A review of clinical trials of cetuximab combined with radiotherapy for non-small cell lung cancer.

0.24 MB·English

by  Nieder, Carsten

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REVIEW Open Access
A review of clinical trials of cetuximab combined
with radiotherapy for non-small cell lung cancer
Carsten Nieder1,2*, Adam Pawinski1, Astrid Dalhaug1 and Nicolaus Andratschke3
Abstract
Treatment of non-small cell lung cancer (NSCLC) is challenging in many ways. One of the problems is
disappointing local control rates in larger volume disease. Moreover, the likelihood of both nodal and distant
spread increases with primary tumour (T-) stage. Many patients are elderly and have considerable comorbidity.
Therefore, aggressive combined modality treatment might be contraindicated or poorly tolerated. In many cases
with larger tumour volume, sufficiently high radiation doses can not be administered because the tolerance of
surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of
radiosensitizing agents, which increase tumour cell kill, might improve the therapeutic ratio. If such agents have a
favourable toxicity profile, even elderly patients might tolerate concomitant treatment. Based on sound preclinical
evidence, several relatively small studies have examined radiotherapy (RT) with cetuximab in stage III NSCLC. Three
different strategies were pursued: 1) RT plus cetuximab (2 studies), 2) induction chemotherapy followed by RT plus
cetuximab (2 studies) and 3) concomitant RT and chemotherapy plus cetuximab (2 studies). Radiation doses were
limited to 60-70 Gy. As a result of study design, in particular lack of randomised comparison between cetuximab
and no cetuximab, the efficacy results are difficult to interpret. However, strategy 1) and 3) appear more promising
than induction chemotherapy followed by RT and cetuximab. Toxicity and adverse events were more common
when concomitant chemotherapy was given. Nevertheless, combined treatment appears feasible. The role of
consolidation cetuximab after RT is uncertain. A large randomised phase III study of combined RT, chemotherapy
and cetuximab has been initiated.
Keywords: non-small cell lung cancer, radiotherapy, cetuximab, chemoradiation
Introduction high-dose radiotherapy and chemotherapy, and many
Non-small cell lung cancer (NSCLC) is among the lead- more.
ing causes of cancer death in the western world and Many patients with inoperable stage III disease are
increasing in many other countries. Survival of patients candidates for combined modality chemo- and radio-
with locoregionally advanced disease (stage III) and therapy (RT). While concomitant administration might
metastatic disease has remained disappointing despite improve survival, parallel increases of toxicity have also
some gradual improvement [1,2]. Patients with stage III been observed [1,4]. The dilemma of simultaneous
disease differ with regard to primary tumour volume increases in efficacy and toxicity becomes even more
and proximity/infiltration to surrounding structures, difficult in elderly patients and those with considerable
extent of lymphatic spread, cancer biology, and host fac- pretreatment weight loss, reduced performance status
tors such as age, cardiopulmonary function and other and comorbidity. Incorporation of novel agents might
comorbidity [3]. Treatment recommendations have to be advantageous in several ways. It might allow for
take into account these differences and stratify patients administration of combined modality treatment in
according to technical resectability, ability to tolerate patients who are not candidates for established chemor-
adiation regimens and where RT alone results in unsa-
tisfactory outcomes. Moreover, certain agents might be
*Correspondence:[email protected] added on top of chemoradiation with the aim of further
1DepartmentofOncologyandPalliativeMedicine,NordlandHospital,Bodø,
Norway
Fulllistofauthorinformationisavailableattheendofthearticle
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improving treatment results in patients who can tolerate in patients irradiated for stage III NSCLC (elective nodal
aggressive approaches. irradiation (ENI) was part of the treatment concept) but
The theoretical solution of simply increasing radiation overall compliance and tolerability suggest that conco-
doses to high biologically effective doses (BED), ideally mitant cetuximab and standard dose RT (60-66 Gy) is
above the threshold of 100 Gy in 2-Gy fractions, which feasible even in patients unfit for chemoradiation. The
has been suggested by several groups [5-8], is hampered median survival of 15.1 and 19.6 months respectively
by the tolerance of surrounding normal tissues that compares favourably with trials of comparable RT alone,
must be respected if a favourable therapeutic ratio is to e.g. the series of 127 patients reported by Jeremic et al.
be maintained. Under such circumstances, simultaneous who found a median survival of 12 months [17], and the
administration of radiosensitizing agents that increase series of 106 patients reported by Wang et al. where
tumour cell kill might improve the therapeutic ratio, median survival was 7.4 months [18]. However, such
provided these agents do not sensitize critical normal inter-study comparison might be hampered by several
tissues in the same fashion. Moreover, radiation dose sources of bias (patient selection, improved staging,
escalation does not address the issue of distant or out- improved RT delivery etc.) and can not prove the super-
of-field relapses. Based on the fact that the epidermal iority of combined treatment. Randomised comparison
growth factor receptor (EGFR) is often over-expressed of RT alone and RT with cetuximab is still necessary. It
or mutated in NSCLC, the impact of such changes on would also be interesting to study whether irradiation to
cellular responses to ionising radiation has been 60-66 Gy plus cetuximab is better than dose-escalated
explored [9-11]. Several drugs interfering with the EGFR RT without cetuximab, given the high cost resulting
signalling pathway have been developed, e.g. cetuximab, from drug treatment.
a human-murine chimeric IgG1 monoclonal antibody
that binds to the extracellular region of the EGFR. Cetuximab and chemoradiation: induction chemotherapy
Under experimental laboratory conditions in animal only
models, cetuximab increases tumour radiocurability Two phase II studies have been published, as shown in
(fractionated and single dose irradiation) [12,13]. Clini- Tables 1 and 2[19,20]. Both included patients with inop-
cally, this effect has been confirmed in head and neck erable stage III disease and good performance status. In
cancer (phase III data with fractionated irradiation) [14]. the Swedish study, 2 cycles of induction cisplatin/doce-
Recently, initial clinical trials of cetuximab and RT for taxel were administered [19]. The small UK study with a
NSCLC have been completed, which are reviewed here median of 3 cycles included patients treated with differ-
in order to guide the development of the next genera- ent regimens [20]. In both studies cetuximab was given
tion of larger prospective studies. The data included in concomitant to RT (total dose 64 and 68 Gy, respec-
this review were identified by comprehensive searches of tively). ENI was administered to selected patients in the
the PubMed database with combinations of the key- UK trial only. Serial computed tomography (CT)
words “NSCLC, RT, cetuximab, EFGR” (last access revealed that the UK trial included some patients with
August 15, 2011) and the reference lists of articles. actual stage IV disease. Only the Swedish trial reported
detailed outcome data. Median survival was 17 months,
Cetuximab in patients who are not candidates for i.e. comparable to the results of the two trials without
chemoradiation any chemotherapy [15,16] or other studies of sequential
As summarized in Tables 1 and 2, two different phase II chemotherapy and RT without cetuximab [18]. Toxicity
trials have studied combined RT and cetuximab without and compliance were also comparable to these afore-
any chemotherapy [15,16]. In the US trial, cetuximab mentioned studies. In the absence of randomised trials,
was given concomitant to 60 Gy RT [15]. In the Ger- these sparse data do not create enthusiasm about
man trial, intensity-modulated RT to a total dose of 66 further studies of comparable approaches. It appears
Gy was combined with concomitant and 13 weekly con- more attractive to put resources into trials of the other
solidation cycles of cetuximab [16]. Another important two categories reviewed here.
difference is that positron emission tomography (PET)
was mandatory in the German trial, which also included Cetuximab and chemoradiation: concomitant
patients with slightly more favourable baseline prognos- chemotherapy
tic factors (some stage II patients, no weight loss > 5%, The Radiation Therapy Oncology Group (RTOG) has
younger median age). Median survival and response recently published a phase II study of chemoradiother-
rates were higher in the German trial. However, such apy with carboplatin and paclitaxel plus cetuximab in
differences might result from treatment itself or inclu- patients with stage III NSCLC [21]. From the loading
sion of prognostically better patients. Mucosal and pul- dose of cetuximab to the end of the consolidation
monary toxicities occurred at the expected frequencies phase, 17 weekly treatments were administered. The
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Table 1Study design andefficacy
Reference Studytype Patients Othercriteria RTschedule Systemictherapy Follow- Results
up
Jensenetal. Single Notcandidatesfor StageIIIAorB, OnlyIMRTtrial,66 CetuximabSR Median MedianOS19.6mo,
[16] institution concomitant nomalignant Gyin33daily followedby13weekly 19mo medianPFS8.5mo,
phaseII, chemoradiation pleuraleffusion, fractionsof2Gy, consolidationcycles 63%PR,noCR,
Germany,n (orrefused),KPSat FEV1≥1.5lor ENIto50Gy(or patternsoffailureNR,
=30 least70,oneof 40%ofnorm 40dependingon survivalnotinfluenced
twotrialswith value,weight lungdose,target byhistology
mandatoryPET loss<5% volumeNR)
Jatoietal.[15] Multi-centre Notcandidatesfor StageIIIAorB, 60Gyin30daily CetuximabSR Median MedianOS15.1mo,
phaseII,US, concomitant nopleural fractionsof2Gy, 17mo medianPFS7.2mo,
n=58 chemoradiation, effusion,FEV1≥ ENItoipsilateral 26%PR,noCR,
eitherage≥65 1l, hilarand patternsoffailureand
yearswithECOG haemoglobin≥ mediastinalnodes impactofhistologyNR
0-2oryounger 9g/dl,V20not (44Gy)
butECOG2 exceeding40%
Hallqvistetal. Multi-centre Medically StageIIIAorB, 68Gyin34daily 2cyclesofinduction Median MedianOS17mo,PFS
[19] phaseII, inoperableor nopleural fractionsof2Gy, cisplatin/docetaxel, 39mo NR,16%PRand7%CR
Sweden,n= unresectable, effusionwith noENI cetuximabSRstarting at12months(NRat
71 WHO0-1 positive oneweekbeforeRT earliertimepoints),
cytology,FEV1 patternsoffailure:31%
≥1lor40%of distantonly,23%local
expected only,7%regionalonly,
volume 11%combinationsof
these,survivalnot
influencedbyhistology
Hughesetal. Dualcentre Inoperable,WHO StageIIIAorB, 64Gyin32 Upto4cycles Median MedianOSNR,PFSNR,
[20] phaseII,UK, 0-1 nopleural fractionsof2Gy, (median3)of 10mo 58%PR,noCR,
n=12 effusion in4casesENIto platinum-based patternsoffailureand
ipsilateralhilarand inductionCTx, impactofhistologyNR
mediastinalnodes cetuximabSRstarting
(50Gy) oneweekbeforeRT
Blumenschein Multi-centre Inoperable, StageIIIAorB, 63Gyin35 CetuximabSRweek1- Median MedianOS22.7mo,
etal.[21] phaseII,US, Zubrod0-1 weightloss< fractionsof1.8Gy, 17,weekly 22mo mediantimeto
n=87 5%,FEV1≥1,2l ENItoipsilateral carboplatin/paclitaxel progressionaround14-
hilarand duringRTfollowedby 15mo,29%CR,33%
mediastinalnodes 2cyclesconsolidation PR,patternsoffailure
(45Gy) carboplatin/paclitaxel andimpactof
histologyNR
Govindanet Multi-centre Inoperable,ECOG StageIIIAorB, 70Gyin35 CetuximabSR(7 Median MedianOS25.2mo*,
al.[23] phaseII, 0-1,oneoftwo nopleural fractionsof2Gy, weeks)plus4cycles 32mo medianfailure-free
randomised, trialswith effusion,weight noENI carboplatin/ survival12.3mo,4%
US,n=101 mandatoryPET loss≤10% pemetrexedvs.same CR,68%PR,patternsof
CTxwithout failureNR,survivalnot
cetuximab(n=48), influencedbyhistology
afterwards4cyclesof
pemetrexed
RT:radiotherapy;IMRT:intensity-modulatedradiotherapy;CTx:chemotherapy;KPS:Karnofskyperformancestatus;ECOG:EasternCooperativeOncologyGroup
performancestatus;WHO:WorldHealthOrganisationperformancestatus;FEV1:forcedexpiratoryvolume1;V20:lungvolumereceiving20Gy;ENI:electivenodal
irradiation;CetuximabSR:standardregimenwith400mg/m2giveni.v.onday1and250mg/m2ondays8,15,22,29,36and43;OS:overallsurvival;PFS:
progression-freesurvival;PRandCR:partialandcompleteremissionasperRECISTcriteria;NR:notreported;PET:positronemissiontomography
*allresultsrelatetothecetuximabarmofthestudy
radiation dose was 63 Gy in 35 fractions and che- with inoperable stage III NSCLC treated with 74 Gy and
motherapy was administered concurrently and in the concomitant carboplatin/paclitaxel [22]. Median survival
consolidation phase. The authors concluded that treat- was numerically longer in the cetuximab trial but the
ment was feasible and survival longer than any pre- absolute difference was 1 month. The second trial in
viously reported by the RTOG. Median survival was this category was also completed in the US [23]. Several
22.7 months. However, median time to progression was important differences exist (mandatory PET, higher
approximately 14-15 months (estimated from the radiation dose of 70 Gy, only 7 weeks of cetuximab con-
graph). In other words, early cancer progression con- comitant to RT, chemotherapy with carboplatin and
tinues to be common. Moreover, RTOG trial 0117 pemetrexed). Median survival was 25.2 months and fail-
reported median survival of 21.6 months in 44 patients ure-free survival 12.3 months. Given the large
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Table 2Baseline characteristics andadverse events (AE)
Reference Median Performance Stage Weight Histology Adverseevents(AE)
age status loss
Jensenetal. 71years NR II:7% Weightloss Adenocarcinoma: 10%diedbeforecompletingprotocoltreatment(deathunlikely
[16] (57-82) IIIA: <5% 33% relatedtotreatment),50%had≥grade3non-hematologicAE
57% required Squamous:57%
IIIB: Otheror
37% unknown:10%
Jatoietal.[15] 77years 0:22% IIIA: NR Adenocarcinoma: Notreatment-relateddeaths,9%stoppedearlybecauseofAE,
(60-87) 1:57% 59% 38% 53%hadatleastoneAE≥grade3
2:21% IIIB: Squamous:43%
41% Otheror
unspecified:19%
Hallqvistetal. 62years 0:62% IIIA: >5%:37% Adenocarcinoma: Onepneumonitis-relateddeath,18%didnotcomplete
[19] (42-81) 1:38% 37% 49% cetuximaband11%received<68Gy,43%AE≥grade3
IIIB: Squamous:39%
63% Unspecified:12%
Hughesetal. 67.5 0:42% IIIA: NR Adenocarcinoma: Onepneumonia-relateddeath,17%didnotcomplete
[20] years 1:58% 33% 33% cetuximab,17%AE≥grade3
(58-76) IIIB: Squamous:50%
50% Otheror
IV: unspecified:17%
17%
Blumenschein 64years 0:47% IIIA: Weightloss NR 6treatment-relateddeaths,20%didnotcompleteRTand
etal.[21] (42-85) 1:53% 46% <5% concurrentcetuximab,68%had≥grade3non-hematologicAE
IIIB: required
54%
Govindanet 66years 0:34% IIIA: Weightloss Adenocarcinoma: 3treatment-relateddeaths,19%didnotcomplete4cyclesof
al.[23]* (32-81) 1:66% 53% ≤10% 42% CTxand7weeksofcetuximab,62%had≥grade3non-
IIIB: required Squamous:34% hematologicAEand70%≥grade3hematologicAE
47% Otheror
unspecified:25%
NR:notreported;RT:radiotherapy
*datashownareforpatientsinthecetuximabarmofthisrandomisedstudy
differences in study treatment, direct comparison This trial confirmed preclinical results obtained in dif-
appears difficult. It is important to mention that the two ferent in vitro and in vivo models [9-13]. The NSCLC
trials reviewed in this category reported higher rates of studies reviewed in the present article suggest that con-
treatment-related deaths and adverse events than all the ventional fractionated RT (3-D conformal or intensity-
other studies where no concomitant chemotherapy was modulated) to a maximum dose of 70 Gy can safely be
given. However, they also reported encouraging survival combined with cetuximab. With additional concomitant
results, which led the investigators to initiate a confir- chemotherapy, toxicity increases to the high degree that
matory intergroup phase III trial that will clarify the role has been observed in several studies of simultaneous
of additional cetuximab in this setting (RTOG 0617). chemoradiation without cetuximab [1,4,6]. Over 60% of
Compared to other phase II studies without cetuximab, patients developed ≥ grade 3 non-hematologic adverse
the survival results found in the two US trials are good events and comparable figures were reported for ≥
but not exceptional. Table 3 contains a brief summary grade 3 hematologic adverse events, which contributed
of relevant data, including selected arms from rando- to the fact that approximately 20% of patients were
mised trials, illustrating the possibility of impressive sur- unable to complete treatment [21,23]. Importantly, no
vival outcomes with quite different approaches. As randomised head-to-head comparison of any of the 3
mentioned previously, several sources of bias make com- strategies reviewed here (RT plus cetuximab, induction
parisons between all these studies unreliable. Therefore, chemotherapy followed by RT plus cetuximab, concomi-
the present overview can not provide definitive tant chemoradiation plus cetuximab) has yet been pub-
recommendations. lished. Therefore, both toxicity and efficacy results must
be interpreted with caution. Non-randomised head and
Discussion neck cancer studies suggested promising efficacy of
Historically, the added value of cetuximab has been pro- combined cetuximab, RT and chemotherapy [24-26].
ven in a pivotal head and neck cancer radiotherapy trial, However, the phase III trial RTOG 0522 could not con-
which did not include cytotoxic chemotherapy [14]. firm improved progression-free or overall survival when
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Table 3Resultsofother recent chemoradiation trials, unresectable stage III(without cetuximab)
Author,patient Treatment Mediansurvival
number (PFS)
Bepleretal.[41],39 2cyclesinductioncarboplatinandgemcitabine,RTupto74Gy(mean70)withweeklycarboplatin 22.7mo
andpaclitaxel (14.3mo)
Socinskietal.[42],43 2cyclesinductioncarboplatinandpaclitaxel,RT74Gywithweeklycarboplatinandpaclitaxel 24.3mo
Krzakowskietal.[43], 2cyclesinductioncisplatinandvinorelbine,RT66Gywith2cyclescisplatinandvinorelbine 23.4mo
54 (12.5mo)
Sejpaletal.[44],62 Weeklycarboplatinandpaclitaxel,RTmedian74Gywithprotons 24.4mo
Segawaetal.[45],99 RT60Gywith4cyclesofconcomitantcisplatinanddocetaxel 26.8mo
(13.4mo)
Choetal.[46],49 Weeklycarboplatinandpaclitaxel,RT60Gyin25fractions 28.1mo
(13.7mo)
Gandaraetal.[47],83 RT61Gywith2cyclesofconcomitantcisplatinandetoposide,consolidationdocetaxel 26mo
(16mo)
RT:radiotherapy;PFS:progression-freesurvival
cetuximab was added to RT with cisplatin [27]. Conflict- Whether these studies truly suggest that inclusion of
ing results have also been reported for rectal cancer any histologic type of NSCLC into future trials should
[28]. be considered remains an open question, given their
This review does not attempt to provide treatment limited sample size and statistical power. However, indi-
recommendations. Its purpose is to contribute to the vidually tailored treatment has the potential to improve
development of future, large-scale prospective studies. cost-effectiveness and spare patients from unnecessary
Such studies seem warranted mainly in two settings 1) toxicity. Unfortunately, at present no established bio-
RT plus cetuximab in patients who can not tolerate che- marker or histology feature has gained widespread
moradiation, and 2) concomitant chemoradiation plus acceptance. A recent analysis of a phase III study
cetuximab in patients who qualify for such aggressive (BMS099; taxane/carboplatin with or without cetuximab;
regimens. Regarding the latter approach, a randomised no radiotherapy) where tumour samples from 225
intergroup study based on the results of the RTOG trial patients were examined, did not find significant associa-
[21] is under way. A question that will not be answered tions between KRAS and EGFR and various outcome
in this trial is the optimal duration of cetuximab treat- parameters [36]. Also in the phase III FLEX study (cis-
ment, provided there is a definitive benefit from this platin/vinorelbine with or without cetuximab; no radio-
drug. As reviewed here, some groups chose to limit therapy) biomarkers (KRAS, EGFR, PTEN) did not
drug administration to the concomitant phase with RT predict treatment efficacy [37]. On the basis of all avail-
while others continued cetuximab for longer durations. able data, it is not justified to exclude molecular sub-
Given the cost of such treatment, the added value of groups of NSCLC from future RT and cetuximab
extended cetuximab therapy must be proven in appro- studies. However, it is important to conduct additional
priate randomised settings. Other well recognised areas biomarker analyses in these future studies. If EGFR inhi-
of controversy that apply to all NSCLC RT strategies bition increases the clinical efficacy of RT for stage III
including the cetuximab trials, are the role of ENI NSCLC, cetuximab might not be the only agent exerting
[7,8,29], PET for staging and treatment planning this effect. Preliminary experience with tyrosine kinase
[8,30-32], radiation dose escalation [8,18,22] and conso- inhibitors and thoracic RT has been published [38,39].
lidation chemotherapy after chemoradiation [2,33]. The However, these small non-randomised studies suffer
variations in the 6 studies reviewed here nicely illustrate from the same limitations as those reviewed here and
the uncertainties around these issues. None of these stu- have not provided definitive data. Because the presence
dies used accelerated RT regimens or hypofractionation of EGFR mutations in general is predictive of respon-
in combination with cetuximab. However, altered frac- siveness to EGFR tyrosine kinase inhibitors, adenocarci-
tionation RT resulting in shorter overall treatment time noma or NSCLC not otherwise specified should be
is one of the possibilities to improve NSCLC outcomes tested for such alterations [40].
[34,35].
Histology has gained increasing importance for the Conclusions
choice of NSCLC systemic therapy but had no signifi- The results of the 6 published clinical trials (none of
cant influence on survival in the 3 cetuximab plus RT them was a phase III study) suggest that larger rando-
studies that looked at this parameter [16,19,23]. mised trials are warranted, primarily addressing the role
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of cetuximab with RT alone in patients unfit for che- 13. NasuS,AngKK,FanZ,MilasL:C225antiepidermalgrowthfactor
moradiation and combined chemoradiation plus cetuxi- receptorantibodyenhancestumorradiocurability.IntJRadiatOncolBiol
Phys2001,51:474-477.
mab in prognostically better patients. Correlative
14. BonnerJA,HarariPM,GiraltJ,CohenRB,JonesCU,SurRK,RabenD,
biomarker studies should be part of these research BaselgaJ,SpencerSA,ZhuJ,YoussoufianH,RowinskyEK,AngKK:
efforts. Radiotherapypluscetuximabforlocoregionallyadvancedheadand
neckcancer:5-yearsurvivaldatafromaphase3randomisedtrial,and
relationbetweencetuximab-inducedrashandsurvival.LancetOncol
2010,11:21-28.
Authordetails 15. JatoiA,SchildSE,FosterN,HenningGT,DornfeldKJ,FlynnPJ,FitchTR,
1DepartmentofOncologyandPalliativeMedicine,NordlandHospital,Bodø, DakhilSR,RowlandKM,StellaPJ,SooriGS,AdjeiAA:AphaseIIstudyof
Norway.2InstituteofClinicalMedicine,FacultyofHealthSciences,University cetuximabandradiationinelderlyand/orpoorperformancestatus
ofTromsø,Tromsø,Norway.3DepartmentofRadiationOncology,Klinikum patientswithlocallyadvancednon-small-celllungcancer(N0422).Ann
rechtsderIsarderTechnischenUniversitätMünchen,Munich,Germany. Oncol2010,21:2040-2044.
16. JensenAD,MünterMW,BischoffHG,HaselmannR,HaberkornU,HuberPE,
Authors’contributions ThomasM,DebusJ,HerfarthKK:Combinedtreatmentofnonsmallcell
CNandNAparticipatedinthedesignofthestudy.CN,APandAD lungcancerstageIIIwithintensity-modulatedradiotherapyand
performedtheliteraturesearch,extractedrelevantarticlesanddraftedthe cetuximab:TheNEARtrial.Cancer2011,117:2986-2994.
manuscript.Allauthorsreadandapprovedthefinalmanuscript. 17. JeremićB,MiličićB,MilisavljevicS:Clinicalprognosticfactorsinpatients
withlocallyadvanced(stageIII)nonsmallcelllungcancertreatedwith
Competinginterests hyperfractionatedradiationtherapywithandwithoutconcurrent
Theauthorsdeclarethattheyhavenocompetinginterests. chemotherapy:single-institutionexperiencein600patients.Cancer2011,
117:2995-3003.
Received:2September2011 Accepted:11January2012 18. WangL,CorreaCR,ZhaoL,HaymanJ,KalemkerianGP,LyonsS,CeaseK,
Published:11January2012 BrennerD,KongFM:Theeffectofradiationdoseandchemotherapyon
overallsurvivalin237patientswithstageIIInon-small-celllungcancer.
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