Rodney J. Landreneau, MD

1
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
2
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

3
Lung Cancer Surveillance
4
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
5
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
20063551763-1771
6
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

7
Controversy
8
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.
9
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
X-rays. Results are not expected until 2010.
10
Sublobar Resection or Lobectomy for stage I
lung cancer
11
Standard of Care For Peripheral Nodules
Surgical Resection of the Lung
1940s Pneumonectomy 1960s Lobectomy 1990s
?Segmentectomy/Wedge (and adjuvant
local/systemic Rx)
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
Sublobar Resection vs. Lobectomy for Stage 1
Non-Small Cell Lung Cancer
Errett LE et alJ Thorac Cardiovasc Surg. 1985
Nov90(5)656-61
23
(No Transcript)
24
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 199560615-23

25
Lobectomy vs Limited Resection Time to death
(from any cause) by treatment
logrank p0.088 (one-tailed)
Ginsberg and Rubinstein Ann Thorac Surg
26
Wedge Resection Versus Lobectomy for Stage I (T1
N0 M0) Non-Small Lung Cancer

• Landreneau, et.al.,
• J Thorac Cardiovasc Surg 1997113691-700

27
Wedge vs Lobectomy for Stage I NSCLC
p0.889
Landreneau, et.al.,J Thorac Cardiovasc Surg
1997113691-700
28
Wedge vs Lobectomy for Stage I NSCLC
Open WR VATS WR Vs. Lobe Plt
Op Mortality () 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
- all WR (n95) vs. Lobe (n124) Statistical
Methods Life Table Analyses Obtained by Log Rank
and Wilcoxson Tests
Landreneau, et.al.,J Thorac Cardiovasc Surg
1997113691-700
29
! Local Recurrence !
30
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?

31
Intraoperative Brachytherapy

• Not a new concept for lung cancer
• Mostly used for Stage IIIA disease
• close or positive margins
• Improved local control
• What is its role in high risk patients with
  totally resectable disease where lobar resection
  is not feasible and adjuvant radiotherapy is
  recommended?

32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
(No Transcript)
41
Comparison Between Sublobar Resection and
125Iodine Brachytherapy After Sublobar Resection
in High-Risk Patients with Stage I NonSmall-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, Oct134(4) 691-7
42
Results
Sublobar Resection (n102) Sublobar Resection With Brachy (n96)
Local Recurrence 19 (18.6) 1 (1) p.0001
Hospital Mortality 0 (0) 3 (3) pns
Hospital Stay 7 days 8 days pns
Survival 1, 2, 3 and 4 year 93, 73, 68, 60 96, 82, 70, 67 pns
Systemic Recurrence 29 (28.4) 22 (23) pns
Pre-op FEV 1 predicted 65 53 pns

• The FEV 1 did not change postoperatively in the
  sublobar resection with brachytherapy group in
  the interval of follow-up

43
(No Transcript)
44
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 Jan129(1)87-93
  
• An evaluation of surgical resection in 1272 NSCLC
  patients

45
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
Jan129(1)87-93
46
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. DAmato 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
47
Patient and Tumor CharacteristicsStage IA
Anatomic Segmentectomy (n182) Lobectomy (n246)
Stage IA 109 (60) 114 (46)
Tumor Size Mean (cm) Range (cm) 1.7 1.9
Schuchert MJ., et. Al. STS 2007
48
Overall Survival
Stage IA Segmentectomy vs Lobectomy
log rank 0.780
Cumulative Survival
Lobectomy
Segmentectomy
Time (months)
Schuchert MJ., et. Al. STS 2007
49
Recurrence Patterns - Stage IA
Anatomic Segmentectomy (n109) Lobectomy (n114) 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 lt0.05
Schuchert MJ., et. Al. STS 2007
50
Anatomic Segmentectomy
Favorable Criteria for Anatomic Segmentectomy
Peripheral location (outer 1/3) Small Tumors
lt 2 cm in diameter Pathologic Margin gt 1 cm
(Margin/Tumor ratiogt1) Age gt75 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
51
Sublobar Resection?
52
Sublobar Resection vs. Lobectomy?
53
Sublobar Resection vs. Lobectomy?
54
Induction (pre-operative )Chemo-radiotherapy for
Stage III-a non-small cell lung cancer
Standard of Care ???
55
(No Transcript)
56
Intergroup trial 0139Chemo-radiation vs
Chemo-radiation followed by surgical resection of
Stage IIIa NSCLC

• Kathy Albain et al.
• ASCO 2005
• Lancet 2009374379-86

57
(No Transcript)
58
(No Transcript)
59
(No Transcript)
60
(No Transcript)
61
(No Transcript)
62
Adjuvant Chemotherapy in NSCLC

• A new standard of care?

63
N Engl J Med 2004350351-60
64
4
New Engl J Med 2004350351-60
65
(No Transcript)
66
NEJM 2004350351-60
Chemotherapy better
67
ASCO 2004

• CALGB 9633

NCIC BR 10
Chemotherapy
Chemotherapy
Observation
Observation
71 59
69 54
HR 0.62 p0.028
HR 0.7 p0.012
YRS
4yrs
5yrs
68
(No Transcript)
69
ASCO 2005 ANITA OS
70
ASCO 2006 (137/155 of total events) ABSTR
7007CALGB 9633 - OVERALL SURVIVAL
1.0
Observation
Chemo
0.8
0.6
Probability
0.4
Chemotherapy Observation
MOS 95 months 78 months
P value 0.10 0.10
HR (90 CI) 0.80 (0.60-1.07) 0.80 (0.60-1.07)
0.2
0.0
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
Survival Time (Years)
71
(No Transcript)
72
Adjuvant ChemotherapyStandard of Care

• Good performance status patients with R0
  Anatomic Resection - Stages IIA-B -
  IIIA NSCLC - Maybe Larger IB ???

73
(No Transcript)
74
(No Transcript)
75
Thank You
City of PittsburghPennsylvania
76
(No Transcript)
77
Still Empiric Therapy Approach!!
78
(No Transcript)
79
Drug Resistance Testing
80
Clinical Correlation in Non-Small Cell Lung Cancer
81
LDR IDR EDR
9
82
10
83
Schema for Future Clinical Trials
Registration
Completely Resected Stage IB-IIIA NSCLC
EDR-Assay
Randomize
Assay Directed
Standard Therapy
vs.
Correlative Studies Molecular Markers
Proteomics Genomics
Survival Disease Free Survival
84
Future Directions
Improvement ?
AD
STD
Patients with micrometastisis Responders to
Chemotx
85
(No Transcript)
86
(No Transcript)
87
Randomized Trial of Induction Chemotherapy
Followed by Anatomic Lung Resection Stage IIIA
SWOG 9900
Eric Vallieries 2007
88
S9900 S9900 Study Design
R A N D O M I Z E D
E L I G I B L E
PACLITAXEL CARBOPLATIN x3 cycles
SURGERY
SURGERY

• Clinical Stage T2N0, T1-2N1, T3N0-1
• Mediastinoscopy if LN gt 1 cm on CT
• Stratification IB/ IIA vs. IIB/ IIIA

Pisters, et. Al. ASCO 2005
89
Surgical Results
S9900
Preop PCb N168 Surgery Only N167
Explored 149 (89) 162 (97)

R0 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 -
19 Refusal, POD, death, medical, wrong arm,
n/a5 Medical, refusal, MD decision, n/a
Pisters, et. Al. ASCO 2005
90
Progression-Free Survival by Treatment
Arm 05/09/2005, median F/U 31 mo
Pisters, et. Al. ASCO 2005
91
Overall Survival by Treatment Arm 05/09/2005,
median F/U 31 mo
Pisters, et. Al. ASCO 2005
92
Randomized Trial of Induction Chemotherapy
Followed by Anatomic Lung Resection Stage IIIA
SWOG 9900
CS (n154) CS (n154) S Only (n160) S Only (n160)
N7 (.045) N7 (.045) N4 (.025) N4 (.025)
Lobectomy Pneumonectomy 3 (.02)4/24 (.17) Lobectomy Pneumonectomy 4 (.035) 0/26
2R, 2L 2R, 2L
p0.32 p0.32
From Eric Vallieries 2007
93
Depierre Randomized Preop Trial

• N355 eligible, stages IB, II and IIIA (35 N2)
• MIP x2 Surgery (2 adj PR/path CR)
• Surgery alone
• Median survival 37 vs 26 months, p0.15

Depierre JCO 2002
94
Depierre Randomized Preop Trial Continued

• Disease free survival 27 vs 13 mo, p0.033
• Risk of DM0.54 0.33-0.88, p0.01
• Stage I-II Risk death 0.68 0.49-0.96,
  p0.027

Depierre JCO 2002
95
Results Overall Survival
BLOT S9900 S9900 Depierre Depierre
BLOT Preop Control 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
96
Management of Non-Small Cell Lung Cancer

Lung CancerSurvival
97
(No Transcript)
98
Still Empiric Therapy Approach!!
99
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!