.0
Chemotherapy better | Control better
Chemotherapy effect
Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.
P = 0.005
Adjuvant Chemotherapy for NSCLC
LACE: Pooled Data Overall Survival
Chemotherapy
Survival (%)
100
No chemotherapy
5.4% survival
advantage at
5 years
80
61.0
60
57.1
40
48.8
43.5
20
0
0
1
2
3
4
5
≥6
Time from Randomization (Years)
Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.
HR = 0.89
95% CI 0.82-0.96
P = 0.005
Adjuvant Chemotherapy for NSCLC
LACE Analysis by Stage
Category
No Deaths
No.
/ No
No. Entered
Stage IA
104 / 347
1.41 [0.96;2.09]
Stage IB
515 / 1371
0.92 [0.78;1.10]
Stage II
893 / 1616
0.83 [0.73;0.95]
Stage III
878 / 1247
0.83 [0.73;0.95]
0.5
Hazard Ratio
HR
(Chemotherapy / Control)
1.0
1.5
2.0
2.5
Chemotherapy better Control better
Adjuvant chemo has greatest benefit for stage II
and III and may be detrimental for stage IA
Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.
[95% CI]
Test for trend: P = 0.051
Adjuvant Chemo for Stage IB – III NSCLC
Absolute Benefit in 5-Year Survival
Die despite
chemo
Alive due
to surgery
Alive due
to chemo
Stage IB
Stage II
Stage III
Based on HR from LACE meta-analysis and 5YS from ANITA trial
Chemotherapy = 4 months of cisplatin + vinorelbine
Pignon JP et al. J Clin Oncol. 2006;24(18S). Abstract 7008; Douillard JY et al. Lancet Oncol. 2006:7;719-727.
“NATCH” Trial
Induction Chemotherapy for NSCLC
Ongoing Trial
“(Neo)adjuvant Taxol Carboplatin Hope” (NATCH)
Stages I and II (T3N1) NSCLC
Goal = 600 patients
Accrual complete - 624
Randomize
Surgery - 212
Surgery - 211
Carboplatin/
Paclitaxel x 3 - 201 (93%)
Surgery
Rosell R, et al. Lung Cancer. 2001;34(suppl 3):S63-S74.
Carboplatin/
Paclitaxel x 3 (65%)
“No” Differences 5 yr
Disease Free Survival
Surgery
– 39%
Induction/Surgery – 41%
Surgery/ Adjuvant – 39%
Felip E., et al. - ASC0 (abst #7500) -2009
Adjuvant Chemotherapy
in NSCLC:
A new standard of care?
Breaking the Sound Barrier
Adjuvant Chemotherapy
Standard of Care
Good performance status patients with
“R0” Anatomic Resection
–
Stages IIA-B
–
IIIA NSCLC
–
Maybe Larger IB ???
PERCENT SURVIVAL
Future Directions
100
90
80
70
60
50
40
30
20
10
0
AD Chemotx
Emperic Chemotx
Observation
Assay directed?
Empiric therapy
STD
1
2
3
4
5
6
YEARS
7
8
9 10
Patients with
micrometastisis
Responders to
Chemotx
? Study Concept ?
“Single Station IIIa NSCLC”
Is There a Role for Surgery for N2 NSCLC?
“Surprise” N2 Disease
Specific Clinical Frequency of
“Single Station” IIIa NSCLC
Historically – 33% to 50% of
patients in “IIIa” surgical series
Mithos P - Ann Thor Surg 2008
Rae F – Lung Cancer 2004
Kang HC – Ann Thor Surg 2008
“Single Station” Stage IIIa Proposal
• Randomized trial: Induction Chemotherapy
followed by anatomic resection “less than”
pneumonectomy compared to anatomic
resection “less than” pneumonectomy with
Adjuvant Chemotherapy [mediastinal staging
accuracy evaluation]
Small T1 Right Upper Lobe
Cancer
Small T1 Right Upper Lobe CancerParatracheal Nodes Clinical Negative
Small T1 Right Upper Lobe CancerPET Positive Single Station
Paratracheal Nodes
Phase III Randomized Study Design
SI
N
G
L
E
S
T
A
TI
O
N
N
2
●Clinical
●
R
A
N
D
Platinum based
Chemotherapy
x3 cycles
SURGERY
O
M
I
Z
SURGERY
E
Stage T1-3, N2 Single Station
Staging Procedures:
Mediastinoscopy, EBUS, EUS, PET
Platinum based
chemotherapy
x3 cycles
Surgical Management
Single Station IIIa Proposal
●
RO anatomic resection (segmentectomy or
lobectomy)
●
Mediastinal node dissection (including 4R, 10,
7 pockets on right and 5, 6, 10L, 7 on left)
●
Tissue acquisition for correlative studies
Study Objectives
• The primary endpoint – evaluation of the
progression-free survival and overall survival
surgery with induction vs adjuvant therapy single
station IIIa disease
• Secondary endpoints
Response rate
Relative toxicity and complications.
• To evaluate the utility of modern staging
techniques of mediastinoscopy, PET imaging
and endoscopic ultrasound guided biopsy
techniques in accurately identifying single
station IIIa disease.
Correlative Studies
Collaborative Studies
• Chemoresponse assay analysis – observational
study – tissues at mediastinoscopy and also at
time of resections.
• Genotypic / mutational analysis of “excision /
repair enzyme” profiles to assess such
biomarker utility in determining individual
response to platinum agents.
• Quality of life determinations related to
induction therapy and adjuvant therapy for
“single station” IIIa disease.
Companion / Integrated
Studies
?Induction Radiation Therapy with Chemotherapy
for multistation disease ( low volume (less 3cm dia
nodes) ?
?Adjuvant PORT with Chemotherapy for multi-station
microscopic disease found at resection?
Nothing happens unless you try!
Thank
You
City of Pittsburgh
Pennsylvania
Case Presentation
“Sublobar Resection” vs.
“Lobectomy” for Stage I
NSCLC
Case Study
• An asymptomatic, well nourished, 77 year old
man, 80 pk/year active cigarette smoker
participating in the National Lung Screening
Trial (NLST) is found to have a 1.4 cm noncalcified lung nodule in the posterior segment of
his right upper lobe without mediastinal or hilar
lymph node enlargement on first “incidence”
scan in 2005.
Case Study
• No history of previous cancer and no
complaints of urinary or bowel problems.
Screening colonoscopy performed 7 years ago
normal without any polpys.
• Chest pain 4 years ago was evaluated with
coronary angiography and ventriculogram
demonstrating diffuse mild (less than 30%)
narrowing and a left ventricular ejection fraction
of 55%.
• No complaint of dyspnea on exertion. – Walks
the 2 miles a day through the hills around home
in Pittsburgh.
Case Study
• PET/CT performed which demonstrated solitary
nodule in Right upper lobe with SUV – 3. No
other abnormal activity noted on fusion scan.
• Pulmonary function studies were performed
demonstrating:
–
–
–
–
–
FEV-1
= 70% of predicted
FVC
= 85% of predicted
FEF 25-75 = 55% of predicted
DLCO% = 60% of predicted
Normal ABG
Question #1
• What diagnostic / therapeutic decisions
would you make for this patient?
– A) percutaneous CT directed biopsy. If negative for
malignant cells, further follow-up scan in 6 months
– B) posterolateral thoracotomy and lobectomy with
lymph node dissection
– C) VATS lobectomy with full nodal sampling
– D) Anatomic Segmentectomy with full nodal
sampling
– E) VATS wedge resection with clear surgical
margins
– F) B,C, or D
Question #1 answer
• What diagnostic / therapeutic decisions would you make for
this patient?
– A) percutaneous CT directed biopsy. False negatives important
issue. ? Influence of “lead time bias” and “over diagnosis” but
generally not accepted.
– B) posterolateral thoracotomy and lobectomy with lymph node
dissection
– C) VATS lobectomy with full nodal sampling
– D) Anatomic Segmentectomy with full nodal sampling
– E) VATS wedge resection with clear surgical margins. Local
recurrence (~20%) and overall survival major negative
influence on using this for primary therapy
– F) B,C or D
Question #2
• Which statement / statements are false
regarding the clinical outcome following
sublobar resection?
– A) wedge resection of stage I lung cancer has equivalent
clinical success to that of anatomic resection.
– B) Anatomic segmentectomy has comparable survival to
lobectomy for stage 1a nsclc
– C) Pulmonary function is preserved relative to lobectomy
following anatomic segmentectomy for stage I nsclc
– D) Visceral pleural involvement does affect survival for clinical
1a, node negative lung cancers undergoing segmentectomy
– E) VATS segmentectomy as equivalent clinical results to open
segmentectomy for stage 1a nsclc
Question #2 answer
• Which statement / statements are false
regarding the clinical outcome following
sublobar resection?
– A) wedge resection of stage I lung cancer has equivalent
clinical success to that of anatomic resection.
– B) Anatomic segmentectomy has comparable survival to
lobectomy for stage 1a nsclc
– C) Pulmonary function is preserved relative to lobectomy
following anatomic segmentectomy for stage I nsclc
– D) Visceral pleural involvement does affect survival for clinical
1a, node negative lung cancers undergoing segmentectomy
– E) VATS segmentectomy as equivalent clinical results to open
segmentectomy for stage 1a nsclc
Case Study
• VATS anatomic posterior segmentectomy of
the right upper lobe with comprehensive
mediastinal nodal sampling (4R, 3,10,11, 7) in
2005. Uneventful 4 day hospital course.
• Typical adenocarcinoma (T1N0) – 1.5 cm dia.
with 2.3 cm surgical margins. No evidence of
neurovascular invasion or visceral pleural
invasion.
• No evidence of local or systemic recurrence
now 6 years from surgical resection.
Breaking the Sound Barrier
“Tragedies of Emperic Therapy”
Sophocles
Greek Tragedian
497-405 BC
Cancer – “The Crab”
NSCLC Staging
Importance of Surgical Staging
* Poor concordance between clinical and pathologic staging
Lopez-Encuentra A et al. Ann Thorac Surg 2005; 79: 974-9
"Fading" Benefit ?
IALT: Cisplatin + a Vinca or Etoposide
Proportion Surviving
100%
Surgery + chemo
Surgery
80%
60%
40%
HR = 0.86; 95% CI 0.76-0.98; P < 0.03
20%
0%
0
1
3
2
4
5
Years
Arriagada R, et al. N Engl J Med. 2004;350:351-360.
N = 1867
"Fading" Benefit ?
IALT: 7.5-Year Median Follow-Up
100%
chemotherapy: 578 deaths
- 495 deaths before 5 years
80%
- 83 deaths after 5 years
60%
HR: 0.91 (0.81-1.02, P = 0.10)
40%
control 590 deaths
- 534 deaths before 5 years
- 56 deaths after 5 years
20%
0%
0
1
2
3
4
5
6
7
8 years
935
775
619
520
447
372
282
208
125
932
780
650
550
487
399
300
208
133
Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.
Multimodality therapy of
Stage IIIa NSCLC ?
The Evolution of Treatment Outcomes
for Resected Stage IIIA Non-Small Cell
Lung Cancer Over 15 Years
at a Single Institution
Linda Martin, Arlene Correa, Wayne Hofstetter, Waun Ki
Hong, Ritsuko Komaki, Joe Putnam, Jr., David Rice, Roy
Smythe, Stephen Swisher, Ara Vaporciyan, Garrett Walsh,
and Jack Roth
The Department of Thoracic and Cardiovascular Surgery
MD Anderson Cancer Center
Houston, Texas
Methods
• 1986-2001 – retrospectively
reviewed all NSCLC patients who
had surgery at UT MDACC (n=
2861, 353 IIIa patients)
• identified pathologically confirmed N2
metastases
• Included all T1-3, N2 cases
Hazard Ratios - Survival
p-value
Male vs. Female
0.003
Low/Mid vs. Upper
Lobe
<0.001
R1/R2 vs. R0
0.002
2 N2 Stations
<0.001
>2 N2 Stations
0.007
Multimodality Rx
vs. Surgery
<0.001
0
1
Protective
2
3
Increased Risk
Survival by Lymph Node
Stations Involved
Cumulative Survival Probability
1.0
0.8
Median Survival
0.6
25.3
1 Station
15.5
0.4
16.8
2 Stations
P<0.001
>2 Stations
0.2
0.0
0
10
20
30
Time (months)
40
50
60
Survival -Treatment Group
Cumulative Survival Probability
1.0
0.8
Median survival
25.3 months
0.6
Multimodality
Treatment
0.4
15.9 months
0.2
Surgery
Alone
P=0.004
0.0
0
10
20
30
Time (months)
40
50
60
Conclusions
• Survival for pIIIA (N2) NSCLC has significantly
improved over time
• Use of multimodality treatment has increased over
time
• Prognostic factors associated improved survival:
 Female gender
 Upper lobe tumor location
 Single N2 station involvement
 R0 resection
• Multimodality therapy is a modifiable factor
significantly associated with improved survival
?? Accuracy of Preoperative
Staging in Identifying
“Single Station” IIIa NonSmall Cell Lung Cancer ??
NSCLC Staging
Radiographic Assessment
• CT Scan
• PET Scan
- Good at primary tumor assessment
- LN sensitivity and specificity: 65-80%
NSCLC Staging
Radiographic Assessment
• CT Scan
• PET Scan
- Superior to CT in detecting mediastinal
LN involvement (90%) and mets
- Good NPV, poor PPV
- Unclear whether cost-effective
NSCLC Staging
PET/CT
- Excellent sensitivity
- Limited PPV
- False positives common
- Better than CT or PET
alone in detecting LN
involvement or mets
- n=202 with CA
- PET neither confirms or excludes involvement of the mediastinum
- Cervical mediastinoscopy with biopsy remains the gold standard
Gonzalez-Stawinsky GV et al. JTCVS 2003; 126: 1900-5
NSCLC Staging
Invasive Staging Techniques
• Cervical Mediastinoscopy
• Chamberlain Procedure
• Thoracoscopy
• EBUS/EUS
EBUS for Station 7
Herth FJ et al. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration.
J Bronchol 2006; 13(2): 84-91
Surgical Resection Associated
with “Induction” or “Adjuvant”
Systemic Therapy for “Single
Station” IIIa NSCLC