Lung Cancer II

Cerard A. SllvesLrl Mu, lCC

rofessor of Medlclne
Medlcal unlverslLy of SouLh Carollna

re-1reatment Lva|uanon
lrom Lhe Lvaluauon Lhus far :
Asslgn a c1nM sLaLus
Classlfy as Lo SLage
SuggesL a LreaLmenL approach
And answer Lhe rsL quesuon:
ls Lhls Lumor resecLable?
now ls Lhe pauenL operable

Barriers to surgical resection
Poor lung
function, co-
morbidity
etc.,
Physiologic
Healthy
Normal
PFT
Anatomic
T4
N3
T3
T2
T1
N2
N1
N0
erspecnve on Stag|ng
1reatment k|sk
lmmedlaLe or shorL Lerm rlsk
erloperauve morbldlLy and morLallLy
luLure or long Lerm rlsk
osL-operauve pulmonary dlsablllLy and resulLanL quallLy
of llfe
uesnon 1
Whlch of Lhe followlng parameLers ls mosL llkely Lo
ellmlnaLe a pauenL from conslderauon of surgery
for an oLherwlse resecLable lung cancer:

A. Pe ls 83 years old
8. Pls posL operauve predlcLed uLCC ls 38 predlcLed
C Pls lLv1 ls 1 llLer
u. Pe has had an Ml wlLh sLenLs placed 8 monLhs ago

Short 1erm k|sk
Low 8lsk auenL
lLv1 > 2L (or > 60 of predlcLed)
uLCC > 60 of predlcLed
Mvv > 30 of predlcLed
ppolLv1 > 0.8 L (or > 40 of predlcLed)
ppouLCC> 40 predlcLed
Absence of hearL dlsease (Coldman lndex)
Short 1erm k|sk
Plgh 8lsk auenL
CC2 > 43
C2 < 30
ppolLv1 < 40 of predlcLed
C uLCC < 40 predlcLed
Age > 70
oor exerclse performance
Short 1erm k|sk
Age ls noL an lndependenL rlsk facLor
hyslologlc age mlghL be

Chronologlc age alone should noL preclude surgery
Short 1erm k|sk
Pypoxemla and Pypercapnla
noL absoluLe conLralndlcauons
Lower ppolLv1 are aL hlgher rlsk
8lsk ls relauve
Short 1erm k|sk
Lxerclse Lolerance ls predlcuve
Self-reporung
1lmed walk LesL (6 and 12 mlnuLe)
AblllLy Lo cllmb sLalrs
Short 1erm k|sk
8allpark rlsk of surgery ls :
3.0 for lobecLomy

6.0 for pneumonecLomy
1.3 for lesser resecuons

1reatment k|sk
lmmedlaLe or shorL Lerm rlsk
erloperauve morbldlLy and morLallLy
luLure or long Lerm rlsk
osL-operauve pulmonary dlsablllLy
8esulung quallLy of llfe
uanntanve Scann|ng
osL-op funcuon may be esumaLed
ercenL funcuon ls measured
8lghL vs Le
ppolLv1 and ppouLCC ls obLalned by muluplylng
pre-op value by Lhe percenL lung LhaL wlll remaln
aer surgery
Approach to Assess|ng Cperab|||ty
Pow do you emclenLly approach Lhe assessmenL of
operablllLy?
Several algorlLhmlc approaches have been proposed
Approach to Assess|ng Cperab|||ty
A useful algorlLhm from Lhe 81S appears ln 1horax
2001,36:89-108
Culdellnes for Lhe evaluauon are lncluded ln Lhe
ACC Culdellnes ln CPLS1 2013
A|gor|thm|c Approach
Cardlac Lvaluauon
All should have an LkC
lf PlsLory, hyslcal, or LkC are abnl, go Lo
full cardlology evaluauon
lf normal, go Lo Lung Lvaluauon
A|gor|thm|c Approach
Lung Lvaluauon - SplromeLry
roceed wlLh surgery
If p8D ILV1 > 1.S L (for p|anned |obectomy)
If >2.0 L (for p|anned pneumonectomy)
lf noL, order full sLudy wlLh A8C and calculaLe ppolLv1
and ppouLCC
erfus|on ( of V]) method for pneumonectomy
Segmenta| method for |obectomy
A|gor|thm|c Approach
CalculaLe ppolLv1 and ppouLCC
lf ppolLv1 and ppouLCC are > 40, proceed wlLh
surgery
lf ppolLv1 < 30 or ppolLv1 x ppouLCC < 1630,
conslder non-op

lf elLher ls < 40, order cardlopulmonary exerclse Lesung
A|gor|thm|c Approach
Lxerclse 1esung
lf vC2max >20 ml/kg/mln
roceed wlLh surgery
lf vC2max < 10 ml/kg/mln
Conslder non-operauve LreaLmenL or less exLenslve
resecuon (wedge, segmenL)
8eLween 10 and 20 ml/kg/mln
lLs a [udgmenL call
1kLA1MLN1
Sma|| Ce|| Lung Cancer
8y Lhe ume of dlagnosls, SCLC ls generally a sysLemlc
dlsease
70 have exLenslve dlsease aL presenLauon
Cnly 30 have whaL appears Lo be LlmlLed dlsease aL
presenLauon
1reatment of Lxtens|ve SCLC
SLandard Lx ls Cls-plaun and v-16 (eLoposlde)
Carboplaun plus v-16 may be less Loxlc
Cls-plaun plus lrlnoLecan (C1-11) ls an opuon
1wo cycles for lnducuon Lhen re-assess
1wo (Lo maybe 4) more cycles for consolldauon
no beneL Lo more Lhan 6 cycles
1reatment of Lxtens|ve SCLC

lnlual response raLe of 60 - 83
CompleLe response ln 20 - 30
Medlan survlval ls 6 - 12 monLhs
8emember 2 - 4 monLhs wlLhouL Lx
1wo year survlval = 20
llve year survlval < 3


1reatment of Lxtens|ve SCLC
no survlval beneL from addlng x81 Lo Lhe prlmary
Lumor, buL
May be oered for Lhose achlevlng a C8 ouLslde Lhe chesL

x81 ls beneclal when glven palllauvely
1reatment of L|m|ted SCLC
ldenucal chemoLherapy, buL
Add x81 (43 Cy)
ConcurrenL ls beuer Lhan sequenual (1
sL
or 2nd)
8uL more Loxlc
Pyperfracuonauon may be sllghLly beuer
1.3 Cy bld versus 1.8 Cy qd
AcceleraLed fracuonauon may be beuer
Cver Lhree weeks
Survlval beneL wlLh addlng x81 Lo chemo
3 aL 3 years, 3 Lo 7 aL 2 years
1reatment of L|m|ted SCLC
lnlual response raLes of 63 - 90
CompleLe response ln 43 - 73
Medlan survlval of 16 - 24 monLhs
40 - 30 2 year survlval
ln some sLudles, up Lo 20 are cured
Sma|| Ce|| Lung Cancer
Cl ls lndlcaLed ln pLs achlevlng a 8/C8
noL only a sllghL survlval beneL
3 year survlval lmproves from 13 Lo 21
3 lmprovemenL ln medlan survlval
8uL, more lmporLanLly, a quallLy of llfe beneL
60 chance of developlng CnS meLs wlLhln 2-3
yrs
uecreases chance of CnS meLs by 30
Sma|| Ce|| Lung Cancer
Slnce SCLC ls generally a sysLemlc dlsease, surgery ls
rarely lndlcaLed
Cccaslonally, very early locallzed Lumors wlLhouL spread
are approprlaLe for surgery
usually an Sn found Lo be SCLC aL Lhe ume of resecuon
Ad[uvanL sysLemlc chemoLherapy ls lndlcaLed aer
such resecuons
Non-sma|| Ce|| Lung Cancer
SLage lA, l8, llA, ll8 = Surgery
Lobe wlLh node sampllng/dlssecuon (?vA1S)
3 or more nodal sLauons aL leasL
neumonecLomy may be necessary
Sleeve over pneumonecLomy, lf posslble
Lesser resecuons (e.g. wedge, segmenLecLomy) may be
approprlaLe ln pLs wlLh marglnal funcuon

Non-sma|| Ce|| Lung Cancer
SLage lA, l8, llA, ll8 = Surgery
3 year survlval ls noL 100
AcLually 39 - 67 dependlng on sLage
1herefore, relapse ls common
ln 2/3rds, relapse occurs dlsLally and 1/3 locally
1hls ls Lhe rauonale behlnd ad[uvanL Lherapy
Ad[uvant Chemotherapy
LACL group pooled Lhe resulLs of 3 Lrlals wlLh 4,384
pauenLs
Medlan follow-up of 3.2 years
Cverall P8 of deaLh was 0.89 for chemo
AbsoluLe 3 year survlval beneL of S.4
uesnon 2
Ad[uvanL chemoLherapy should be oered Lo
pauenLs followlng resecuon for lung cancer for all
of Lhe followlng sLages excepL:

A. SLage lA
8. SLage llA
C. SLage ll8
u. SLage lllA

Ad[uvant Chemotherapy
8eneL varled wlLh SLage
Stage IA = nk of 1.4
Stage I8 = nk of 0.93
Stage II = nk of 0.83
Stage III = nk of 0.83
uld noL vary wlLh cholce of 2
nd
agenL
vlnorelblne, LLoposlde, vlnca alkalolds, oLhers
Ad[uvant Chemotherapy
Ad[uvanL posLoperauve cls-plaun based
chemoLherapy slgnlcanLly lmproves survlval 3 year
survlval
Should be consldered ln fully resecLed llA, ll8, and
lllA pauenLs

Non-sma|| Ce|| Lung Cancer
lollow-up and Survelllance
P& plus lmaglng every 6 monLhs for 2 years Lhen yearly
unul
Second prlmarles are common
1reaLmenL ls no dlerenL from lnlual Lhough ouLcome ls
poorer
Non-sma|| Ce|| Lung Cancer
1hose who are noL candldaLes for surgery may be
consldered for oLher forms of Lherapy
SLandard x81 wlLh curauve lnLenL ls a dlsLanL 2
nd
Lo
surgery ln SLage l dlsease
13 - 33 cure

S881 ls a promlslng new Lherapy
Stereotacnc 8ody kad|otherapy
SLereoLacuc body radlauon Lherapy (S881) ls a
nonlnvaslve cancer LreaLmenL ln whlch numerous
small, hlghly focused, and accuraLe radlauon beams
are used Lo dellver poLenL doses ln 1 Lo 3 LreaLmenLs
Lo Lumor LargeLs ln exLracranlal slLes.
Stereotacnc rad|otherapy (S8k1)
Plgh-preclslon lmage-gulded 81 characLerlzed by:
AccuraLe LargeL denluon
8eproduclble pauenL/Lumor posluonlng
Muluple non-coplanar 81 beam
Arc Lheraples
60 Gy
180 Gy
>200 Gy
Features of SBRT delivery
Steep dose-gradients
Hypofractionation (3-8 sessions)
High biological effective dose
Advances in image-guided SBRT
AvallablllLy of volumeLrlc lmaglng, speed of dellvery
97% three year local control rate.
Timmerman, R. et al. JAMA 2010;303:1070-1076.
Patient Course After Initiation of Stereotactic Body Radiation
Therapy
1reatment Stage IIIA
noL recognlzed by A!CC, buL lllA may be
pragmaucally dlvlded lnLo:
lllA1 = + nodes found ln speclmen
lllA2 = + nodes found aL surgery
lllA3 = + nodes found durlng pre-op w/u
lllA4 = + 8ulky (mulusLauon) nodes

Non-sma|| Ce|| Lung Cancer
lllA1 (ln speclmen) = 8eneL from ad[uvanL x81 and/or
Chemo
lllA2 (aL surgery) = CompleLe surgery lf fully resecLable Lhen
ad[uvanL Lx
lllA3 (durlng work-up)=Chemo/x81 ls Lhe LreaLmenL of cholce,
Conslder neoad[uvanL followed by surgery (only ln a cllnlcal
Lrlal),
lllA4 (bulky) = Chemo/x81
Neoad[uvant 1herapy
SLage lllA3
2 recenL large randomlzed Lrlals have found no survlval
beneL ln pauenLs glven several cycles of chemo prlor Lo
surgery

ldea belng LhaL such Lherapy may resulL ln Lumor
shrlnkage and eradlcauon of mlcromeLasLases
1hus enabllng compleLe resecuon
8esL consldered experlmenLal requlrlng furLher valldauon
before becomlng sLandard pracuce
Non-sma|| Ce|| Lung Cancer
SLage lllA1,lllA2, and lllA3 (Ad[uvanL 1x)
8ecenL sLudy of 7463 pauenLs found LhaL posL-op x81
lmproved survlval ln pauenLs wlLh lnvolved n2 nodes buL
noL n1 or n0
Ad[uvanL x81 should be consldered aer ad[uvanL
chemoLherapy wlLh lllA1 and lllA2

Non-sma|| Ce|| Lung Cancer
SLage lll8
lor good performance sLaLus
ConcurrenL chemo and x81 ls besL
Sequenual may be beuer LoleraLed
lor poor performance sLaLus
x81 only
WeL lll8 ls now SLage lv
ancoast (Sup Su|cus)1umor
1umors ln Lhe apex of Lhe lung LhaL may lnvade
conuguous sLrucLures
May cause local paln
May lnvolve brachlal plexus wlLh paln down Lhe medlal
aspecL of Lhe arm
Porners syndrome wlLh lnvolvemenL of Lhe
sympaLheuc chaln and sLellaLe gangllon
unllaLeral enopLhalmos, pLosls, melosls, lpsllaLeral
anhydrosls
ancoast (Sup Su|cus)1umor
1reaLmenL
lf posslble, Ln bloc resecuon
lf resecLable, good resulLs wlLh preop x81 wlLh a 3 yr
survlval raLe of 30
8ecenLly, beuer resulLs wlLh pre-op chemorads
wlLh a 3 yr survlval of 34
lf noL compleLely resecLable, concurrenL chemo/rads
Non-sma|| Ce|| Lung Cancer
SLage lv (noL curable)

lor good performance sLaLus (LCCC0/1)
ChemoLherapy provldes a survlval beneL
Medlan survlval lmproves by 4 mos
20 lmprovemenL ln 1 yr survlval
CuallLy of llfe beneL
CosL-eecuve Lherapy

Non-sma|| Ce|| Lung Cancer
SLage lv (noL curable)

lor Llderly or LCCC 2
Slngle drug or launum doubleL
lor LCCC 3 or 4
8esL supporuve care
Non-sma|| Ce|| Lung Cancer
SLage lv (noL curable)
Cls-plaun, vlnblasune, vlnorelblne, pacllLaxel, doceLaxel,
carboplaun, LopoLecan, and gemclLablne are acuve
1wo drug comblnauons are more eecuve
2 monLh lncrease ln medlan survlval wlLh Lhe
addluon of bevaclzumab ln selecLed pauenLs
non-squamous, no braln meLs, no
hemopLysls
AnoLher found a 1.2 monLh advanLage wlLh
ceLuxlmab
Reprinted with permission from Schiller JH et al. N Engl J Med. 2002;346:92-98.
All recenL
randomlzed sLudles
have slmllar resulLs
no clear emcacy
beneL among Lhe
plaunum-based
doubleLs
Cisplatin/Paclitaxel
Cisplatin/Gemcitabine
Cisplatin/Docetaxel
Carboplatin/Paclitaxel
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15 20 25 30
Months
Patient
Survival,
%
LCCG 1S94
Surv|va| by 1reatment Arm
Non-sma|| Ce|| Lung Cancer
! Clln Cnc 2008:26:3343-3331
8andomlzed 1932 pLs wlLh nSCLC Lo Cls/CemclLablne or
Cls/emeLrexed


ln a prespecled subseL analysls
Cls/em was superlor for adenocarclnoma (Survlval 12.6
vs 10.9 mos)
Cls/Cem was superlor for squamous cell carclnoma
(Survlval 10.8 vs 9.4 mos)
Non-sma|| Ce|| Lung Cancer
uurauon of LreaLmenL
lor responders
4 - 6 cycles for responders Lhen observe
8ecenLly approved, ln non-squamous cell, malnLenace
pemeLrexed unul progresslon
CS 13.3 mos versus 10.3 monLhs
8ecenLly reporLed, malnLenance erlounlb
lS of 22 weeks versus 16 weeks
lor progresslve dlsease
2
nd
llne chemoLherapy
Non-sma|| Ce|| Lung Cancer
SLage lv (noL curable)
vlrLually all pauenLs wlll recur
WlLh good S, conslder 2
nd
llne Lherapy
uoceLaxel (8.8 respond, lmproves by 2 mo)
emeLrexed (9.1 respond), ? Less LoxlclLy
Lrlounlb (small 2 monLh survlval beneL)
no beneL from doubleL Lx ln 2
nd
llne
Non-sma|| Ce|| Lung Cancer
Speclal case ls presenLauon wlLh sollLary braln meL
Cure |s poss|b|e w|th resecnon of met f]b dehn|nve
resecnon of pr|mary |n |ung
8ecurrence as a sollLary braln meL
ro|onged d|sease-free surv|va| w|th resecnon f]b who|e
bra|n kk1
System|c 1herapy
Many have concluded LhaL Lhe LreaLmenL of SLage lv
nSCLC has reached a plaLeau
Llule can be expecLed of new cyLoLoxlc agenLs or new
comblnauons of exlsung drugs
new approaches are needed
1argeLed 1herapy
ersonallzed 1herapy


1argeted 1herapy
ulrecLed aL speclc cell-slgnallng and regulaLory
paLhways LhaL are alLered ln Lhe neoplasuc cell
Cpposed Lo a non-speclc generallzed auack on cell
prollferauon
So-called cyLoLoxlcs
MCLLCULAk A1nCGLNLSIS
LplLhellal CrowLh lacLor 8ecepLor (LCl8)
Cverexpressed |n many cancers
In up to S0 of |ung cancers
8|nd|ng of LGI to the ce|| surface receptor tr|ggers
|ntrace||u|ar s|gna||ng events through at |east 3 ma[or
pathways (Akt, MAk, and S1A1 )

1urn|ng Cn the LGIk-1k S|gna|
A |vota| Lvent |n Ma||gnancy
rollferauon
lnvaslon
Ang|ogenes|s
MeLasLasls
lnhlbluon
of apopLosls
ln Lumor cells, Lhe
LCl8-1k slgnal ls
lnapproprlaLely Lurned
on by varlous
mechanlsms lnslde or
ouLslde Lhe cell
LCl8-1k enzyme
acuvlLy drlves
unconLrolled Lumor
growLh
MCLLCULAk A1nCGLNLSIS
LplLhellal CrowLh lacLor 8ecepLor (LCl8)

Small molecule 1k lnhlblLors (LCl8-1kl) may block Lhls
slgnallng paLhway
Ceunlb and Lrlounlb are besL sLudled 1kls
1urn|ng C the LGIk-1k S|gna|
Ins|de the Ce||
Sma|| Mo|ecu|e
LGIk-1k
Inh|b|tors, such
as gehnn|b and
er|onn|b
Anglogenesls
rollferauon
lnvaslon MeLasLasls
lnhlbluon
of apopLosls
Adapted with permission from Ritter CA, Arteaga CL. Semin Oncol. 2003;30(suppl 1):3-11.
MCLLCULAk A1nCGLNLSIS
LCl8
LCl8-1kls have mlnlmal eecL ln mosL lung cancers
uramauc eecL ln oLhers
Cllnlcal facLors LhaL predlcL response:
Adeno, never smokers, fema|es, Last As|an
her|tage
8ecenLly, muLauons ln Lhe 1k domaln of Lhe LCl8 have
been ldenued
Lspeclally exon 19 and 21 deleuons
CorrelaLed wlLh LreaLmenL response
MCLLCULAk A1nCGLNLSIS
1hese muLauons occur mosL commonly ln adenocarclnomas,
never smokers, females, LasL Aslan eLhnlclLy
1he exacL populauon where dramauc eecLs wlLh LCl8-1kls
occur
Much more Lo Lhe sLory as Lhe correlauon ls noL perfecL

rogress|on-free surv|va| |n LGIk mutanon
pos|nve and neganve panents
EGFR mutation positive EGFR mutation negative
Treatment by subgroup interaction test,
p<0.0001
HR (95% CI) = 0.48 (0.36, 0.64)
p<0.0001
No. events gefitinib, 97 (73.5%)
No. events C / P, 111 (86.0%)
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)

ITT population
Cox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98)
p<0.0001
No. events gefitinib , 88 (96.7%)
No. events C / P, 70 (82.4%)

132 71 31 11 3 0
129 37 7 2 1 0
108
103
0 4 8 12 16 20 24
Gefitinib
C / P
0.0
0.2
0.4
0.6
0.8
1.0
P
r
o
b
a
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i
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s
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i
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a
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At risk :
91 4 2 1 0 0
85 14 1 0 0 0
21
58
0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0
P
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b
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b
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p
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s
u
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i
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a
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Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)

Months Months
1argeted 1herapy
AnoLher LargeL ls anglogenesls
Lnhanced blood supply ls necessary for Lumor growLh
beyond a cerLaln polnL
vLCl blnds Lo recepLors on endoLhellal cells
1rlggerlng several lnLracellular paLhways
Leads Lo endoLhellal cell prollferauon and lncreased
permeablllLy
1argeted 1herapy
Several ways Lo lnhlblL Lhese anglogenesls paLhways
8evaclzumab ls a humanlzed anu-vLCl monoclonal
anubody
8lnds Lo and neuLrallzes vLCl
1hus prevenung lnluauon of Lhe slgnallng paLhway LhaL
leads Lo anglogenesls
Non-sma|| Ce|| Lung Cancer
8adlauon 1herapy - lndlcauons
Medlcally lnoperable
oLenually curauve
SLandard Lherapy ls 60 Cy over 6 weeks
S81, 3-u Conformal and lM81 may change Lhe
lndlcauons and ouLcomes
useful ln pLs wlLh posluve marglns or lncompleLely
resecLed Lumors
Non-sma|| Ce|| Lung Cancer
8adlauon 1herapy - lndlcauons
neoad[uvanL x81/chemo ln ancoasL
Locally advanced dlsease (lllA, lll8)
Cen wlLh concurrenL or sequenual chemo
alllauon
aln, hemopLysls, SvC syn, aLelecLasls
Mets to the Lung
Common
lound ln 20 - 30 dylng of mallgnancy
MosL common prlmary slLes
Lung, 8reasL, Colon, kldney
MeLasLecLomy may be beneclal
8esL resulLs wlLh sarcoma, colon, and kldney
8esL resulLs wlLh slngle leslon
So||tary u|monary Metastas|s
% (N=5206) 5-year survival*, %
Sarcoma 42 34
Colon 14 38
Breast 9 34
Renal Cell 8 43
Germ Cell 7 80
Melanoma 6 16
Head and Neck 5 44
Sadoff and Detterbeck, 2001.
* Following metastasectomy
Cverv|ew of NSCLC 1reatment
Stage I
Surgery (Radiation
if inoperable)
Radiation
With Chemotherapy
Chemotherapy
Targeted Therapy
Stage IV
or
kecurrent D|sease
Stage II
Surgery With Adjuvant
Chemotherapy
Stage III