1. Treatment Approaches for Stage IIIa(N2) Lung Cancer
Frank Detterbeck MD
Thoracic Surgery, Yale University
Yale Thoracic Oncology Program
No conflicts to disclose with respect to this presentation

2. Disclosures
Medela Research Grant (chest drainage device) Olympus Data Safety Monitoring board Covidien Research advisory board participation Lilly Lectures on 7th edition Lung Cancer Stage classification system in the past

3. “The answer
to cancer”
“If it bleeds…
I can kill it!”

5. Fact: Survival is the same for ChemoRT and for Chemo/RT/Surgery

6. Bi- vs Tri-Modality Tmt of Stage III
% Overall Survival
Surgery (n = 167)
RT (n = 165)
Van Meerbeck JNCI 2007;99:442-50

7. Intergroup 0139/RTOG 9309 Overall Survival by Treatment Arms
CT/RT/S /202
CT/RT /194
Logrank p = 0.24
Hazard ratio = 0.87 (0.70, 1.10)
Odds Ratio at 5 yrs 0.63 ( )
% Alive 25 50 75
100
Months from Randomization 12 24 36 48 60
Dead/Total

8. Stage III: Ch/RT vs Ch/RT/Surg
Intergroup 0139
Is overall survival the same?
Is one curve flatter than the other?
100 75 50 25 12 24 36 48 60
Is the glass:
Half
Full
Half
Empty? or

9. Fact: We have identified prognostic factors, (most are applicable only retrospectively) These ARE NOT predictive that surgery is beneficial

10. IIIa (N2) – It’s a Spectrum of Patients!
Mediastinal Infiltration
Discrete node enlargement
Clinically occult N2
Schematic of types of patients included in studies using different treatment approaches
Curative-
Intent
Chemo-RT
Palliative
Treatment
(PS ≥ 2)
Neoadjuvant
+ Surgery
Primary
Surgery
(occult N2)
Figure legend: Representative examples of infiltrative mediastinal nodal involvement (left) in which patients should generally be treated with chemotherapy (CT) and radiotherapy either concurrently fir good performance status patients (PS) or sequentially. Clinically occult N2 involvement, (far right; as suggested by the lack of uptake on PET scanning) that is discovered after thorough pre-operative staging and after surgical resection should be treated post-operatively with adjuvant cisplatin pbased chemotherapy, and radtiotherapy is reserved for when concern for local recurrence is high. Discrete N2 nodal involvement (center) MUST be confirmed pathologically before deciding on a treatment course that can include CT/RT or induction therapy followed by complete surgical resection. Incomplete resection should be avoided and patients in whom complete resecton is not feasible should be treated with CT/RT.
IIIa (N2) – It’s a Spectrum of Patients!
↑ Performance Status
↑ Tumor Burden
Stage III patient characteristics

11. Fate of Patients selected for Trimodality Tmt
402 Good-risk patients, N2 at EBUS/Mediastinoscopy
Thought to be good candidates for Trimodality Tmt
Died
Lost
R1,2
N2 at
Restage
Indctn Toxicity
Progresed R0
Ref: Cerfolio Ann Thor Surg 2008;86:912-20

12. Fate of Patients selected for Trimodality Tmt
402 Good-risk patients,
N2 at EBUS/Mediastinoscopy
selected for Trimodality Tmt
5-Yr Survival (%)
% of pts
Neg at
Restage
Ref: Cerfolio ATS
2008;86:912-20

13. Common Arguments for Surgery in N2
Selection Criteria
Assessment of commonly cited arguments
Summary: Justifica-tion for Surgery
Pre-operatively identifiable?
Prognostic value?
Potential Flaw
Defines treatment value?
“Minimal” N2
Moderate
Probably
Out-of-context
Unclear
Single station
Yes
cN0,1
Non-bulky nodes
Good surg risk - No
Not Applic
Downstaged
Limited
Landmark
Shrinkage
Subjective
Lobectomy

14. Fact: Surgery causes Morbidity And Mortality

15. INT 0139: Pneumonectomy Pts vs Matched CT/RT Subset
100 75 /
% Overall Survival 50
45%
36% / / / / / /
24%
22%
ChRT / 25 / /
ChRT/S
logrank p = NS 12 24 36 48 60
Months

16. Op. Mortality of Neoadj  Pneumonectomy
Study
N (pneum)
Ind Tmt
% Mort
Stamatis 02
127 Ch 7
Alifano 08
113 6
Doddoli 05
100 12
Martin 01 97 11
Van Schil 05 69
Matsubara 04 68 4
Mansour 07 60
Albain 05 54
Ch/RT 26
Gudbjartson 08 35
Daly 06 30 13
Perrot 05 27
Roberts 01 20
Average 8
Inclusion Criteria: Studies of ≥20 pts

17. Are there any Answers?

18. Treatment of Stage III NSCLC
Role of Trimodality is based on flawed arguments
Retrospective selection
Inappropriate application of subset results to the whole
But: Trimodality and Bimodality are the same
So if the patient really wants it, it is OK
IF your periop morbid/mortality is minimized
IF you can achieve a complete resection
IF you can manage the distant disease