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VOLUME 26 • NUMBER 1 • JANUARY 1 2 8

JOURNAL OF CLINICAL ONCOLOGY N A L R E P O R T

From the National Cancer Institute ofCanada Clinical Trials Group, Kingston,Ontario, Canada.

Subnnitted May 30, 2007; acceptedAugust 21 , 2007.

Supported by the Canadian CancerSociety Grant No. 4493, and supportedin part by Grant Nos. CAÍ 61003 fromBristol Myers Squibb IBR 18), CA0432 6from the National Cancer Institute(JBRIO), 12150 from the NationalCancer Institute o f Canada, andCA31946 from the Cancer and Leuke-mia Group B.

Presented at the 42nd Annual Meetingof the American Society of ClinicalOncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Corresponding author: Glenwood G oss,MD , Medical Oncology, The OttawaHospital Regional Cancer Centre, Theuniversity of Ottawa, 503 Smyth Rd,Ottawa, Ontario, Canada, Kl H 1C4;e-mail; [email protected].

© 2008 by American Society of ClinicalOncology

0732 183X/08/2601 -54/ 20.00

DOI; 10.1200/JCO.2007.12.8322

Age and C om orbidity As

Independent Prognostic Factorsin the Treatment of Non-Sm all-Cell Lung Cancer:A Review of National Cancer Institute o fCanada ClinicalTrials Group TrialsTimothy R . Asmis Keyue Ding Lesley Seymour Prances A. Shepherd Natasha B. Leighl Tim WintoMario Whitehead Johanna N. Spaans arbara C. Graham and Glenwood D . Goss

A B S T R A C T

PurposeThis study analyzed patients enrolled in two large, prospectively randomized tr of systemchemotherapy (adjuvant/palliative setting) for non-small-cell lung Cancer (NSCLC). objective was to determine if age and/or the burden of chronic medical conditions (are independent predictors of survival, treatment delivery, and toxicity.Patients and MethodsBaseline com orbid conditions were scored using the Charlson com orbidity indexmeasure of patient comorbidity that is weigh ted according to the influence of comorbiditoverall mortality. The CCI score (CCIS) was correlated with demographic data,(ieperformance status (PS), histology, cancer stage, patient weight, hemoglobin, altase, lactate dehydrogenase, outcomes of chemotherapy delivery (ie, type, total dintensity), survival, and response.ResultsA total of 1,255 patients were included in this analysis. The median age was 61 to 89 years); 34% of patients w ere elderly (at least 65 years of age); and 31 % had comoconditions at randomization. Twenty-five percent of patients had a CCIS of 1, wCCIS of 2 or greater. Elderly patients were more likely to have a CCIS equal to ocompared with younger patients (42% v/26%; P .0001), as were male patients (35% 1^2P .0001) and patients with squamous histology (36% v 29% ; P = ,001). Although ageinfluence overall survival, the CCIS appeared prognostic (CCIS 1 vO; hazard ratio 1.28; 95%Cto 1.5; P = .003).ConclusionIn these large, randomized trials, the presence of com orbid conditions (CCIS > 1), rather thanmore than 65 years, was associated with poorer survival.

J Clin Oncol 26:54 59. © 20 08 by Am erican Society of C linical Oncology

The incidence o non-small-cell lung cancer(NSCLC) increases with age; 60% occur in patientsaged 60 years and older, and 30% to 40 % occur inpatients aged 70 years and older.''^ The median ageof individuals diagnosed with NSCLC in developedcountries is 8 years. ̂Eighty-five pe rcent of pa tientseither present with or eventually will develop ad-vanced or re current NSCLC. In large meta-analyses,the use of chemotherap y in addition to best support-ive care (BSC) has been shown to improve overallsurvival (OS) co mpa red with BSC alone.̂ '^ Survival

benefits from chemo therapy have also been demo n-

strated in trials design ed specifically or elder

patients*'^. Despite this, elderly patients are odenied therapy, prematurely discontinued frtherapy , and excluded from clinical trials becausperceptions that elderly patients are unable to toate aggressive chemotherapy and are more likelsuffer increased toxicity with a resultan t poo r quaof ife.** However, many studies demo nstrate that elderly patient with a good performance status (can tolerate chemothe rapy tha t has similar toxiand benefits as nonelderly patients.' ''^

Although the definition of elderly is the subjeof some debate, two benchmarks are often use

peopled either 65 years and older'^ or 70 years

5



Age and Comorbidity As Prognostic Factors in NSCLC

older.'-' ' ' The age of 70 years has been described as the lower boundar yof senescence, because the incidence of age-related organ dysfunctionand the development of comorbid conditions increase sharply be-tween ages 70 and 75 years.'^ The clinical significance o fth e relation-ship between age and comorbid conditions is complex in patients withcancer. Althoug h chronologic age is associated with certain age-related conditions,'^ chronologic age may not be as clinically relevant

as physiologic age, which also

takes into account the burd en of ch ronicdisease (comorbidity).'*The measurement of comorbidity is challenging. Several scales

for determining the burde n of illness in a particular patient have beenexplored for use in an oncology setting,'^ The Charlson comorbidityindex (CCI) was developed based on a longitudinal study of 559patients who were admitted to a medical service during a 1-month

period, and it has been validated for predicting major comp lications ofsurgery in patients with resectable, stages IA to IIIB NSCLC.^ Thesum of the weighted scores of a ll the como rbid con ditions is used todevelop a CCI score (CCIS),^'

We report here the results of a pooled analysis of two large,prospectively random ized trials of systemic chemotherapy conductedby the National Cancer Institute of Canada Clinical Trials Group(NCIC CTG ) that examined the relationship between age and com or-bidity—specifically, wheth er age and /or co mor bidity are predictive ofchemotherapy-related toxicity and whether age and/or comorbidityare independent predictors of outcome.

PatientsBR 8 was a random ized, phase II/III study of 774 patients with advanced

S C ^ ̂ that compa red paclitaxel and carboplatin plus placebo (n = 386)with the same regimen plus BMS-275291 (n = 388), an oral matrix metallo-

proteinase inhibitor (M MPI), P atients were to receive a maxim um of eightcycles of chemotherapy b ut could continue oral M MPI or placebo thereafteruntil progression or unacceptable toxicity, IBR 10 was a study in which 482patients with com pletely resected, stage IB or II NSCLC were rand om lyassigned to adjuvant vinorelbine and cisplatin chemotherapy (n = 242)or to observation alone (n = 240),^ ' Four cycles of vinorelbine/cispla-t in were p lanned.

CCIS Toxicity an d Objective ResponseBaseline medical conditions and medications were scored using the

CCI^' (Table Al), Laboratory parameters and adverse events were gradedusing the National Cancer Institute Common Toxicity Criteria ExpandedCom mo n Toxicity Criteria (in IBR 10) and version 2.0 ofthe National C ancerInstitute Common Toxicity Criteria toxicity scale (in BR 18), All adverseevents, irrespective of causality, were included in the analyses. Objective re-

sponse (in BR 18 only) was evaluated using the Response Evaluation CriteriaIn Solid Tu mo rs guidelines.

hemotherapy and Dose IntensityFor each drug, the total dose administered was calculated and was sum -

marized by median, minimum, and maximum for each group.

Statistical onsiderationsOS was defined as the time from random ization to death or was censored

at the last known alive date. Progression-free survival (PFS) was defined as th etime from randomization to the time of docum ented disease progression ordeath, whichever came first. Disease-specific survival (DSS) was defined as th edate from randomization to the time of death for those who died of lung canceror of com plications of its treatme nt, and it was censored at the date of death forthose who died of other causes or at the date ofthe last known follow-up, forpatients alive at the time of analysis. Exploratory analyses were perform ed to

characterize the relationship between age and CCIS with baseline charac-teristics and outcomes, including age, sex, race/ethnicity, performancestatus (PS), histology, stage, hemoglobin, alkaline phosphatase, time fromdiagnosis to random assignment, and chemotherapy (type, total dose,survival, and tum or response).

The following factors were assessed in both univariate and multiva-riant analyses for their influence on survival (OS , PFS, and DFS): age ( < 65years v s 65 years), CCIS (0 v v 2-I-), sex, race/ethnicity (w hite v othe rs),PS (0 V 1 V 2-I-), hem oglob in ( a 120 v < 120 g/dL), alkaline phosp hatas(norm al v increased), and time from diagnosis to random assignment( < 6 V a 6 mo nths ). The Cochran-Mantel-Haenszel x^ test was used toassess associations between categorical variables; Kaplan-Meier curveswere used to estimate the distributions of t ime to event outcom es; and theCox regression model stratified by assigned treatment and by disease stagewas used to correlate age, CCIS grou ps, and oth er baseline factors with thetime to event outco me s (OS, PFS, and DS S). The logistic regression mod ewas used to study the effects of age and CCIS on response a nd toxicity whileadjusting for other important prognostic factors. Statistical analyses werecarried out using SAS version 8.1 (SAS Institute, Cary, NC), All reportedP values are two-sided u nless otherwise specified.

A total of 1,255 patients were included in this analysis; 481 (38%)were enrolled onto JBR 10, and 774 (62%) were enrolled onto BR18, One patient was excluded from the analysis because of missingbaseline data. The median age was 61 years (ran ge, 34 to 89 years),and 34% were 65 years or older. Elderly patients were more likelyt h a n n o n e l d e r l y t o h a v e a P S o f > P= .007), squam ous histology(34% V 26%; P = .00 5), time from diagnosis to rand om assignmenof more than 6 months (13% v 5%; P < ,000 1), and com orbidconditions (42% v 26%; P < .0001; Table 1). As listed in Table 1,31% ofpatients had com orbid conditions in addition to NSCLC; 310had a CCIS of 1; and 81 had CCIS of > 2. A greater CCIS wa

associated with male sex (35% v 21%; P < .0001), a worse PS (P =.003), nonadenoca rcinoma histology (P = .001), and a time fi-omdiagnosis to random assignment of more than 6 months (P = .004)Comparison between covariates was performed, and there was noevidence of interaction.

Treatment Delivery and R elated ToxicitiesElderly patients received significantly lower me dian total doses o

chemotherapy (paclitaxel 1,680 mg v 1 410.5 mg, P = ,001; carbopla-tin 3 283 m g V 2,285 mg, P < .0001; cisplatin 610.5 mg v 326 mg,P < .0001; vinorelbine 418 mg v 249 mg, P < .0001) but not oBMS-275291/placebo (Table 2). Patients with a CCIS of or 2 alsoreceived lower median total doses, but the difference was significanonly for paclitaxel and carboplatin (Table 3).

Univariate analysis, stratified by the treatment received, showethat elderly patients were more likely to suffer grade 3 or highetoxicities, including gastrointestinal symptom s (P = .03), neurologisymptoms (P < .001), and fatigue (P = .01). Patients with a com obidity were more likely to have grade 3 or higher gastrointestinatoxicity (P = .02), infection (P = .03), rash (P = .01), or nause( P = . 0 1 ; T able 4).

Objective Response Rate BR 18)Neither age nor comorbidity was predictive of objectiv

response. However, a PS of 0 or (P = .02), squamous histolog(P < .001), stage III disease at diagnosis (P < .001), weight lo

www.jco.org



Asmis et al

Factors

Total participants*No .

SexMaleFemale

Race/ethnicityWhiteOther

ECOG PS012

HistologySquamousAdenocarcinomaOther

Hemoglobin, g/L< 120a: 120

Time from diagnosis to randomassignment, months

< 6£ 6

Alkaline phosphataseNormalIncreased

Abbreyiations: NS, not significant'Median age, 61 years (range, 34

Table 1

< 6 5Years

82766

.6568

6568

706455

607065

6666

6845

6667

3aseline Factors by Age

Age Group ( )

> 6 5Years

42834

3532

3532

303645

4030

, 35

3434

3255

3433

ECOG PS, Eastern Cooperatiye Oncologyto 89 years) for al patients stud ied.

Group and by Comorbidity Index

NS

NS

.007

.005

NS

< .0001

NS

Group performance

0

864

69

6579

6873

756658

647463

7069

7059

7064

status.

Group

Charlson

1

310

25

2718

2524

192733

272227

2425

2527

2429

Comorbidity Index

ä 2

81

6

83

74

579

849

67

614

67

.00

.05

.00

.00

NS

.00

NS

less than 5 (P = ,05), and a serum albumin level greater than35 g/L (P = .004) were significantly associated with a higherresponse rate. In multivariate analyses, PS (P = ,01), histology(P < .001), stage (P = .002), and normal albumin (P = ,02)remained significant.

urviv l

In univariate analyses, age was not prognostic (hazard ratio[HR], 1.03; P = .72; Fig 1 ), but a CCIS > was associated with shorte rsurvival (overall P = .01 [CCIS = v CCIS > 2] ; CCIS = 1: HR, 1,28;95 CI, 1.09 to 1,5; P = .003 [CCIS = vCCIS = 0] ; CCIS > 2: HR,1.09; 9 5 CI, 0.83 to 1.44; P = .52 [CCIS > 2 v CCIS = 0]; Fig 2).Other poor prognostic factors included PS, male sex, increased alka-line phosphatase, and anemia (Table 5), In multivariate Cox regres-

Table 2 Median

Treatment (mg)

BMS-275291/placeboPaclitaxelCarboplatinCisplatinVinorelbine

Cumulatiye Treatment Received by Age

Age Group

< 6 5

99,6001,6803,283

610.5418.1

(years)

a 65

76,2001,410.5

2,285

326248.5

Group

.19

.001< .0001< .0001< .0001

sion models that were stratified by assigned treatment and disestage, age was not prognostic, but a CCIS of was associated sicantly with shorter survival (P = ,03; Table 5). Neither age nor combidity was significantly assoc iated w ith PFS in univariate or multivariate analyses.

In univariate analysis, a trend suggested that a CCIS S; 1 associated with shorter DSS (P = .06) but that age was not(P = ,68), In the multivariate analysis, neither CCI nor age wassignificantly associated with DSS. Ot her base line factors assowith shorter DSS were PS, anemia, elevated serum alkaline phatase, and male sex.

Table 3 Median

Treatment (mg)

BMS-276291/placeboPaclitaxelCarboplatinCisplatinVinorelbine

Cumulative Treatment Received

0

100,8001,6803,060

588384

Abbreviation: CCIS, Charlson Comorbidity

CCIS

1

75,6001,4102,512.3

462318

Index score.

by CCIS

> 1

58,2001,3162,011

368391

.1

.0

.0

.5

.3

J O U R N A L OF CLINICAL O NCO



Age and Comorbidlty As Prognostic Factors in NSCLC

Table 4 Summary of Adverse Events by

Association

Event With Age =: 65 Years

CardiovascularGIInfectionNeurologyPainRashVomitingNauseaStomatitisFatigue

Grades 3 through

YesYesNoYesNoNoNoNoNoYes

5.

Univariate Analysis

by Univariate Analysis

.09

.03

<.OO1

.01

With Comorbidity

YesYesYesNoNoYesNoYesNoNo

.06

.02

.03

.01

.01

Although NSCLC is largely a disease oft he elderly, significant d ispar-ities exist in the delivery of chemotherapy^ '^' and in clinical trialparticipation^*^ for elderly patients, partlybe cause of fears of un acce pt-able toxicity related to com orbid conditions,^ The impacts of age andcomorbid conditions on efficacy and toxicity outcomes of standardchemothera py regimens are imp ortant considerations in clinical prac-tice and in clinical trial design.

In this retrospective analysis of more than 1,200 patients, weconfirmed a relationship between age and com orbidity. Both age andcom orbidity w ere associated with m ore severe toxicity and with lowerchemotherapy dose intensity. This effect was more pronounced forage in the metastatic trial (BR 18), which suggests that patien ts in theadjuvant trial (JBR 10) ma y have been carefully selected. To be eligible

for JBR 10, patients needed to be surgical candidates, which likelyprecluded patients with a serious comorbidity, such as cardiac disease,Comorbidity, but not age, was prognostic and was associated withpoorer OS, This prognostic effect seemed more pronounced for aCCIS of 1, but this observation may be confounded by the selected

100-

„— 8 0 -

15, > 6 0 -

= 4 0 -co >

° 20-

\

\

\\\

0

No, at riskAge < 65 827Age i 65 428

* *•

10

298141

* .

20

Time

20890

~ ~ • • « J

30

A ge 65Ag e > 65

P = . 7 2HR = 1.03(95% C l, 0.89 to 1

40 100

(months)

12350

53 1320 7

,19)

120

00

-

urvv

l

v

ral

No, at rScore =Score =Score >

1 0 0 -

8 0 -

6 0 -

4 0 -

2 0 -

0

sk0 8651 3101 81

20

3189824

40

Time

2206513

- -

-

•• l

60

Score = 0Score = 1Score > 1

CCI 1:P=,D03

HR 1,28(95 CI,1,09to1CCI 2+: P= ,52HR 1.09 (95% C l, 0,83 to

-

80 100

(months)

134336

61 169 23 2

,5)

1.44)

120

000

Fig 1 , Overa l i surv iva l by age . HR, hazard ra t io .

Fig 2, Overall survival by Charlson como rbidity index (CCI) scor e. HR, hazard ratio.

clinical trial population that contained few patients with a CCISgreater than 1, Interestingly, efficacy outcomes were similar in theelderly compa red w ith younger patients, despite lower apparent chem-other apy dose intensity an d higher toxicity, which suggests the lack ofa clear dose-response effect of chemotherapy used for NSCLC,^^ Al-ternatively, elderly patients may have less aggressive disease or mayhave age-related decreases in drug clearance that provide a higher-than-anticipated exposure,̂ *

Our analysis resulted in several observations that are hypothesisgenerating and warrant further research, Male sex was associated witha higher CCIS, but adenocarcinomas were associated with a lowe

CCIS, These results are similar to those reported by Colinet et al,^who used a simplified comorbidity score, although age was prognosticin their study, whereas in ours it was not. Poorer o utcome s in males isa comm on observation in NSCLC clinical trials,' and our studysuggests that this may be accounted for in par t by increased com orbidity. The role that sex-dependent horm one pathways might play ias yet not fiJly understood,'' The observed relationship among ageCCIS, and histological subtype may be related to tobacco use, assquam ous carcinom a is most closely associated with dose and duration of exposure to tobacco. Younger patients may have a shorteexposure to tobacco and may have exposure to a changing tobaccocontent of cigarettes, so they may be less likely to have comorbidityand m ore likely to have ade nocarcinom a,'^

Our study was limited in several respects, because this was retrospective analysis and because both studies excluded patients witpoor S or with significant co morb id cond itions, although PS and thCCIS may not be directly correlate d, Our study population also haa relatively young median age and therefore m ay not b e representativof the larger NSCLC population. Furthermore, the CCI was not designed specifically for patients v«th neoplastic disease, and scales designed specifically for cancer patie nts may be mo re applicable. Va riouauthors have reviewed c omorbidity scales that have been validated ithe elderly,'^'' bu t further wo rk is necessary to develop a validatedoncology-specific comorbidity scale.

In conclusion, although elderly patients who met the entry

criteria for these trials received less chemotherapy, they appeare

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Asmis et a l

Factors

Age group, years2:65< 6 5

Cumulative comorbidityscore

> 210

SexMaieFemale

Race/ethnicityWhiteOther

ECOG PS210

Hemoglobin, g/La 12< 12

Alkaline phosphataseNormalIncreased

HistologyOthersSquamous

Abbreviation: ECOG PS,

Hazard Ratio

1.031

1.091.281

1.271

10.92

2.451.281

11.35

11.32

1.02

Eastern Cooperative

Table 5 Univariate and Multivariate Analysis

Univariate Analysis

95 Cl

0.89 to 1.19

0.83 to 1.441.09 to 1.50

1.08 to 1.48

0.73 to 1.18

89to3 7

1.10 to 1.49

4to 6

2to 1.55

0.87 to 1.20

Oncology Group performance

Log-Rank P

.72

.01

.52

.003

.003

.52

< .0001< .0001

.002

.0007

.0009

.77

status.

for Overall Survival

Hazard Ratio

0.97

0.961.21

1.27

2.241.25

1.30

1.25

Multivariate Analysis

95 Cl

0.84 to 1.13

0.72 to 1.231.02 to 1.42

1.08 to 1.49

Not in multivariate

1.70 to 2.951.06 to 1.46

1.08 to 1.56

1.06 to 1.48

Not in multivariate

Log-Rank

72

.75

.03

.004

< .000.006

.006

.007

to derive the s me benefit s younger patients in terms of OS . Basedon our fin ings and on those of others,' '^ elderly patients shouldnot be denied access to clinical trials nor to effective therapies onthe basis of ge alone. In con trast, the presence of comorbid diseasewas prognostic in this retrospective study and may be a morerelevant selection or exclusion criterion for treatment than chro-nologic age. Further prospective studies should be conducted toexamine the relationship am ong age, comorbidity, and treatmentoutcomes such as efficacy and toxicity to better tailor therapy forindividual patients.

Although all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subjectmatter under consideration in this article. Certain relationships markedwith a U are those for which no compensation was received thoserelationships marked with a C were compensa ted. For a detaileddescription ofthe disclosure categories, or for mo re information aboutASCO 's conflict of interest policy, please refer to the Author isclosure

Declaration and the isclosures of Potential Conflicts of Interest section inInformation for Contributors.

Employment or Leadership Posit ion None Consultant or Advisory

Role None Stock Ownership None Honoraria N o n e ResearchFimding Natasha B. Leighl, GlaxoSmithKline Expert Testimony NoOther Remuneration None

Conception and design Timothy R. Asmis, Keyue Ding, LesleySeymour, Frances A. Shepherd, Natasha B. Leighl, Glenwood D . GoAdministrative support Lesley Seymour, Mario Whitehe adProvision ofstu dy materials or patients Lesley Seymo ur, Franc es AShepherd, N atasha B. Leighl, Tim L. Win tonCollection and assembly of data Timothy R. Asmis, Natasha B. Leig

Mario Whitehead, Barbara G. GrahamData analysis and interpretation Timothy R. Asmis, Keyue Ding, LSeymour, Frances A. Shepherd, Johann a N. Spaans, Barbara G. GraGlenwood D. GossManuscript writing Timothy R. Asmis, Lesley Seymour, Frances A.Shepherd, Johanna Spaans, Glenwood D. GossFinal approval of manuscript Timothy R. Asmis, Keyue Ding, LeSeymour, Frances A. Shepherd , Natasha B. Leighl, Tim L. Win toMario Whi tehead, Johanna N. Spaans , Barbara G. Graham,Glenwood D. Goss

58 JOURNAL OF CLINICAL ONCO



ge an d Co morb id i ty s Prognostic Factors in NSCLC

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knowledgmentThe following institutions participated in the study: The Eastern Cooperatative Oncology Gr oup , the Southwest Oncology Grou p, and t

Cancer and Leukemia Gro up B participated in JBRIO.

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