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

4

Disclosures

• None

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

11

Surgery: NSCLC

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

15

Special Surgical Situations

• N2

• N3

• T4 Local Invasion

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

Question and Answer Session

Kemp H. Kernstine, MD, PhD

Professor and Chairman

UT Southwestern Medical Center

Dallas, TX