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Transcript of Small Cell Lung Cancer Review [Chan & Coward]
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8/13/2019 Small Cell Lung Cancer Review [Chan & Coward]
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R E V I E W A R T I C L E
Introduction
For several decades, lung cancer has been and remains by arhe mos common malignancy in he world wih an esimaed
1.6 million new cases per annum (12.7% o oal) (1). I is
also he leading cause o cancer-relaed moraliy wih an
esimaed 1.38 million deahs per annum (1). Small-cell lung
cancer (SCLC) accouns or beween 10% o 15% o all lung
cancer cases and is closely linked o he inensiy and duraion
o obacco smoking (2). As such, ypical SCLC paiens
are elderly, curren or pas heavy smokers wih muliple
cardiovascular and pulmonary comorbidiies ha may impede
opimal managemen. SCLC is characerised by is aggressive
naure wih rapid growh, paraneoplasic endocrinopahiesand early measasis (3). In developed counries, he incidence
o SCLC peaked in he 1980s corresponding o peak raes o
cigarete smoking 20 years prior, bu is now slowly decreasing
due o changing smoking paterns (2).
Unreaed SCLC is rapidly aal wihin wo o our monhs(3,4). Iniial managemen sraegies or SCLC included
surgery or radioherapy alone i deemed unresecable (3,5).
Ulimaely, boh modaliies proved o be subopimal wih very
low long-erm survival raes and early relapses, usually wih
disan measaic disease. In 1969, chemoherapy wih single
agen cyclophosphamide doubled survival when compared o
bes suppor ive care alone (6). Following ha , comb inaion
chemoherapy was rialled and shown o be superior o single
agens (7,8). Dramaic response raes, including complee
responses (C), brough orward he analising promise o a
cure in he 1980s. However, whils SCLC is iniially sensiive ochemoherapy and radioherapy, relapse is almos ineviable and
he efficacy o reamen beyond firs line dwindles as i becomes
increasingly resisan o reamen (9,10).
For many oher solid-umour malignancies, advances in
diagnosis and reamen have resuled in improved survival.
However or SCLC, he 5-year survival raes have no improved
significanly over he las 40 years and have currenly plaeaued
(2,11,12). In Ausralia, he 5-year survival rae improved only
marginally beween he years o 1982-1987 and 2000-2007 wih
males improving rom 3% o 5% and emales 5% o 8% (12).
Over he las 30 years, phase III rials o chemoherapy
Chemotherapy advances in small-cell lung cancer
Bryan A. Chan1,2
, Jermaine I. G. Coward1,2,3
1Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia; 2School of Medicine,
University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; 3Inflammation & Cancer Therapeutics Group, Mater Research, Level 4,
Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia
ABSTRACT Alhough chemoherapeuic advances have recenly been heralded in lung adenocarcinomas, such success wih small-cell
lung cancer (SCLC) has been ominously absen. Indeed, he dismal oulook o his disease is exemplified by he ailure
o any significan advances in firs line herapy since he inroducion o he curren sandard plainum-eoposide double
over 30 years ago. Moreover, such sluggish progress is compounded by he dearh o FDA-approved agens or paiens
wih relapsed disease. However, over he pas decade, novel ormulaions o drug classes commonly used in SCLC (e.g.
opoisomerase inhibiors, anhracyclines, alkylaing and plainum agens) are emerging as poenial alernaives ha could
effecively add o he armamenarium o agens currenly a our disposal. is review is inroduced wih an overview on he
hisorical developmen o chemoherapeuic regimens used in his disease and ollowed by he recen encouraging advances
winessed in clinical rials wih drugs such as amrubicin and beloecan which are orging new horizons or uure reamen
algorihms.
KEY WORDS Small cell lung cancer (SCLC); amrubicin; beloecan; picoplain; relapsed SCLC
J Thorac Dis 2013 Jul 30. doi: 10.3978/j.issn.2072-1439.2013.07.43
Corresponding to: Dr Jermaine I. G. Cowa rd, MRCP (UK), FRACP, PhD.
Inflammation & Cancer Therapeutics Group, Mater Research, Level 4, Translational
Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia.
Email: [email protected].
Submitted Jul 18, 2013. Accepted for publication Jul 30, 2013.
Available at www.jthoracdis.com
ISSN: 2072-1439
Pioneer Bioscience Publishing Company. All rights reserved.
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Chan and Coward. Chemotherapy advances in SCLCXX
or SCLC have yielded only a wo monh improvemen in
median survival ime (10). adioherapy in he orm o
prophylacic cranial irradiaion (PCI) has provided incremenal
improvemens in hose achieving a complee or near-complee
response wih iniial chemoherapy (5.4% improvemen in 3-year
survival rae rom 15.3% o 20.7%) (13).
In conras o non-small cell lung cancer, he advances in
umour genomics, chemoherapy and argeed herapy have been
relaively sluggish or SCLC. ere has been a disinc pauciy o
change o chemoherapy regimens beyond hose firs used in he
1970s and 1980s and currenly plainum-eoposide remains he
backbone o herapy (14,15). ecen advances in undersanding
molecular pahways and genomic aberraions involved in SCLC
pahogenesis will hopeully ranslae ino novel herapeuic
arges o improve oucomes (16,17).
his review commences wih a synopsis o he hisory and
evoluion o SCLC and is reamen (able 1), wih a ocus on
chemoherapy. his is ollowed by a comprehensive overview
o he curren sysemic opions or de novoand relapsed disease
as well as novel chemoherapeuic agens and regimens on he
horizon.
SCLC: histology and staging
SCLC was iniially believed o be caused by arsenic exposure
in miners and was previously labelled as lymphosarcoma o
he mediasinum (18). In 1926, Barnard discovered ha he
oa cell sarcoma umour in ac had an epihelial origin arising
rom he lung (19). In 1967, he World Healh Organisaion
(WHO) firs caegorised SCLC ino our hisological subypes
based on Barnards observaions including: (I) lymphocye-like;
(II) polygonal; (III) usiorm and (IV) oher (3,9). Numerous
revisions were made by he WHO beore he Inernaional
Associa ion or he Sudy o Lung Cancer (IASLC) modi ied
i urher in 1988, replacing he erm oa-cell wih small cell
carcinoma.
e original saging sysem or SCLC was inroduced in 1968
by he Veerans Adminisraion Lung Cancer Sudy Group and
consised o wo clinical subgroups namely limied disease
(LD-SCLC) and exensive disease (ED-SCLC) (20). LD-SCLC
was deined as umour and nodes conined o one hemihorax
and able o be encompassed wihin a single radioherapy por,
whils all else was ED-SCLC (11,20).
Table 1.Hisory o reamens or SCLC.
1940s Surgery
Radiotherapy
Nitrogen mustard
1960s Recognition that SCLC was a different entity compared to other bronchogenic carcinomas (non-small cell lung carcinoma)
2 tier clinical staging system (limited and extensive) introduced by the Veterans Administration Lung Cancer Study Group
for SCLC
Single agent chemotherapy trialscyclophosphamide
1970s Combination chemotherapy superior to single agents
Combination anthracycline-based chemotherapy (CAV or CEV)
1980s Combination platinum-based chemotherapy (EP)
Chemotherapy combined with thoracic radiation for LD-SCLC
1990s Early concurrent thoracic radiation with chemotherapy for LD-SCLC
Chemotherapy for relapsed disease
Prophylactic cranial irradiation (PCI) for those with good performance status and complete response following combined
chemoradiation for LD-SCLC
2000s Hyperfractionated thoracic radiation
Irinotecan plus cisplatin (IP) for ED-SCLC (Japan)
PCI also offered to those with ED-SCLC with good performance status and good response following initial treatment
Novel regimens (incorporating taxanes, gemcitabine)
Trials of sequencing, cycling and maintenance chemotherapy
2010s IASLC introduce TNM staging for SCLC
Novel agents (amrubicin, belotecan, bendamustine, picoplatin, palifosfamide)
CAV, cyclophosphamide, doxorubicin, vincrisine; CEV, cyclophosphamide, epirubicin, vincrisine; EP, eoposide, cisplain; IP, irinoecan,
cisplain.
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Approximaely 30-40% o paiens presen wih LD- SCLC
and are opimally reaed wih combinaion chemoherapy wih
horacic radiaion. Median survival is beween 15 o 20 monhs wih
2- and 5- year survival raes o 20-40% and 10-20% respecively (21).
Unorunaely, mos paiens (60-70%) will presen wih
ED-SCLC and are reaed wih combinaion chemoherapy resuling
in a median survival beween 8 o 13 monhs. Moreover, boh
2- and 5-year survival raes remain poor a approximaely 5% and
1-2% respecively (21).
As mos o SCLC lieraure uilises he wo-subgroup clinical
saging sysem, i remains relevan or clinical decision-making
regarding herapy. However here are signiican dierences
beween survival oucomes wihin he limied disease subgroup.
When LD-SCLC is urher sraiied according o he IASLCs
umour, Node, Measasis (NM) classiicaion (7 hediion
2010), 5-year survival raes range rom 38% or sage IA o 9%
or sage IIIB (11). his highlighs he need or more precisesraificaion and as such he NM saging is now recommended
a leas in clinical rials or non-measaic disease (11,15).
Evolution of combination chemotherapy
Alhough combinaion chemoherapy is now widely acceped o
be inegral in he reamen o all sages o SCLC, his conrass
wih hisorical sysemic sraegies (15,22,23). In he 1940s,
iniial effors o rea SCLC involved surgery unil radioherapy
was shown o be super ior, even or opera ble cas es in 1969
(5,14,18). Alkylaing agens such as nirogen musard were usedas early as 1942, bu a he ime, he rue naure o SCLC was ye
o be discovered and all bronchogenic carcinomas were reaed
similarly (18,23-26). Nirogen musard did improve inoperable
bronchogenic carc ino mas median sur vival ime rom 93 o
121 days (noably only 81 o 468 had oa cell carcinoma) (25,26).
In 1962, Wason and Berg argued ha oa cell carcinoma
wih is disincly aggressive naure and propensiy or early
measasis migh be beer reaed wih combinaion inensive
chemoherapy and radiaion raher han local reamens such as
surgery or radiaion alone (23).
Cyclophosphamide was he irs cyooxic chemoherapy
agen o demonsrae a saisically significan survival advanage
over placebo [1969] or bronchogenic carcinoma including
SCLC (4.0 vs. 1.5 monhs) (6). Furhermore, in 1979, he
combinaion o cyclophosphamide-based chemoherapy plus
horacic radiaion was shown o be superior compared o
radioherapy alone (7,27).
Following hese promising resuls wih cyclophosphamide,
urher single agen cyooxics were sudied wih objecive overall
response raes (O) o up o 62% including; anhracyclines,
eoposide, enoposide, iosamide, hexamehylmelamine,
cisplain, carboplain, vindesine, vincrisine and nimusine (28).
From his, i was recognised ha he epipodophyllooxins
(eoposide and enoposide) were some o he mos acive single
agens in SCLC (29-32). Indeed, a randomised rial using hree
differen schedules o eoposide showed response raes beween
20-62% (33). Alkylaing agens including iosamide showed
response raes o up o 46% (28) and oher alkylaors including
cisplain and carboplain were less acive bu animal sudies
suggesed synergism wih eoposide (28-33). As single agens
in heavily pre-reaed SCLC, cisplain and carboplain had
Os o 15% and 24% respecively (28).
Following his, he combinaion o cyclophosphamide wih an
anhracycline (doxorubicin or epirubicin) and vincrisine (CAV
or CEV) was invesigaed. In exensive disease, CAV showed
14% C rae, 57% O and median survival o 26 weeks. In
limied disease, CAV had a 41% C rae, 75% O and median
survival o 52 weeks (8). e addiion o eoposide o he CAV
regimen (CAVE) did no reproducibly improve survival bu
came a he cos o increased haemaological oxiciy (34). usunil he mid-1980s, CAV was he sandard regimen or firs line
inducion chemoherapy (34,35).
In cases where anhracyclines were conraindicaed due o
severe cardiac or hepaic dysuncion, an alernaive regimen
was sug ges ed using a combinai on o he mos ac ive and
synergisic drugs in pre-clinical models. VP-16 or eoposide was
combined wih cisplain (EP) and he combinaion yielded an
impressive O o 86-89% (29,30). O approximaed 55% in
hose reracory o previous anhracycline-based chemoherapy.
Median survival imes were 70 and 43 weeks or limied and
exensive sage disease respecively (30,31). In he realms oSCLC managemen, his sudy proved o be ground-breaking
as i yielded responses comparable o anhracycline-based
chemoherapy in paiens wih poorer perormance saus,
serious cardiac disease or exensive liver and brain measases
(30,31).
Following his, direc comparisons beween CAV and EP
showed equivalen response raes (61% or CAV versus 51% or
EP) (36). C raes and median survival raes were 10% versus
7% and 8.6 versus 8.1 monhs or CAV and EP respecively (36).
Al er na ing CAV and EP was also inves iga ed and was no
dieren excep or a rend owards longer median ime o
progression (4 monhs wih EP versus 5.2 monhs wih EP/CAV
alernaing) (36). However, Fukuoka et al.conduced a similar
rial in Japan showing ha EP or CAV alernaing wih EP (CAV/
EP) had signiicanly higher response raes compared o CAV
(78%, 76% and 55% respecively) (37). Survival imes avoured
he alernaing regimen CAV/EP (11.8 monhs) compared o EP
(9.9 monhs) (P=0.056) or CAV (9.9 monhs) (P=0.027) (37).
hese resuls avouring plainum-conaining regimens
have been conirmed by a subsequen randomised phase III
rial wih 5 years o ollow up (38). In LD-SCLC, EP was
superior o CEV wih 2- and 5-year survival raes o 25% and
10% respecively in he EP arm compared o 8% and 3% in he
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Chan and Coward. Chemotherapy advances in SCLCXX
CEV arm (P=0.0001) (38). For ED-SCLC, here was a rend
owards survival benei wih EP over CEV bu hese were
no saisically signiican wih median survival 8.4 versus
6.5 monhs respecively (38). When combined wih concurren
horacic radiaion, EP is also beter oleraed han anhracycline-
based regimens (e.g. less oesophagiis and pneumoniis) and
so became he mos requenly used chemoherapy regimen or
SCLC (10,22,30,31,37-40).
he increasing use o plainum in a hos o solid umours
has simulaed a plehora o sudies comparing is efficacy wih
non-plainum regimens along wih head o head comparisons
beween cisplain and carboplain. Wih respec o SCLC, a mea-
analysis by Pujol et al. ound ha cisplain-based regimens had
an increased probabiliy o response over hose wihou cisplain
(O 1.35, 95% confidence inerval o 1.18-1.55) (41). Cisplain
is associaed wih signiican nephrooxiciy, neurooxiciy and
gasroinesinal adverse effecs whereas carboplain is associaedwih more myelosuppression (42). he COCIS mea-analysis
by ossi oc used on wh eh er or no cispl ai n was requir ed
or i carboplain could be subsiued (42). I suggesed ha
carboplain-based regimens were equivalen in erms o O,
progression-ree survival (PFS) and overall survival (OS)
compared o cisplain-based regimens (42). hus i seems
reasonable o subsiue carboplain or cisplain o avoid non-
haemaological oxiciies.
First-line chemotherapy
Curren combinaion chemoherapy wih eiher EP or CAV
achieves parial or complee responses raes beween 50% o 85%
alongside median survival imes ranging rom 9 o 12 monhs
(4,10). In he hope o improving he oulook or SCLC, several
novel agens have been invesigaed upron in view o encouraging
preliminary resuls winessed wih hese drugs in relapsed disease.
Much o he progress seems o have been ocussed around he
DNA opoisomerase enzymes ha are criical or DNA replicaion
and ulimaely cell survival (able 2). Dual inhibiion o boh
opoisomerase I and II can produce significan cyooxic effecs by
arresing boh DNA and NA replicaion by mainaining orsional
sresses ha ulimaely impede umour cell division (53).
Irinotecan
Irinoecan, a opoisomerase I inhibior, has shown much promise
in numerous phase II rials. he Japanese Clinical Oncology
Group (JCOG) conduced a phase III rial combining cisplain
wih irinoecan (IP) and compared i o EP in reamen nave ED-
SCLC (43). e rial was erminaed early due o an inerim analysis
showing a significan benefi in median survival wih IP compared
o EP (12.8 versus 9.4 monhs respecively, P=0.002) (43). OS raes
a 2 years were 19.5% and 5.2% respecively suggesing new hope
in ED-SCLC (43). Myelosuppression was more common wih
EP whils diarrhoea was more common in he IP arm (43).
W hil s his regimen was adoped as irs-line herapy or
SCLC in Japan, conirmaory sudies were required prior
o changing sandard pracice in oher counries. wo large
Norh American sudies looked a he IP combinaion
bu ound con lic ing res ul s o h e JCOG sudy (44,45 ).
he irs used a sl ighly modiied proocol (cisplain
30 mg/m2 i .v.i. plus irinoecan 65 mg/m 2 i .v.i. on days
1 and 8 every 21 days) compared o he JCOG (cisplain 60 mg/m2
i.v.i. day 1 and irinoecan 60 mg/m 2 i.v.i. on days 1, 8, and
15 q28 days) and ound no dierences in survival (44). he
ollow up SWOG S0124 rial used an IP proocol idenical o
ha used in he JCOG rial bu ound ha IP was equivalen o,
bu no superior o EP, boh in erms o O and OS (45). I is
posulaed ha pharmacogenomic variabiliy amongs differen
ehnic populaions could be a poenial reason or he differingresuls; a concep covered urher in his review.
Belotecan
Beloecan is a novel campohecin derivaive ha inhibis
opoisomerase I and posiive resuls rom single agen herapy in
previously unreaed ED-SCLC were seen in a phase II rial (46). I
had an impressive O o 53.2%, ime o progression (TP) o
4.6- and 10.4-monh median OS (46). e mos common oxiciy
was haemaological wih up o 71% grade 3/4 neuropenia (46).
Subsequenly, beloecan was combined wih cisplain in wophase II sudies which boh showed an O 70% and median
survival ime o 10 monhs (47,48). e resuls o an ongoing
phase III rial (COMBA) are eagerly anicipaed as i compares
beloecan-cisplain wih he gold sandard EP in chemoherapy
nave SCLC (54).
Amrubicin
Amrubicin is a synheic anhracycline derivaive which shares
srucural eaures wih doxorubicin and also sabilises he
opoisomerase II-DNA complex (55). Is acive meabolie
amrubicinol is believed o preerenially accumulae in umour
cells and is hus associaed wih reduced oxiciy including
anhracycline-cardiooxiciy (53,56,57). A phase II sudy in
previously unreaed ED-SCLC paiens ound ha single agen
amrubicin had an O o 75.8%, median survival ime (MS)
o 11.7 monhs and 2-year survival rae o 20.2% (50).
Consequenly, he inroducion o amrubicin in irs
line plainum double herapy has been invesigaed wih
response and survival raes comparable o hose documened
wih plai num -eop oside reg imens. Ohe et al. conduced a
phase I-II sudy o amrubicin combined wih cisplain in irs
line ED-SCLC o deermine he maximum oleraed and
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Journal of Thoracic Disease, Jul 30, 2013 XX
recommended dose o he novel combinaion consising o
amrubicin 40 mg/m2/day and cisplain 60 mg/m2/day (49).
ey repored an impressive O o 87.8% (36 o 41 paiens)
a he recommended dose schedule. e MS was 13.6 monhs
and 1-year survival rae 56.1%, however hese oucomes were
couneraced by significan grade 3/4 neuropenia (95.1%) (49).he Wes Japan horacic Oncology Group 0301 rial was
a phase II sudy invesigaing sequenial riple chemoherapy
w ih I P ol lowed by amr ubic in in pre v iousl y rea ed
ED-SCLC (51). ey repored an O o 79% wih median PFS
6.5 monhs. Median OS was 15.4 monhs bu his came a he cos
o significan myelosuppression wih 91% grade 3/4 neuropenia
and 15% ebrile neuropenia associaed wih amrubicin (51).
he EOC 08062 randomised phase II rial compared
amrubicin monoherapy (A) or in combinaion wih cisplain (AP)
versus he sandard EP regimen in a non-Asian populaion (52).
Independen reviewer O was repored as 61%, 67% and 67%
or A, AP and EP respecively (52,58). Alhough amrubicin
is associaed wih signiicanly more grade 3 haemaological
oxiciies, is impressive response raes are generaing ineres o
urher invesigae is poenial use or SCLC (52).
More recenly, Noro et al.conduced a phase II sudy o non-
cross resisan chemoherapy by alernaing AP wih weekly
IP or reamen nave ED-SCLC (59). Whils his showedan impressive O o 85% including 20% C, signiican
myelosuppression was eviden wih 83.3% grade 3 neuropenia.
However, weekly IP was associaed wih signiicanly more
diarrhoea. he MS was 359 days (12 monhs), median PFS
227 days (7.5 monhs) and one-year OS rae o 40% (59). Hence,
he combinaion o amrubicin-cisplain (AP) or alernaing AP
wih IP seems o be a very acive regimen or SCLC and AP is
now being compared o EP in a phase III rial (60).
Maintenance and consolidation therapy
Due o he propensiy or SCLC o promply relapse, mainenance
Table 2.rials o firs-line chemoherapy in small-cell lung cancer.
Author [Year] PhaseDisease
stageRegimen Number ORR (%)
Median TTP or
PFS (wks/mo.)
Median survival
time (wks/mo.)
1 yr
OS (%)
2 yr
OS (%)
Evans et al.
[1985] (30)
ED & LD EP 31 (ED: 20/31;
LD: 11/31)
86 LD (39 wks)
ED (26 wks)
LD (70 wks)
ED (43 wks)
NR NR
Noda et al.
[2002] (43)
III ED IP
EP
77
77
84
68
(P=0.02)
-
-
12.8 mo.
9.4 mo.
(P=0.002)
58.4
37.7
19.5
5.2
Hanna et al.
[2006] (44)
III ED IP
EP
221
110
48
43.6
P value
NR
4.1 mo. (TTP)
4.6 mo. (TTP)
(P=0.37)
9.3 mo.
10.2 mo.
(P=0.74)
34.95
35.19
8
7.9
Lara et al.
[2009] (45)
III ED IP
EP
324
327
60
57
(P=0.56)
5.8 mo. (PFS)
5.2 mo. (PFS)
(P=0.07)
9.9 mo.
9.1 mo.
(P=0.71)
41
34
NR
NR
Kim et al.
[2010] (46)
II ED B 62 53.2 4.6 mo. (TTP) 10.4 mo. 49.9 NR
Hong et al. [2012] (47) II ED BP 35 71.4 5.7 mo. (PFS) 10.2 mo. NR NR
Lim et al. [2013] (48) II ED BP 42 73.8 6.9 mo. (PFS) 11.2 mo. NR NR
Ohe et al. [2005] (49) I-II ED AP 44 87.8 NR 13.6 mo. 56.1 NR
Yana et al. [2007] (50) II ED A 33 75.8 NR 11.7 mo. 48.5 20.2
Kobayashi et al.
[2010] (51)
II ED IP-A 45 79 6.5 mo. (PFS) 15.4 mo. 61 NR
OBrien et al.
[2011] (52)
II ED A
AP
EP
28
30
30
61
67
67
5.2 mo. (PFS)
6.9 mo. (PFS)
5.8 mo. (PFS)
11.1 mo.
11.1 mo.
10 mo.
NR
NR
NR
NR
NR
NR
ED, exensive disease; LD, limied disease; N , no recorded; TP, ime o Progression; PFS, progression ree survival; OS, overall survival;
BSC, bes supporive care; EP, eoposide/cisplain; IP, irinoecan/cisplain; B, beloecan; BP, beloecan/cisplain; A, amrubicin; AP, amrubicin/
cisplain; IP-A, irinoecan/cisplain ollowed by amrubicin.
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Chan and Coward. Chemotherapy advances in SCLCXX
herapy has been a sraegy employed o prolong ime o recurrence
or progression. he Easern Cooperaive Oncology Group
(ECOG) conduced a phase III rial o mainenance opoecan
(opoisomerase I inhibior) or paiens wih sable or responding
disease ollowing our cycles o inducion cisplain-eoposide (61).
Alhough PFS was significanly improved, here was no difference
in paien-relaed qualiy o lie or OS beween observaion
and opoecan arms (8.9 versus 9.3 monhs; P=0.43) (61).
Subsequenly, a sysemaic review and mea-analysis by ossi
et al. ound ha he addiion o mainenance chemoherapy,
inererons or biological agens only produced a very small and
clinically insignifican survival benefi (62).
Second-line chemotherapy
Alhough iniial objecive chemoherapeuic responses o irs
line reamen are generally observed, his is seldom winessedbeyond his seting wih a median OS ofen 6 monhs, rechallenging wih
he same drugs used in primary herapy can achieve response
raes o 50% (65,66). hese early sudies helped deine he
curren nomenclaure o sensiive relapsed (PFS >3 monhs),
resisan (PFS 3 monhs, rechallenging
wi h pl ainum-ba sed doubles presens a possib le opi on.
his approach has been conirmed in a recen mea-analysisconduced by Garassino et al. amongs 161 paiens w ih
SCLC undergoing second line herapy having ailed EP (78).
In his sudy, subjecs were reaed independen o heir
plainum sensiiviy and only 30 (18.6%) were rechallenged
wih plainum. Noably, paiens rom his paricular cohor wih
plainum sensiive disease showed a rend owards superior O
(34.5% vs.17.5%, P=0.06) and OS (9.2 vs.5.8 monhs, P=0.08)
in comparison wih hose reaed wih non-plainum agens (78).
Ineresingly, clinical benefi (i.e. SD + P) was obained in 30%
o paiens wih reracory/resisan disease who underwen
plainum rechallenge (78). Despie hese resuls, rechallengingwih plainum is mainly reserved or paiens wih boh sensiive
relapsed disease and a FI >6 monhs.
Despie he modicum o success wih such regimens, a clear
herapeuic ceiling has been reached wih he curren armamen
o cyooxic agens available or second line reamen and
beyond. For his reason, research has ocused on developing
novel ormulaions o drug classes such as plainum sals,
anhracyclines, campohecins and alkylaing agens; all o which
have been he cornersone o progressive SCLC reamen or
several decades (able 3).
Amrubicin
e encouraging resuls emanaing rom he aoremenioned firs-
line phase II/III sudies wih amrubicin conaining regimens have
simulaed significan ineres in relapsed SCLC. Wihin his sphere,
several small Phase II rials have been conduced or boh sensiive
and reracory SCLC (53) (able 3) which could poenially help
esablish an alernaive 2ndline regimen o opeecan.
he irs o hese sudies highlighing he salvage poenial
o amrubicin was published by Onoda et al.in 2006 (79). is
mulicenre phase II sudy enrolled 60 paiens wih relapsed
SCLC; 16 reracory (i.e. P
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Table 3. rials o second-line chemoherapy in small-cell lung cancer.
Author [Year] PhaseTreatment
free intervalRegimen
NumberORR (%)
Median TTP or
PFS (wks/mo.)
Median survival
time (weeks/mo.)Survival rates (%)
Von Pawel
et al. [1999](68)
III >6 mo. T vs.CAV 107 T: 24.3
CAV: 18.3P=0.285
TTP
T: 13.3 wksCAV: 12.3 wks
P=0.552
T: 25 wks
CAV: 24.7 wksP=0.795
NR
OBrien et al.
[2006] (69)
III All relapsed
SCLC
T (oral) vs.
BSC
141 T: 7; (44 SD) TTP
T: 16.3 wks
T: 25.9 wks
BSC: 13.9 wks
(P=0.01)
6 month survival, T: 49
BSC, 26
Eckhardt et al.
[2007] (70)
III 90 days T (oral) vs.T
(i.v.i.)
309 T (oral): 18.3
T (i.v.i.): 21.9
P value NR
NR T (oral): 33 wks
T (i.v.i.): 35 wks
1 yr survival, T (oral):
32.6, T (i.v.i.) : 29.2
2 yr survival, T (oral):
12.4, T (i.v.i.) : 7.1
Onada et al.
[2006] (79)
II 60 days A 60
(16 refractory,44 sensitive)
Refractory: 50
sensitive: 52
PFS
refractory: 2.6 mo.sensitive: 4.2 mo.
Refractory: 10.3 mo.
sensitive: 11.6 mo.
1 yr survival, refractory:
40, sensitive: 46
Inoue et al.
[2008] (80)
II 90 days A vs.T 59 evaluable
(A=29,
T=30)
23 refractory,
36 sensitive)
A: 38
(Refractory 17,
sensitive 53)
T: 13
(refractory 0,
sensitive 21)
PFS
A: 3.5 mo.
(refractory 2.6 mo.,
sensitive 3.9 mo.)
T: 2.2 mo.
(refractory 1.5 mo.,
sensitive 3.0mo)
A: 8.1 mo.
(refractory 5.3 mo.,
sensitive 9.9 mo.)
T: 8.4 mo.
(refractory 5.4 mo.,
sensitive: 11.7 mo.)
NR
Ettinger et al.
[2010] (81)
II
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Table 3(coninued)
Author [Year] PhaseTreatment
free intervalRegimen
NumberORR (%)
Median TTP or
PFS (wks/mo.)
Median survival
time (weeks/mo.)Survival rates (%)
Ciuleanu
et al. [2010](86) (SPEAR
study)
III 60 days pos reamendisconinuaion). In line wih he curren recommended dosing
schedule, single agen amrubicin was adminisered a 40 mg/
m2d1-3 every 3 weeks. e median number o reamen cycles
was 4 (range, 1-8 cycles). Ineresingly, he O or reracory
and sensiive paiens were almos equivalen a 50% (95% CI,
25% o 75%) and 52% (95% CI, 37% o 68%) respecively.
However, superior PFS (2.6 vs. 4.2 monhs), OS (10.3 vs.
11.6 monhs) and 1-year survival (40% vs.46%) avoured
paiens wih sensiive disease (79). Wih respec o oxiciy,
grade 3/4 myelosuppression was mos commonplace wih high
raes o neuropenia (83%), ollowed by anaemia (33%) andhrombocyopenia (20%). Imporanly, only 3 paiens (5%)
experienced ebrile neuropenia and no reamen-relaed deahs
were documened (79).
Naurally, hese indings uelled he developmen o a
subsequen sudy direcly comparing he eicacy o amrubicin
(40 mg/m2d1-3 q3 weeks) and opeecan (1 mg/m2d1-5 q3
weeks) wihin he second line seting. Anoher phase II Japanese
sudy conduced by Inoue et al.enrolled 60 SCLC paiens
pre-reaed wih plainum-based chemoherapy (80). O he
59 evaluable, 23 had reracory (deined as no response o 1 s
line herapy or relapse 3 were higher in he amrubicin
arm and unorunaely, one reamen relaed deah secondary o
neuropenia was observed in his group o paiens (80).
Analogous o oher success sories wih novel herapeuics
iniially rialled in Asian populaions [e.g. IPASS in non-smallcell lung cancer (NSCLC) (91)], hese resuls were greeed wih
iniial cauion as cerain pharmacogenomic proiles exclusive
o such cohors could possibly preclude he same responses
in Caucasian paiens. Speciically, nicoinamide adenine
dinucleoide phosphae (NADPH) oxidase is an enzyme criically
involved in he meabolism o amrubicin and he polymorphisms
o his enzyme which are recognised in Asian populaions could
poenially inluence response (92). Consequenly, wo sudies
ocusing on 2ndline amrubicin reamen in reracory and
sensiive SCLC have been conduced in paiens rom Wesern
populaions. Wih respec o plainum-reracory disease, Etinger
et al.conduced a phase II sudy wih single agen amrubicin in
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75 paiens who achieved a median PFS o 38 days ollowing 1s
line chemoherapy (81). O hese, 69 paiens received a median
o 4 cycles (range, 1-12 cycles), wih a modes O o 21.3% (95%
CI, 12.7% o 32.3%). In addiion 1 C (1.3%) and 15 P (20%)
were winessed alongside a PFS and OS o 3.2 monhs (95% CI,
2.4 o 4.0 monhs) and 6.0 monhs (95% CI, 4.8 o 7.1 monhs),
respecively (81). Ineresingly, amongs he 43 (57%) paiens
who ailed o respond o iniial plainum-based herapy, a 16.3%
O (95% CI, 6.8% o 30.7%) was observed (81).
e subsequen Jote et al.sudy wih amrubicin in plainum-
sensiive SCLC (i.e. FI 90 days) bore similariies o he Inoue
rial by employing a opoecan-conaining comparaor arm (82).
Paiens (n=76) were randomised 2:1 o amrubicin (n=50; 40 mg/
m2i.v.i. d1-3, q21 days) or opoecan (n=26; 1.5 mg/m2i.v.i. d1-5,
q21 days). Again, significanly higher O was winessed wih
amrubicin compared wih opoecan (44% vs.15%; P=0.021)
and his also ranslaed ino superior median PFS (4.5 vs.3.3monhs) and OS (9.2 vs.7.6 monhs). In conras o he Inoue
sudy, here was a rend owards more myelosuppression ( grade
3) wih opoecan as opposed o amrubicin (82). In conclusion,
he avourable resuls winessed wih amrubicin in O, PFS,
OS in sensiive/reracory SCLC and he superioriy over
opoecan in Asian cohors are also apparen in paiens rom he
Wesern world and has consequenly simulaed he developmen
o a urher larger scale sudy. Namely, he randomised phase III
AC-1 sudy aimed o compare he efficacy o 2ndline amrubicin
wih opo ecan in paiens wih relapsed SCLC (83). In his
rial 637 paiens were randomized 2:1 o amrubicin (n=424)40 mg/m2 i.v.i. d1-3 or opoecan (n=213) 1.5 mg/m2i.v.i. d1-5.
In line wih similar aoremenioned sudies wih hese regimens,
he resuls presened a he 2011 American Sociey o Clinical
Oncology (ASCO) Annual Meeing conirmed ha amrubicin
had signiicanly improved O compared o opoecan (31%
vs.17%; P=0.0002) (83). Furhermore, despie no dierences
in PFS, OS rends avoured amrubicin (H 0.88; 95% CI, 0.73-
1.06; P=0.17), wih a paricular leaning owards paiens wih
reracory disease (H 0.77; 95% CI, 0.59-1.00; P=0.049) (83).
In addiion, small Phase I/II sudies have explored he
eicacy o combining amrubicin and opoecan as a poenial
2ndline regimen (93,94). However despie he 60-70% Oachieved, any opimism generaed rom hese rials is empered
by unaccepable oxiciies including grade 4 myelosuppression,
aal diarrhoea and pneumoniis (94). Neverheless, he resuls
rom he larger amrubicin monoherapy sudies have cerainly
shed significan ligh on a plausible alernaive herapeuic agen
ha could salvage paiens wih relapsed SCLC.
Picoplatin
Picoplain (ZD0473) is a novel organic plainum analogue
developed specifically o circumven he developmen o plainum
resisance mediaed by sulphur-conaining compounds such as
gluahione and meallohionein (95,96); hiol agens ha deoxiy
hrough avid plainum binding (97). his propery exends is
ani-neoplasic aciviy beyond he sandard uncionaliy o
plainum revolving around DNA alkylaion, iner- and inra-srand
cross-linking which all aciliae apoposis. More specifically, an in
vitrosudy has confirmed he reversal o resisance o boh cisplain
and carboplain wih picoplain in plainum resisan H69 and
SBC-3 SCLC lines (98). Moreover, i appears ha he mechanism
o acion underlying his phenomenon relaes o a decrease in
plainum accumulaion (98). e firs clinical repors confirming
single agen aciviy o picoplain in relapsed SCLC were published
by reaet al.wih a phase II sudy in SCLC paiens wih plainum
resisan (deined as PD
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Belotecan
he modes eicacy winessed in irs-line herapy wih he
novel opoisomerase I inhibior; beloecan is also mirrored in
a ew small sudies in he relapse seing. hee et al.published
he resuls o a Phase II rial in 25 paiens wih relapsed SCLC
(sensiiviy saus unknown) reaed wih beloecan a an iniial
dose o 0.5 mg/m2i.v.i. d1-5 q21 days (87). In accordance wih
oxiciy, appropriae dose adjusmens were only allowed o
be implemened once dur ing subsequen cyc les. Ou o he
21 evaluable paiens, 6 had an objecive umour response; i.e.
O 24% on he inenion o rea analysis. Furhermore, he
median PFS and OS were 2.2 and 9.9 monhs respecively wih
a 1-year survival rae o 38.3% (87). Alhough he incidence o
grade 3/4 neuropenia was paricularly high (88%), severe non-
haemaological oxiciies were no commonplace (87). Similarly,
anoher single agen sudy was execued in 27 paiens wihreracory disease who had relapsed wihin 3 monhs o obaining
response rom plainum-irinoecan based irs line herapy (88).
h e O wa s 22%, wih med ia n PFS o 4 .7 monh s
(95% CI, 3.6-5.8 monhs) and a reasonable median OS o
13.1 monhs (95% CI, 10.4-15.8 monhs) (88). e later resul
is o paricular ineres as i suggess ha beloecan has a role in
salvaging paiens who are resisan o oher opoisomerase I
inhibiors.
More recenly, Kim et al. have published a larger sudy
invesigaing he efficacy o beloecan monoherapy in 50 paiens
wih sensiive relapsed (n=20) or reracory SCLC (n=30) (89).he O was 14% (95% CI, 4-24%) wih a median ollow up
period o 4.2 monhs (range, 0.1-19.2 monhs), and median PFS
and OS o 1.6 and 4.5 monhs respecively. As expeced, paiens
wih sensiive relapsed disease ared significanly beter compared
o reracory counerpars or O (20% vs.10%), OS (6.5 vs.
4.0 monhs; P=0.003) wih a rend owards superior PFS (2.8 vs.
1.5 monhs; P=0.053). O noe, he mulivariae analysis
conirmed ha he ype o relapse and prior response o
chemoherapy were independen prognosic acors or OS (89).
Ag ai n, gr ade 3/ 4 mye losupp res si on wa s ev id en wi h h e
highes rae associaed wih neuropenia (54%) ollowed
by h ro mb oc y o pen ia (3 8%) an d an ae mi a (3 2%) (8 9) .Furhermore, one reamen-relaed deah secondary o sepsis
was documened in his sudy. Despie he expeced deleerious
side eecs, beloecan has shown modes aciviy wihin he
second line seting or boh sensiive and reracory SCLC and,
as wih amrubicin, warrans urher exploraion in his paricular
domain.
Future directions and closing remarks
e novel chemoherapeuic agens previously highlighed have
indeed provided some opimism, albei shor lived. Oher drugs
have recenly come o he ore and similarly demonsrae variable
degrees o eicacy. Bendamusine; a biuncional alkylaing
agen, has shown aciviy in combinaion wih carboplain in
chemoherapy-nave ED-SCLC. Amongs 55 paiens, Koser
et al.documened an O o 72.7% which included a single
complee responder. In addiion median P (5.2 monhs),
MS (8.3 monhs) and oxiciy profiles all compared avourably
in comparison o oher sandard 1s line plainum conaining
regimens (99). Bendamusine also appears eecive in sensiive
relapsed SCLC (i.e. FI 60 days) wih O 29% and median
PFS and OS o 4 and 7 monhs respecively (90). In view o his
preliminary daa, a curren phase I/IIa sudy is acively recruiing
30 paiens wih chemoherapy-nave SCLC o be reaed wih 3
cycles o bendamusine combined wih irinoecan ollowed by 3
cycles o sandard carboplain and eoposide (Clincalrials.gov
idenifier: NC00856830).
Following on rom he success o pemerexed in non-squamousnon-squamous NSCLC and mesohelioma (100,101), aemps
have been made o add his o he armamen o herapeuic
regimes in SCLC. However he oucomes o wo recen phase II
sudies using pemerexed monoherapy (500 and 900 mg/m2) in
paiens wih sensiive and reracory relapsed SCLC have been
inadequae wih minimal efficacy seen in his seting (102,103).
hese damning resuls are no enirely unexpeced. he
discrepancies in he efficacy o pemerexed in non-squamous and
squamous NSCLC seen wih he seminal Scaglioti sudy (100),
are based on he higher hymidylae synhase (S; he principal
subsrae or pemerexed) expression associaed wih squamoushisoypes (104). Indeed, a subsequen sudy has urher shown
ha lower S expression in advanced non squamous NSCLC is
associaed wih longer PFS (105). Moreover, S expression in
SCLC (boh rom reseced umours and cell lines) is significanly
higher han pulmonary squamous and adenocarcinomas
(106,107). Hence, i would appear counerinuiive o adop
sraegies involving S inhibiors or SCLC herapy.
his review has aemped o ouline he hisorical and
curren progress in he chemoherapeuic managemen o
SCLC. Plainum-eoposide doubles sill represen he gold
sandard o irs line herapy and aemps o swich he mode
o opoisomerase inhibiion may prove o be he mos sraegicmehod in improving survival. Alhough he survival advanages
garnered rom subsiuing eoposide or irinoecan in he JCOG
sudy were no recapiulaed in he subsequen SWOG S0124
rial; curren sudies comparing he eicacy o amrubicin or
bel oecan wih pla inum wih EP (52 ,54) could poen ial ly
change pracice. Similarly, boh o hese agens are showing
promise as single agens in salvaging paiens wih eiher
sensiive or reracory relapsed disease. aking ino consideraion
he dearh o FDA approved 2ndline regimens in SCLC, here is
an obvious urge o develop larger clinical rials wih hese agens.
Furhermore, despie he dishearening oucomes in he SPEA
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sudy, picoplain may sill serve as a viable alernaive o eiher
cisplain or carboplain in is abiliy o aver he developmen
o resisance. Hence, rials comparing picoplain doubles wih
oher plainum conaining regimens in previously unreaed
SCLC could also be considered.
As wih oher sol id umour y pes, he success ul ques in
prolonging survival in SCLC will mos likely involve appropriae
combinaions wih he novel drugs oulined in his review
alongside emerging herapies such as muli-argeed recepor
yrosine kinase inhibiors or oher agens which serve o block
signalling cascades inheren o he aggressive umorigeniciy
o SCLC (e.g. inhibiors o IGF, mO, ME and hedgehog
signalling). Exhausive preclinical sudies wih such combinaorial
herapies will be required o examine boh heir eicacy and
he ineviable upregulaion o resisance pahways ha ensue.
e developmen o uure clinical rials emanaing rom hese
sudies will require robus design in order o make signiicanseps in changing he landscape o his bleak disease.
Acknowledgements
Disclosure:e auhors declare no conflic o ineres.
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Cite this article as:Chan BA, Coward JI. Chemoherapy advances
in small-cell lung cancer. J horac Dis 2013 Jul 30. doi: 10.3978/
j.issn.2072-1439.2013.07.43