small cell lung cancer review [chan & coward]

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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Journal of Thoracic Disease, Jul 30, 2013 XX

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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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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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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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.


sensitive 3.0mo)

A: 8.1 mo.


sensitive 9.9 mo.)

T: 8.4 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


9/14


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


10/14


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


11/14


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

small cell lung cancer review [chan & coward]

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