Post on 07-May-2018
Surgical Approaches to Locally
Advanced NSCLC
Kemp H. Kernstine, MD, PhD
Professor and Chairman
UT Southwestern Medical Center
Dallas, TX
“Keep it real simple. Do one
thing and do it the best you can.”-Harry Snyder, co-founder of In-N-Out Burger1
1 In-N-Out Burger: A Behind-the-Counter Look at the Fast-Food Chain that Breaks All the Rules. Stacy Perman, Harper Collins, 2009. 2http://wiki.ask.com/Dallas 3from Ca Cancer Jrnl 2010 av for Texas 88.3 and 51.2 for men and women respectively, 25% resectable; 4est. 5/100,000 and
40% resectable; 5 http://www.asbestos.com/states/texas/dallas.php 6STS National Database Results for UTSW 5-18-11 assumes all are cancer cases
3
Surgical Approaches to Locally
Advanced NSCLC
Kemp H. Kernstine, M.D., Ph.D.
Division of Thoracic Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
August 11, 2011
5
Outline
• Definition of Locally
Advanced Disease
• Not all resections are
equal
• Evaluation
• Special circumstances
6
Locally-Advanced Disease (IIIA/IIIB):
Definition UICC 7
UICC 6
IIIA (T1-2N2, T3N1-2)
IIIB (T1-3N3, T4N0-3)Effusions excluded from trials
UICC 7
IIIA (T1-2N2, T3N1-2)
IIIB (T1-3N3, T4N0-3)
T>7cm,
M1 (ipsilateral
nodules) T4(same lobe
nodules)N0 = IIB
Pleural Eff = M1a
Clinical Stage, J T Oncol 2(8):706-714
Quality Determinants of a
Surgical Procedure?Patient Factors
Surgeon
Technique
Surgical
Team
Hospital
Management
Team
1º MD
Med Onc
Rad Onc
Pulm
Rehab
Hospital
MortalityHospital
Morbidity
DFS
Function QOL
College
Medical School
General
Surgical
Training
Cardiothoracic
Surgical
Training
Adult
Cardiac
Heart Failure/LVAD
Revascularization
TMR
Transplantation
General
Thoracic
Congenital
Heart
Great Vessels
Valves
Transplantation
Cardiothoracic
Sub-Specialties
5 yrs
4 yrs
4 yrs
2-3 yrs
1 yr
1-2 yrs
1 yr
1 yr
Reasons to Refer to
Specialist Surgeon
• 3-5 x lower Op
Mortality
• 50% reduced
morbidity
• 30% improved 5-year
survival
• ↑ Potential Surgical
Candidates
11 General Thoracic Track Programs
PostCT Residency Training Programs 1-2 yrs addnl’ mostly at these locations
Thorax 58:996, 2003 Lung Cancer 46:227, 2004 Ann Thor Surg 87, 995, 2009
10
2011: Surgical Patients Likely
Insufficiently Staged
• 1990 40% no CT, Mediastinal Staging or
systematic node resection1
• 2001 Mediastinoscopy used in 27.1%
– 46.6% no nodes in specimen
– no mediastinal nodes evaluated in 42%2
• 2004 40% had 3 nodal stations sampled3
• 2011 37% of node negative patients had
no nodes examined4
1Thorax. 1992 47:3-52Ann Thorac Surg. 2005 80:2051-6
3Lung Cancer 2005 47:243-514Ann Thorac Surg 2011 91:1486
Initial Assessment
• Labs, PFTs, Risk
Assessment
• CT of the chest and upper
abdomen
• Whole-body PET
• Bronchoscopy
• MRI Apex (MRI Angio)
• Brain MRI
• Mediastinoscopy
(EBUS/EUS?)
The Acceptable Surgical
Evaluation & Treatment• Anatomical resection-
Lobectomy
• R0 Resection
• Resect hilar lymph nodes
• Resect/sample ipsilateral mediastinal lymph node stations > 4
• 1 contralateral station examined/resected
• >16 nodes examined1-3
• Preserve lung
• Segment > Wedge in hi risk (IMRT vs RFA?)
• 60-d mortality < 1%
• Ready for adjuvant w/i 4-6 weeks
1Gajra JCO 2003, 2Ludwig Chest 2005, 3Ou J Thor Oncol 2008
14
Determination of Extent of
Resection
Lesion Size
Solid Portion
CT Border, Density
Histology
Tumor Location (Peripheral, Lobe)
Presence of Other Lesions/Nodules
Nodal Involvement
FDG-PET Information
Tissue and/or Serum Molecular Features
Health Status of the Patient
PneumonectomyWedge Resection
Segmentectomy
Extended Segmentectomy
Lobectomy
Lobe + Wedge/Segmentectomy
Bilobectomy
16
N2 Heterogeneity
Good Prognosis
– Single node
– Microscopic
– Station 5 or 6 for LUL,
4R for RUL
Poor Prognosis
– Gross disease
– Fixed to adjacent
structures or Matted
Nodes
– Multi-node
– Multi-station
– Bulky
– Station 7 > 4L > 9
– Transcapsular
– Skip metastases
Adapted Govindan ASCO 2009, Kassis Thorac Surg Clin 18: 333, 2008
Prospective Trials (IIIA(pN2)): Comparison of
Induction Chemotherapy Trial Results to
Chemoradiotherapy Results
Trial Patients R0 pCRNodal
pCR
Local
FailureSurvival
Induction
Chemotherapy
Betticher,
2003 SAKK90 57% 15% 31% 60% 38% (4 yr)
Van
Zandwijk,
2000 EORTC
8955
47 71% 6% 53% Not Stated 34% (2 yr)
O'Brien, 2003
EORTC 895852
Not
StatedNot Stated 17% Not Stated 68% (1 yr)
Induction Chemoradiotherapy
Albain, 2009
INT 0139161 81% 18% 46% 16% 27% (5 yr)
Choi, 1997 42 81% 9.50% 24% 25% 37% (5 yr)
RCTs: Stage IIIA (N2) Surgery
vs NonSurgical Treatment
Trial Patients TreatmentAccrual Target
Reached
Specialty
Surgeons
Required
Overall
Survival
Johnstone,
2002 RTOG
8901
73 (54%
bulky)CT →S →CT No No 22%
CT →RT(65 Gy) →CT 22%
(4 yr)
Shepherd, 1998
NCI-C
31
(62.5%
R0) CT →S →CT Underpowered No 40%
RT(60 Gy) 40%
(2 yr)
Albain, 2009 INT
0139 396 CT-RT(45 Gy) →S Yes No 27%
CT-RT (61 Gy) 20%
(5 yr)
van Meerbeeck,
2005 EORTC
08941 333 CT →S +/- RT Yes No 16%
CT →RT (60 Gy) 14%
(5 yr)
IIIB Bulky Disease:
Parenchymal Sparing
Induction ChemoRT
E.M. PreChemoRT
4/13/06
PostChemoRT PreOp
6/12/06
N3 Disease
• Contralateral N3 no 5-year survivors in prior trials
• >30% of clinically N3 patients are incorrectly upstaged, confirm stage by biopsy
• Scalene node positive patients may have survival advantage
• Microscopic PET negative nodal disease may have survival advantage
• Bilateral lymphadenectomy w or w/o radical neck dissection may confer survival advantage
• Adjuvant CT or CT-RT may offer survival advantage
21
T4 Local Invasion
• Overall 8% 5-year survival with surgery in this
group[i]
T4 status must be clear and incontrovertible
• MIS exploration may be an opportunity to
accurately stage
• Induction CT or CT-RT vs exploration w
resection and adjuvant therapy
[i] Naruke et al. J Thorac Cardiovasc Surg 96:440, 1988.
22
Carina
• 13-30% operative mortality (prior radiation increases likelihood of death and complication)
•Op Mortality R carina pneumonectomy 16% vs L
carina pneumonectomy 31%
•20% 5-year survival in R0 resections
•Preserved for young, healthy, mediastinoscopy
negative patients
Grillo, JTCVS 2001
23
Superior Vena Cava
• High morbidity 36%, mortality 12%
• Incomplete resection 20%
• 0[i]-29%[ii] 5-year survivors
• Differentiation of bulky N2 from T4 may be difficult
• T4, not bulky N2, may be curable w resection
[i] Burt et al. Clin North Am 67:987, 1987
[ii] Spaggiari et al. Ann Thorac Surg 69:233-236, 2000
24
Other Organ Invasion
• Extended operations w induction chemotherapy, w or w/o RT 3-year survival 54% improved, but higher complications[i]
• Esophageal 1/7 reported 5-year survivors
• L Atrium, SVC, vertebra may be resected and reconstructed w 19-25%[i], [ii] 5-year survival in selected R0 resections
• Aorta Advential better survival
• Atrium 22% 5-year survival[i]
[i] Lung Cancer 29:135, 2000
[ii] J Neurosurg 91:74, 1999.
[i] Macchiarini et al. Ann Thorac Surg 57:966-973, 1994.
[i] Tsuchiya et al. Ann Thorac Surg 57:960 -- 965, 1994
Pancoast
• NSCLC that involves at the least the parietal pleura of the superior sulcus above the 2nd rib level
• Frequency is estimated to be less than 3%
• 40% symptomatic, usually due to local invasion rather than typical NSCLC symptoms
Surgical TechniquesPosterior Approach
Shaw-Paulson
2004, Thorac Surg Clin, Kent
• Posterolateral thoracotomy
• Conventional approach
• Advantage
– Excellent exposure for
posterior structures
– Feasible for vertebral resection
• Disadvantage
– Difficult to dissect thoracic inlet
structure (esp. vessels)
Surgical techniquesanterior approach
2004, Thorac Surg Clin, Macchiarini
Transclavicular approach
– Initially proposed by Dartevelle et
al
• Advantage
– Excellent exposure
– All type of lung resections
feasible without accessory
thoracotomy
• Disadvantage
– Resection of the clavicle
– Risk of winged scapula
Surgical techniquesanterior approach
2004, Thorac Surg Clin, Macchiarini
Hemiclamshell incision Trap-door incisionTrans-sternal approach
• Advantage– Excellent exposure for anterior structures
• Disadvantage– Difficult posterior dissection
– Risk of flail chest
– Excessive incision for true apical tumors
– Resection of the clavicle (trap-door)
Surgical techniquesanterior approach
2004, Thorac Surg Clin, Macchiarini
Trans-scapular approach
• Advantage
– Adequate exposure
• Disadvantage
– Very long (ischemic) incision
– Time-consuming closure
– Increased shoulder girdle
dysfunction
Brief Review of Data Guiding
Clinical Management
Meta-Analysis Induction CRT
vs Induction RT vs Adj RT Meta-Analysis Induction CRT
Better than other Options
T3 > T4 Resect Lobe > Wedge R0 a must!
Historical: What we know• Without treatment, survival is 12-14 months
• Advanced T, N, M status worsens the prognosis
• Without surgery, long term survival is uncommon, <5%
• > Lobectomy provides survival advantage
• Induction chemotherapy and radiation combined are synergistic
• R1 and R2 resections do not appear to provide a survival advantage
• Induction therapy increases resection and R0 rate
• Combined chemotherapy and radiation appear to provide better response than either alone
• Platinum based double drug therapy appears to improve survival
• >45 Gy appears to be effective to achieve pCR
• pCR after induction increases survival
3 Phase II Pancoast Trials Compared
Trial Group
and Name
Author
and Date
Special Section
Criteria
Special
Exclusions
PET
Included
in w/u
and %
#
Patients
How
Long to
Reach?
Tumor
Size
PreRx
(median)
Chemo Regimen w
dose # Cycles
# (%)
Completing
Induction
Therapy
Radiatio
n Dose
(Gy)
Radiation
to Include
Mediastin
um?
Concurre
nt?
IMRT
Technique
Included%
Determinan
t for
Surgical
Intervention
SWOG 9416Rusch,
2007
T3N0-1 or T4N0-1
NSCLC,
Mediastinoscopy
All
PS >2 No
110, 78
T3, 32 T4
(116
entered
trial)
April 1995
to
November
1999
6 cm (2-
14.5 cm)
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33
2 104 (95%) 45patients
excludedYes No
Stable or
Responding
to Induction
JCOG 9806Kunitoh,
2008
ipsilateral N3
eligible, no
mediastinosc
opy, if node <
1 cm
considered
negative
No76 (20 w
T4)
May 1999
to
November
2002
mitomycin 8 mg/m2 on
day 1, vindesine 3
mg/m2 on days 1 and 8,
and cisplatin 80 mg/m2
on day 1 Q 4wks
245 (1 wk
split)
patients
excludedYes No
SWOG 0220Kraut
TBA
T3N0-1 or T4N0-1
NSCLC,
Mediastinoscopy
All
No 44
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33 then 3 cycles of
docetaxel 75mg/m² Q 21
days
2 45patients
excludedYes No
Stable or
Responding
to Induction
3 Phase II Pancoast Trials Compared-Early Results
Trial Group
and Name
Author
and Date
Chemo Regimen w
dose
Induction
Rx Related
Deaths #
(%)
Inoperable
Due to
Disease
Progressio
n
# (%)
Surgically-
Treated
%
Sublobar
% Open
and
Closed % R0 CR% CR+Min%
# (%) No
Chest Wall
Resection
Necessary p
Induction
Hospital
Length-
of-Stay
(d)
PostOp
Morbidity
%
PostOp
30-d
Mortality
%
PostOp
Therapy
Planned
#(%)
Completing
Planned
Postop
Therapy
SWOG 9416Rusch,
2007
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33
3 (2.7%) 9 (8.2%) 88 (80%)
83 (76%),
surgically-
Rx 83/88
(94%)
32/88
(36%)61 (56%) 13/88 (15%) 7 (3-64) 52%
2 (2.3%)
wrong in
abstract
2 more
cycles of
Cist/Etop
59/88 (67%)
started Chemo,
45% completed,
no mention of
what % or #
surgical
JCOG 9806Kunitoh,
2008
mitomycin 8 mg/m2 on
day 1, vindesine 3
mg/m2 on days 1 and 8,
and cisplatin 80 mg/m2
on day 1 Q 4wks
1/76 (1.3%),
83-84%
hematologic
Gr 3-4
Toxicity
57/75
(76%)
3/57
(5.3%)
1/57
(1.8%)
51/57
(89%)
12/57
(21%)
12/75
(16%)
SWOG 0220Kraut
TBA
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33 then 3 cycles
of docetaxel 75mg/m² Q
21 days
29 (66%) 29 (100%) 8 (28%) 23 (79%)3 cycles
Docetaxel45% initiated
3 Phase II Pancoast Trials Compared-Long Term Results
Trial Group
and Name
Author
and Date Chemo Regimen w dose
MST
(mo)
2 yr
Overall
Survival
%
2-yr Overall
Survival for
those
surgically-
resected %
3-yr DFS
(%)
3-yr OS
(%)
5-yr
Disease
Free
Survival
%
5-yr
Overall
Survival
%
If pCR, 5-
yr
Survival
% LR # (%)
Systemic
Recurrenc
e # (%)
Brain
Recurren
ce # (%)
SWOG 9416Rusch,
2007
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33
33, 94 mo
if R0 not
reached
55% 70% - - - 44%54%,
T3=T4
(10 local
only + 7
Local +
systemic)
/57
(30%)
19 distant
+ 7 L +D
/57 (46%)
19 of 57
who
recurred
(41%)
JCOG 9806Kunitoh,
2008
mitomycin 8 mg/m2 on day
1, vindesine 3 mg/m2 on
days 1 and 8, and cisplatin
80 mg/m2 on day 1 Q 4wks
PFS 28
mo,
median
OS not
reached
- - 49% 61% 45% 56%T3 better
outcome
Resected,
2+4/20
recurred
(30%)
Resected,
14+4/20
(20%)
Resected,
4/20
(20%)
SWOG 0220Kraut
TBA
Cisplatin 50 mg/m2
d1,8,29,36
Etoposide 50 mg/m2 d1-
5,29-33 then 3 cycles of
docetaxel 75mg/m² Q 21
days
- - - - - - - - - - -
Summary of Conclusions
from 3 Phase II Trials to Date• Induction-related deaths 1-
3%
• Induction progression 8%
• Resectability is 70-80%
• R0 rate is 90%
• pCR 20-35%
• 10-20% avoid chest wall resection
• Postoperative mortality 2%
• Postoperative morbidity ~50%
• pCR and R0 risk factors for survival
• 5-yr OS is ~50%
N2 Disease in Pancoast
• Estimates are 10-20%
• None of the phase II trials included PET in the analysis
• All 3 of them excluded N2 disease, 1 clinical by criteria
• There was no standardization of mediastinoscopy or lung resection-related lymphadenectomyquality
SummaryLocally Advanced
Patients are a
Heterogeneous
Group
Surgical Quality is
Varied and Often
Inadequate
Trimodality in selected
Patients appears to
improve survival