Transcript Management of Non-Small Cell Lung Cancer

Management of Non-Small
Cell Lung Cancer
Rodney J. Landreneau, MD
Professor of Surgery
Heart, Lung & Esophageal Surgery
Institute
University of Pittsburgh Medical Center
St. Margaret Grand Rounds
September 10,2009
Management of Non-Small Cell
Lung Cancer
CT surveillance for lung cancer
Sublobar Resection vs. Lobectomy
Role of surgical resection for regionally advanced lung
cancer
Adjuvant Systemic Therapy for regionally advanced
“resectable” lung cancer
Lung Cancer
Surveillance
Original Article
Survival of Patients with Stage I Lung
Cancer Detected on CT Screening
The International Early Lung Cancer Action Program
Investigators
N Engl J Med
Volume 355(17):1763-1771
October 26, 2006
Kaplan-Meier Survival Curves for 484 Participants with Lung Cancer and 302
Participants with Clinical Stage I Cancer Resected within 1 Month after Diagnosis
The International Early Lung Cancer Action Program
Investigators. N Engl J Med 2006;355:1763-1771
Conclusion
●
Annual spiral CT screening can detect
lung cancer that is curable
● Comparable screening efficacy as
mammographic screening for breast
cancer (prevalence 1.6%; incidence 0.6%)
● Cost effective - low energy, fast scanning
about $200
● Treatment of early stage disease less
expensive than advanced disease
Controversy
CT scans have radiation risks
and sometimes detect cancers
that would not have
progressed, leading to risky
procedures like biopsies and
lung surgery when not needed.
The National Cancer Institute
started in 2002 the $200 million
“National Lung Screening Trial”
comparing death rates among
55,000 people randomly assigned
to have CT scans or chest Xrays. Results are not expected
until 2010.
“Sublobar Resection”
or “Lobectomy” for
stage I lung cancer
Surgical Resection of the Lung
Standard of Care For Peripheral Nodules
1940’s
Pneumonectomy
1960’s
Lobectomy
1990’s
?Segmentectomy/Wedge (and
adjuvant local/systemic Rx)
Sublobar Resection vs. Lobectomy for
Stage 1 Non-Small Cell Lung Cancer
Errett LE et al
J Thorac Cardiovasc Surg. 1985 Nov;90(5):656-61
Randomized Trial of Lobectomy Versus
Limited Resection for
T1 N0 Non-Small Cell Lung Cancer
(125 Lobectomy , 122 Limited Resection)
RJ Ginsberg, LV Rubinstein and Lung
Cancer Study Group
Ann Thorac Surg 1995;60:615-23
Lobectomy vs Limited Resection
120
100
80
60
40
20
0
Lobectomy
Limited Resection
10
8
12
0
96
84
72
60
48
36
logrank p=0.088 (one-tailed)
24
0
12
% Survival
Time to death (from any cause) by treatment
Ginsberg and Rubinstein
Ann Thorac Surg
Wedge Resection Versus
Lobectomy for Stage I (T1 N0
M0) Non-Small Lung Cancer
Landreneau, et.al.,
J Thorac Cardiovasc Surg
1997;113:691-700
Wedge vs Lobectomy for
Stage I NSCLC
120
% Survival
100
80
Wedge
Lobectomy
60
40
p=0.889
20
0
0
10
20
30
40
50
60
Landreneau, et.al.,
J Thorac Cardiovasc Surg 1997;113:691-700
Wedge vs Lobectomy for
Stage I NSCLC
Open
WR
VATS
WR
Vs.
Lobe
0
0
Vs.
3.3
0.20*
Postop Stay
(days)
7.7
6.5
Vs.
10.1
0.0002*
Local Recur (%)
17
15
Vs.
5
0.08*
Local/Systemic
Recurrence (%)
24
23
vs.
17
0.43*
Op Mortality (%)
P<
*- all WR (n=95) vs. Lobe (n=124) Statistical Methods: Life Table Analyses
Obtained by Log Rank and Wilcoxson Tests
Landreneau, et.al.,
J Thorac Cardiovasc Surg
1997;113:691-700
! Local Recurrence !
Adjuvant Radiation Therapy
●
External beam radiation therapy
-
●
Potential risk of increased injury to
surrounding pulmonary parenchyma
What is efficacy of intraoperative
brachytherapy when external beam
radiation may otherwise be applied?
Intraoperative Brachytherapy
●
Not a new concept for lung cancer
● Mostly used for Stage IIIA disease
-
●
close or positive margins
Improved local control
● What is it’s role in high risk patients with
totally resectable disease where lobar
resection is not feasible and adjuvant
radiotherapy is recommended?
Comparison Between Sublobar
Resection and 125Iodine Brachytherapy
After Sublobar Resection in High-Risk
Patients with Stage I Non–Small-Cell
Lung Cancer
R. Santos, A. Colonias, D. Parda, M. Trombetta, RH
Maley, R. Macherey, S. Bartley, T. Santucci, RJ Keenan,
RJ Landreneau
Surgery 2003, Oct;134(4): 691-7
Results
Sublobar
Resection
(n=102)
Sublobar
Resection
With Brachy
(n=96)
Local Recurrence
19 (18.6%)
1 (1%) p=.0001
Hospital Mortality
0 (0%)
3 (3%) p=ns
Hospital Stay
7 days
8 days p=ns
93, 73, 68, 60%
96, 82, 70, 67%
p=ns
29 (28.4)
22 (23%) p=ns
65%
53% p=ns
Survival %
1, 2, 3 and 4 year
Systemic
Recurrence
Pre-op FEV 1%
predicted
The FEV 1 did not change postoperatively in the sublobar
resection with brachytherapy group in the interval of follow-up
Lobectomy vs Sublobar
Resection
“Effect of Tumor Size on Prognosis in
Patients with Non-Small Cell Lung
Cancer: The Role of Segmentectomy as a
Type of Lesser Resection”
Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T,
Nakagawa A, Tsubota N.
“J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”
An evaluation of surgical resection in 1272 NSCLC
patients
Lobectomy vs Sublobar
Resection
5 Year Cancer Specific Survival
“Stage I”
TUMOR SIZE
Segmental
Resection
Lobectomy
Wedge
Resection
20 mm or less
96.7
92.4
85.7
20-30 mm
84.6
87.4
39.4
More than 30
mm
62.9
81.3
0
“Okada, M, et al J Thorac Cardiovasc Surg. 2005
Jan;129(1):87-93”
Efficacy of Anatomic Segmentectomy in
the Treatment of Stage I NSCLC
Matthew J. Schuchert M.D., Brain L. Pettiford M.D., Samuel Keeley M.D., Thomas
A. D’Amato M.D., Ph.D., Arman Kilic B.S., Hiran C. Fernando M.D., John Close
M.A., Ricardo Santos M.D., James R. Landreneau, James D. Luketich M.D.,
Rodney J. Landreneau M.D.
Division of Thoracic Surgery
Heart, Lung and Esophageal Surgery Institute
UPMC Health System
Pittsburgh, Pennsylvania
Patient and Tumor Characteristics
Stage IA
Stage
IA
Tumor Size
Mean (cm)
Range (cm)
Schuchert MJ., et. Al.; STS 2007
Anatomic
Segmentectomy
(n=182)
Lobectomy
(n=246)
109
(60%)
114
(46%)
1.7
1.9
Overall Survival
Cumulative Survival
Stage IA – Segmentectomy vs Lobectomy
log rank = 0.780
Lobectomy
Segmentectomy
Time (months)
Schuchert MJ., et. Al.; STS 2007
Recurrence Patterns - Stage IA
Anatomic
Segmentectomy
(n=109)
Lobectomy
(n=114)
P Value
NED
97
(89%)
102
(83.3%)
NS
Recurrence
Locoregional
Distant
12 (11.0%)
5 (4.6%)
7 (6.4%)
12 (10.5 %)
6 (5.3%)
6 (5.3%)
NS
NS
NS
Follow-Up (Mos)
18.3
30.0
<0.05
Schuchert MJ., et. Al.; STS 2007
Anatomic Segmentectomy
Favorable Criteria for Anatomic Segmentectomy
• Peripheral location (outer 1/3)
• Small Tumors: < 2 cm in diameter
• Pathologic Margin > 1 cm (Margin/Tumor ratio>1)
• Age >75
• Marginal pulmonary function
• Ground glass opacities – Bronchoalveolar
UPMC Experience
• 452 Anatomic Segmentectomies
- 224 Stage I NSCLC
- 114 Stage II-III NSCLC
- 31 Metastasectomies
- 9 Benign Neoplasms
- 53 Inflammatory/Granulomatous
- 15 Bullous Disease
- 5 Infection/Abscess
- 1 Trauma
ACOSOG Z0030: Mortality 3%; Complications 46%
UPMC: Mortality 1.1%; Complications 32%
Sublobar Resection?
Sublobar Resection vs. Lobectomy?
Sublobar Resection vs. Lobectomy?
Induction (pre-operative )
Chemo-radiotherapy for Stage
III-a non-small cell lung cancer
Standard of Care ???
Intergroup trial 0139
Chemo-radiation vs Chemoradiation followed by surgical
resection of Stage IIIa NSCLC
Kathy Albain et al.
ASCO 2005
Lancet 2009;374:379-86
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
NEJM 2004;350:351-60
Chemotherapy better
ASCO 2004
CALGB 9633
NCIC BR 10
1.0
100
Chemotherapy
Probability
Observation
40
HR 0.7
p=0.012
0
0.0
2.0
4.0
6.0
239
243
182
193
94
121
47
51
71%
59%
0.2
69%
54%
20
Observation
0.4
60
0.6
0.8
Chemotherapy
8.0 YRS10.00
13
10
0
0
20
40
Observation
Vinorelbine
5yrs
SUMMARY STATISTICS:
Log-Rank test for equality of groups: p=0.0164
p=0.028
60
Survival Time (Months)
Time (years)
# At Risk(Observation)
# At Risk(Vinorelbine)
HR 0.62
0.0
Per cen tage
80
4yrs
80
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
ASCO 2006 (137/155 of total events)
ABSTR #7007
1.0
CALGB 9633 - OVERALL SURVIVAL
0.6
0.4
Chemotherapy
Observation
95 months
78 months
0.2
MOS
P value
0.10
HR (90% CI)
0.0
Probability
0.8
Observation
Chemo
0
1
2
0.80 (0.60-1.07)
3
4
5
6
Survival Time (Years)
7
8
9
Adjuvant Chemotherapy
Standard of Care
●
Good performance status patients with
“R0” Anatomic Resection
- Stages IIA-B
- IIIA NSCLC
- Maybe Larger IB ???
Thank
You
City of Pittsburgh
Pennsylvania
Still Empiric Therapy
Approach!!
Drug Resistance Testing
Clinical Correlation
in Non-Small Cell
Lung Cancer
Survival of Lung Cancer Patients
Correlated to Plat EDR Score
Percent survival
100
Plat LDR
LDR
Plat IDR
IDR
Plat EDR
EDR
75
50
p=0.027
25
0
0
250
500
750
Time
9
1000
1250
1500
Survival Curve for Treated Patients:
Time to First Event
Percent survival
100
LDR
mixed
EDR
75
50
p=0.03
25
0
0
250
500
750
1000
Days to First Event
10
1250
1500
Schema for Future Clinical Trials
Registration
Completely Resected Stage IB-IIIA NSCLC + EDR-Assay
Randomize
Assay Directed
vs.
Standard Therapy
Survival
Disease Free Survival
Correlative Studies
Molecular Markers
Proteomics
Genomics
PERCENT SURVIVAL
Future Directions
100
90
80
70
60
50
40
30
20
10
0
AD Chemotx
Emperic Chemotx
Observation
Improvement ?
AD
STD
1
2
3
4
5
6
YEARS
7
8
9 10
Patients with
micrometastisis
Responders to
Chemotx
Randomized Trial of
Induction Chemotherapy
Followed by Anatomic
Lung Resection – Stage IIIA
– SWOG 9900
Eric Vallieries 2007
S9900 S9900 Study
Design
R
E
A
L
N
I
D
G
O
I
M
B
I
L
Z
E
E
D
Pisters, et. Al. – ASCO 2005
PACLITAXEL
CARBOPLATIN
x3 cycles
SURGERY
SURGERY
●
Clinical Stage T2N0, T1-2N1, T3N0-1
●
Mediastinoscopy if LN > 1 cm on CT
●
Stratification: IB/ IIA vs. IIB/ IIIA
S9900
Surgical Results
Preop PCb
N=168
Surgery Only
N=167
149 (89%)*
162 (97%)**
Intent to Treat
84%
84%
Explored
94%
89%
Pneumonectomy
16%
16%
Lobectomy
68%
68%
Wedge/Segment
5%
11%
Open/Close
3%
4%
Incomplete Data
8%
1%
Path CR
10%
-
Explored
R0
*19: Refusal, POD, death, medical, wrong arm, n/a
**5: Medical, refusal, MD decision, n/a
Pisters, et. Al. – ASCO 2005
Progression-Free Survival by Treatment Arm
05/09/2005, median F/U 31 mo
Pisters, et. Al. – ASCO 2005
Overall Survival by Treatment Arm
05/09/2005, median F/U 31 mo
Pisters, et. Al. – ASCO 2005
Randomized Trial of Induction
Chemotherapy Followed by Anatomic
Lung Resection – Stage IIIA – SWOG
9900
CS (n=154)
S Only (n=160)
N=7* (.045)
N=4 (.025)
Lobectomy
Pneumonectomy
3 (.02)
4/24 (.17)
Lobectomy
Pneumonectomy
4 (.035)
0/26
[2R, 2L]
*p=0.32
From: Eric Vallieries 2007
Depierre Randomized
Preop Trial
●
N=355 eligible, stages IB, II and IIIA (35% N2)
●
MIP x2
Surgery (+2 adj: PR/path CR)
Surgery alone
●
Median survival 37 vs 26 months, p=0.15
Depierre JCO 2002
Depierre Randomized
Preop Trial
Continued
●
Disease free survival 27 vs 13 mo, p=0.033
●
Risk of DM=0.54 [0.33-0.88], p=0.01
●
Stage I-II: Risk death= 0.68 [0.49-0.96],
p=0.027
Depierre JCO 2002
Results Overall Survival
S9900
BLOT
Preop Control
Depierre
Preop
Control
Median OS
(months)
43
47
40
37
26
1 year (%)
84
82
79
77
73
2 year (%)
68
69
63
59
52
Pisters, et. Al. - ASCO 2005; JCO
2002
Management of Non-Small
Cell Lung Cancer
Lung Cancer
Survival
Still Empiric Therapy
Approach!!
Dr. Henschke has asserted that
allowing hundreds of thousands
of people to die in the meantime
is unethical. Therefore, “off
study” CT screening should be
approved by insurance for high
risk patients!