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Adjuvant Chemotherapy for Non–Small-Cell Lung
Cancer in the Elderly: A Population-Based Study in
Ontario, Canada
Sinead Cuffe, Christopher M. Booth, Yingwei Peng, Gail E. Darling, Gavin Li, Weidong Kong,
William J. Mackillop, and Frances A. Shepherd
Listen to the podcast by Dr Langer at www.jco.org/podcasts
Sinead Cuffe and Frances A. Shepherd,
Princess Margaret Hospital, University
Health Network and the University of
Toronto; Gail E. Darling, Toronto General
Hospital, University Health Network and
the University of Toronto, Toronto; Christo-
pher M. Booth, Yingwei Peng, Gavin Li,
Weidong Kong, and William J. Mackillop,
Queens University Cancer Research Insti-
tute; and Christopher M. Booth, Gavin Li,
Weidong Kong, and William J. Mackillop,
Institute for Clinical Evaluative Sciences
Research Facility, Kingston, Ontario,
Canada.
Submitted September 2, 2011; accepted
December 20, 2011; published online
ahead of print at www.jco.org on April 23,
2012.
Parts of this material are based on data and
information provided by Cancer Care
Ontario. However, the analysis, conclu-
sions, opinions, and statements expressed
herein are those of the authors and not
necessarily those of Cancer Care Ontario.
No endorsement by the Institute for Clini-
cal Evaluative Sciences or the Ontario
Ministry of Health and Long-Term Care is
intended or should be inferred.
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article.
Corresponding author: Sinead Cuffe, MD,
Department of Medical Oncology, Princess
Margaret Hospital, 610 University Ave,
Toronto, Ontario, Canada M5G 2M9;
e-mail: sinead.cuffe@uhn.on.ca.
© 2012 by American Society of Clinical
Oncology
0732-183X/12/3015-1813/$20.00
DOI: 10.1200/JCO.2011.39.3330
ABSTRACT
Purpose
Non–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective
analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung
Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant
chemotherapy. However, the elderly were under-represented in these studies, raising concerns
regarding the reproducibility of the study results in clinical practice.
Patients and Methods
By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with
surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of
chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ⱖ80 years. As
a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to
2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of
surgery served as a proxy of severe chemotherapy-related toxicity.
Results
In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age ⱖ70 years). Uptake of adjuvant
chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among
evaluable elderly patients, 70% received cisplatin and 28% received carboplatin-based regimens. Require-
ments for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates
within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age ⬍70 years; 27.8%
for patients age ⱖ70 years; P⫽.54). Four-year survival of elderly patients increased significantly (47.1% for
patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P⫽.01). Survival
improved in all subgroups except patients age ⱖ80 years.
Conclusion
Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following
reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger
than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant
survival benefit in the elderly (age ⱖ70 years), with tolerability apparently similar to that of patients
who are younger than age 70 years.
J Clin Oncol 30:1813-1821. © 2012 by American Society of Clinical Oncology
INTRODUCTION
Non–small-cell lung cancer (NSCLC) is predomi-
nantly a disease of the elderly, with a median age at
diagnosis of 70 years.
1
With increasing life expec-
tancy and population aging, it is predicted that there
will be 67% more patients with lung cancer who are
age ⱖ65 years by 2030.
2
Furthermore, lung cancer
mortality rates are rising in elderly females, and the
decline in mortality of elderly men lags behind im-
provements seen in younger patients.
3
Since the
mean remaining life expectancy of a 70-year-old is
approximately 15 years, an opportunity exists to im-
prove outcomes in this population, particularly in
early stages in which potentially curative thera-
pies exist.
4
Surgery is increasingly being offered to elderly
patients with NSCLC, and survival outcomes are
similar to those of younger patients.
5-9
However,
relapse is common, with 5-year overall survival less
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
VOLUME 30 䡠NUMBER 15 䡠MAY 20 2012
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than 50%.
10
Recently, randomized trials and meta-analyses have es-
tablished cisplatin-based adjuvant chemotherapy as standard of care
in resected stage II to IIIA NSCLC.
11-15
Although no elderly-specific
trials of adjuvant chemotherapy in NSCLC have been reported, retrospec-
tive analyses of the National Cancer Institute of Canada Clinical Trials
Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation
(LACE) meta-analysis suggest that older patients benefit from treat-
ment with acceptable toxicity.
16,17
However, the elderly were under-
represented in these studies, leading to lack of statistical power.
The elderly typically have more comorbidities and age-related organ
dysfunction, which may lead to difficulty tolerating combination chemo-
therapy.
18
Because clinical trials traditionally exclude such elderly pa-
tients,
19
toxicities of new treatments may be higher than expected when
administered to the elderly in general practice. In addition, uncertainty
regarding the benefits and risks of treatment in the elderly may lead to
reluctance to implement therapy within that subgroup.
Population-based cohort studies provide an opportunity to eval-
uate whether new treatments have been adopted in general practice
and to analyze associated benefits and toxicities.
20,21
Because ad-
vanced age is known to be a negative predictor of referral of patients
with NSCLC to medical oncology,
22,23
it is possible that potentially
curative adjuvant chemotherapy may be underutilized in the elderly.
There is little knowledge of how early-stage NSCLC is managed in
general practice, with previous reviews often being those of single
institutions or antedating reporting of pivotal adjuvant trials.
24-29
Here, we evaluate the uptake of adjuvant chemotherapy by age among
patients with surgically resected NSCLC.
PATIENTS AND METHODS
Study Design and Population
This population-based, retrospective cohort study was designed to evaluate
the uptake and outcome of adjuvant chemotherapy, by age, among patients with
surgically resected NSCLC in Ontario, a province with approximately 11 million
residents representing 38.5% of Canada’s population. It has a single-payer univer-
sal health insurance program. All incident patients with NSCLC diagnosed in
Ontario and undergoing surgery within 24 weeks of diagnosis from 2001 to 2006
were eligible, excluding patients treated with preoperative radiotherapy or chem-
otherapy. Because adjuvant chemotherapy for NSCLC was not adopted as stan-
dard until about 2004, we divided our population into pre- (diagnosis from 2001 to
2003) and postadoption (diagnosis from 2004 to 2006) cohorts. Elderly patients
were defined as age ⱖ70 years. To account for potential heterogeneity, we subdi-
vided the elderly into three age subgroups: 70 to 74, 75 to 79, and ⱖ80 years. This
study was approved by the research ethics boards of Queen’s University and the
University Health Network in Toronto.
Data Sources
The population-based Ontario Cancer Registry captured diagnostic and
demographic information on approximately 98% of incident patients with
cancer in the province and provided the following: International Classification
of Diseases, Ninth Revision (ICD-9) code, ICD Ontario histology code, dates
of birth and diagnosis, place of residence at diagnosis, and date and cause of
death. Complete data were available up to October 2008. The Ontario Cancer
Registry was linked to other electronic databases.
30
The Canadian Institute for
Health Information provided information regarding hospitalizations, physi-
cian providers, and surgical procedures. Socioeconomic status was derived
from Statistics Canada. Chemotherapy physician billing codes from the On-
tario Health Insurance Plan database captured all patients receiving chemo-
therapy. The clinical databases of Cancer Care Ontario’s regional cancer
centers provided details of chemotherapy delivery to the approximately 50%
of patients treated in these centers.
Definitions of Comorbidity, Management, and Outcomes
Comorbidity was classified by using a modified Charlson index based on
non-cancer diagnoses recorded on any hospital admission within 5 years before
surgery. Surgical resection was defined as pneumonectomy, lobectomy, or seg-
mentectomy. A minimum length of stay was set at 3 days; patients who died during
that period were included to account for early postoperative deaths. Adjuvant
chemotherapy was defined as chemotherapy begun within 16 weeks following
surgery. Hospitalization records were used to evaluate treatment- and disease-
related toxicity by comparing frequency and duration of hospitalizations within 6
months of surgery. The primary end point was 4-year overall survival.
Statistical Analysis
Overall survival was determined by using the Kaplan-Meier method.
Differences between age groups and across time cohorts were analyzed by
using the log-rank test. Factors associated with receipt of chemotherapy were
evaluated by using the
2
or Fisher’s exact tests for univariable analysis and
logistic regression for multivariable analyses. Prespecified covariables with
univariable Pvalues less than .1 were entered into multivariable analyses.
Stepwise selection was used with a significance level for entry and exit Pvalues
of .10. Analyses were performed by using SAS 9.1 (SAS Institute, Cary, NC).
RESULTS
Study Population
Among 28,862 incident patients with NSCLC diagnosed in On-
tario from 2001 to 2006, 6,570 underwent surgical resection. There
was a significant increase in the proportion of surgical patients who
were elderly (42.5% from 2001 to 2003 to 45.0% from 2004 to 2006;
P⫽.006). After excluding 266 patients (4%) treated with preoperative
therapy, the final study population consisted of 6,304 patients, of
whom 2,763 (43.8%) were elderly. Table 1 provides patient character-
istics by age. Older patients were more likely to be male (P⬍.001),
have more comorbidities (P⬍.001), and required longer postopera-
tive inpatient stays (P⬍.001). They were less likely to be treated at
regional cancer centers (P⬍.001) or to undergo pneumonectomy
(P⬍.001). Squamous histology was more frequent and adenocarci-
noma was less common in the elderly (P⬍.001).
Adoption of Adjuvant Chemotherapy
Uptake of adjuvant chemotherapy among the elderly increased
significantly (3.3% from 2001 to 2003; 16.2% from 2004 to 2006). The
likelihood of receiving chemotherapy during 2004 to 2006 signifi-
cantly declined with advancing age: 42.7% for those younger than 70
years; 23.1%, 70 to 74 years; 13.3%, 75 to 79 years; and 4.6%, ⱖ80
years (P⬍.001; Table 2). Elderly patients with shorter postoperative
inpatient stays were more likely to receive adjuvant chemotherapy
(P⫽.021; Table 3). In keeping with guidelines, stage II to III elderly
patients were more likely to be treated (P⬍.001). There were signifi-
cant provincial regional variations in chemotherapy delivery to the
elderly, varying from 9.3% to 28.4%. In multivariable analysis, geo-
graphic location (P⬍.001), pathologic stage (P⬍.001), and advanc-
ing age (P⬍.001) remained significant for receipt of adjuvant
chemotherapy. There was no significant association for comorbidity
score in the elderly, although there was a trend for patients with at least
three comorbidities not to receive treatment.
Chemotherapy
Details of chemotherapy delivery were available for 584 pa-
tients treated at Cancer Care Ontario’s regional cancer centers
(Table 4). Cisplatin-vinorelbine, the treatment of choice across all
Cuffe et al
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
age groups, was administered to more than two thirds of the pa-
tients. However, use of carboplatin-based regimens, particularly
carboplatin-paclitaxel, increased significantly with advancing age: 7%
for patients younger than 70 years; 18%, 70 to 74 and 74 to 79 years;
29%, older than 80 years (P⫽.007).
Chemotherapy appeared to be tolerated equally well across all
ages. Rates of substitution of carboplatin for cisplatin (P⫽.22) or
other chemotherapy drug changes (P⫽.63) did not vary significantly by
age. Of all evaluable patients, 29.6% required chemotherapy dose modi-
fications; however, the frequency of dose reduction (P⫽.53) and/or
omissions (P⫽.48) did not vary significantly by age.
Outcomes
There was an increase in the proportion of elderly patients diag-
nosed with NSCLC in Ontario (38.6% from 1992 to 1995; 47.8% from
2004 to 2006). Similarly, the proportion of elderly patients with
Table 1. Demographics and Clinical Characteristics of Patients Diagnosed With NSCLC Who Underwent Surgical Resection in Ontario From 2001 to 2006
by Age Group
Characteristic
Age (years)
⬍70
(n ⫽3,541)
70-74
(n ⫽1,317)
75-79
(n ⫽980)
ⱖ80
(n ⫽466)
PNo. % No. % No. % No. %
Sex ⬍.001
Male 1,766 50 744 57 559 57 250 54
Female 1,775 50 573 44 421 43 216 46
Charlson comorbidity index ⬍.001
0 2,749 78 901 68 618 63 291 62
1-2 701 20 351 27 303 31 149 32
ⱖ3 913 655596266
Time cohort .0056
2001-2003 1,697 48 623 47 446 46 184 40
2004-2006 1,844 52 694 53 534 55 282 61
Socioeconomic status
ⴱ
.1974
Q1 779 22 298 23 208 21 97 21
Q2 856 24 346 26 218 22 99 21
Q3 742 21 283 22 215 22 97 21
Q4 639 18 205 16 180 18 92 20
Q5 514 15 182 14 157 16 81 17
Surgery ⬍.001
Pneumonectomy 529 15 150 11 111 11 30 6
Lobectomy 2,069 58 777 59 598 61 290 62
Segmentectomy 943 27 390 30 271 28 146 31
Median No. of days LOS after surgery 6 7 7 8 ⬍.001
Histologic subtype ⬍.001
Adenocarcinoma 2,079 59 680 52 477 49 240 52
Squamous carcinoma 988 28 470 36 379 39 161 35
Large-cell carcinoma 83 2 22 2 21 2 10 2
Mixed 96 3 27 2 26 3 7 2
Carcinoma NOS 295 8 118 9 77 8 48 10
Pathologic stage ⬍.001
I 496 14 177 13 106 11 37 8
II 271 8 85 7 57 6 25 5
III 246 7 57 4 48 5 16 3
IV 146 4 31 2 20 2 9 2
Unknown 2,382 67 967 73 749 76 379 81
Referral to regional cancer centre ⬍.001
Yes 1,919 54 645 49 435 44 182 39
No 1,622 46 672 51 545 56 284 61
Adjuvant chemotherapy ⬍.001
Yes 939 27 191 15 81 8 13 3
No 2,602 74 1,126 86 899 92 453 97
Postoperative radiotherapy ⬍.001
Yes 462 13 106 8 47 5 22 5
No 3,079 87 1,211 92 933 95 444 95
NOTE. Percentages may not add to 100% because of rounding.
Abbreviations: LOS, length of stay; NOS, not otherwise specified; NSCLC, non–small-cell lung cancer.
ⴱ
By quintiles 1-5 (Q1-Q5) based on community median household income reported in the 2001 Canadian census. Q1 represents the communities where the poorest 20% of the
Ontario population resided. Percentages may not add up to 100% given that socioeconomic status data were not available for a small proportion of patients.
Adjuvant Chemotherapy for NSCLC in the Elderly
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NSCLC undergoing surgery increased from 33% in 1992 to 1995 to
44.6% in 2004 to 2006.
During the study period, 4-year survival for all patients with surgical
resections improved (52.5% in 2001 to 2003; 56.1% in 2004 to 2006;
P⫽.001). Four-year survival of elderly patients also improved (47.1% in
2001 to 2003; 49.9% in 2004 to 2006; P⫽.01), suggesting possible benefit
from adoption of adjuvant chemotherapy. The hazard ratio (HR) of
mortality in the post- versus preadoption cohorts was 0.85 (95% CI, 0.76
to 0.94) for patients younger than 70 years, 0.83 (95% CI, 0.71 to 0.98) for
patients age 70 to 74 years, 0.84 (95% CI, 0.70 to 1.00) for patients age 75
to 79 years, and 1.00 (95% CI, 0.77 to 1.3) for patients age ⱖ80 years
(Fig 1).
We evaluated hospital admission within 6 months of surgery
as a proxy measure of treatment-related toxicity (Table 5). Hospi-
talization rates for elderly patients declined from 40.0% in 2001 to
2003 to 38.3% in 2004 to 2006, suggesting that adoption of chem-
otherapy was well tolerated. During 2004 to 2006, elderly patients
were significantly more likely to be hospitalized within 6 weeks of
surgery than their younger counterparts (P⬍.001), possibly sug-
gesting increased postoperative morbidity in this population.
Table 2. Variables Associated with Use of ACT Among 3,354 Surgical Patients With NSCLC in Ontario From 2004 to 2006
Variable
Total No.
of Patients
% of Patients
With ACT
Univariate Analysis Multivariate Analysis
OR 95% CI POR 95% CI P
Age, years
⬍70 1,844 43 Ref Ref
70-74 694 23 0.4 0.3 to 0.5 ⬍.001 0.4 0.3 to 0.5 ⬍.001
75-79 534 13 0.2 0.2 to 0.3 ⬍.001 0.2 0.2 to 0.3 ⬍.001
ⱖ80 282 5 0.07 0.04 to 0.1 ⬍.001 0.07 0.04 to 0.1 ⬍.001
Sex
Male 1,718 30 Ref
Female 1,636 32 1.1 0.9 to 1.3 .30
Charlson comorbidity index
0 2,460 33 Ref Ref
1-2 764 25 0.7 0.6 to 0.8 ⬍.001 0.8 0.7 to 1.0 .08
ⱖ3 130 15 0.3 0.2 to 0.6 ⬍.001 0.5 0.3 to 0.8 .004
Socioeconomic statusⴱ†
Q1 717 29 Ref Ref
Q2 783 35 1.4 1.1 to 1.7 .01 1.4 1.1 to 1.8 .01
Q3 718 30 1.1 0.8 to 1.3 .65 1.0 0.8 to 1.3 .95
Q4 603 29 1.0 0.8 to 1.3 .77 1.0 0.8 to 1.3 .99
Q5 529 31 1.1 0.9 to 1.4 .33 1.0 0.8 to 1.4 .88
Surgery
Pneumonectomy 398 47 2.1 1.7 to 2.6 ⬍.001 1.6 1.3 to 2.1 ⬍.001
Lobectomy 2,007 30 Ref Ref
Segmentectomy 949 26 0.8 0.7 to 1.0 .02 0.8 0.7 to 1.0 .05
Length of postoperative hospital stay
⬍Median 1,648 35 Ref Ref
ⱖMedian 1,706 27 0.7 0.6 to 0.8 ⬍.001 0.8 0.7 to 0.9 .01
Histologic subtype
Adenocarcinoma 1,830 31 Ref
Squamous carcinoma 1,018 29 0.9 0.8 to 1.1 .50
Large-cell carcinoma 72 32 1.1 0.6 to 1.8 .79
Mixed 102 36 1.3 0.9 to 2.0 .22
Carcinoma NOS 332 35 1.2 1.0 to 1.6 .11
Pathologic stage
I 581 36 Ref Ref
II 281 66 3.4 2.5 to 4.6 ⬍.001 3.8 2.8 to 5.3 ⬍.001
III 215 61 2.8 2.0 to 3.8 ⬍.001 3.0 2.1 to 4.2 ⬍.001
IV 128 38 1.1 0.7 to 1.6 .75 0.9 0.6 to 1.4 .70
Unknown 2,149 21 0.5 0.4 to 0.6 ⬍.001 0.5 0.4 to 0.6 ⬍.001
Geographic region of Ontario†
A 1,386 30 Ref Ref
B 502 22 0.7 0.5 to 0.9 .001 0.5 0.4 to 0.6 ⬍.001
C 291 38 1.4 1.1 to 1.8 .01 0.8 0.6 to 1.1 .15
D 335 28 0.9 0.7 to 1.2 .59 0.5 0.4 to 0.7 ⬍.001
E 73 44 1.8 1.1 to 3.0 .01 1.2 0.7 to 2.1 .54
F 106 35 1.3 0.8 to 1.9 .28 0.7 0.5 to 1.2 .21
G 207 37 1.4 1.0 to 1.8 .05 0.9 0.6 to 1.2 .47
H 452 35 1.3 1.0 to 1.6 .05 0.8 0.6 to 1.1 .21
Abbreviations: ACT, adjuvant chemotherapy; NOS, not otherwise specified; NSCLC, non–small-cell lung cancer; OR, odds ratio; Ref, reference group.
ⴱ
By quintiles 1-5 (Q1-Q5) based on community median household income reported in the 2001 Canadian census. Q1 represents the communities where the
poorest 20% of the Ontario population resided.
†Percentages may not add up to 100% given that data were not available for a small proportion of patients.
Cuffe et al
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
However, in the critical 6 to 24 weeks postsurgery, when adjuvant
chemotherapy was likely to be delivered, hospitalization rates did
not vary significantly by age (P⫽.54).
DISCUSSION
The elderly constitute an increasing proportion of patients with NSCLC,
yet there is a lack of data regarding optimal management of early-stage
disease in this population, despite the availability of potentially cura-
tive therapies. Indeed, guidelines from Cancer Care Ontario and the
American Society of Clinical Oncology highlight the lack of data
concerning adjuvant chemotherapy in patients age ⱖ75 years, citing
insufficient evidence to make recommendations.
31
In this study, we
have addressed some of the uncertainties surrounding adjuvant treat-
ment in the elderly.
We have demonstrated increased uptake of adjuvant chemother-
apy among elderly patients with NSCLC from 3.3% in 2001 to 2003 to
Table 3. Variables Associated With Use of ACT Among 1,510 Surgical Patients With NSCLC Age ⱖ70 Years in Ontario From 2004 to 2006
Variable
Total No.
of Patients
% of Patients
With ACT
Univariate Analysis Multivariate Analysis
OR 95% CI POR 95% CI P
Age, years
70-74 694 23 Ref Ref
75-79 534 13 0.5 0.4 to 0.7 ⬍.001 0.5 0.4 to 0.7 ⬍.001
ⱖ80 282 5 0.2 0.1 to 0.3 ⬍.001 0.2 0.1 to 0.3 ⬍.001
Sex
Male 821 16 Ref
Female 689 16 1.0 0.7 to 1.3 .74
Charlson comorbidity index
0 1,004 17 Ref
1-2 428 15 0.8 0.6 to 1.2 .29
ⱖ3 78 9 0.5 0.2 to 1.0 .06
Socioeconomic statusⴱ†
Q1 322 17 Ref
Q2 346 20 1.2 0.8 to 1.8 .30
Q3 329 14 0.8 0.5 to 1.2 .28
Q4 270 13 0.7 0.4 to 1.1 .13
Q5 242 16 0.9 0.6 to 1.4 .66
Surgery
Pneumonectomy 137 23 1.5 1.0 to 2.4 .05
Lobectomy 924 17 Ref
Segmentectomy 449 13 0.8 0.6 to 1.1 .10
Length of postoperative hospital stay
⬍Median 629 19 Ref Ref
ⱖMedian 881 14 0.7 0.5 to 1.0 .02 0.8 0.6 to 1.0 .10
Histologic subtype
Adenocarcinoma 748 16 Ref
Squamous carcinoma 537 16 1.0 0.7 to 1.4 .95
Large-cell carcinoma 31 10 0.6 0.2 to 2.0 .38
Mixed 41 22 1.5 0.7 to 3.3 .27
Carcinoma NOS 153 21 1.4 0.9 to 2.2 .10
Pathologic stage
I 233 21 Ref Ref
II 108 44 3.0 1.8 to 4.9 ⬍.001 3.6 2.1 to 6.3 ⬍.001
III 74 45 3.1 1.8 to 5.4 ⬍.001 4.7 2.5 to 8.9 ⬍.001
IV 38 21 1.0 0.4 to 2.4 .95 1.3 0.5 to 3.2 .57
Unknown 1,057 10 0.4 0.3 to 0.6 ⬍.001 0.5 0.3 to 0.7 ⬍.001
Geographic region of Ontario†
A 654 15 Ref Ref
B 246 9 0.6 0.4 to 0.9 .03 0.4 0.2 to 0.7 ⬍.001
C 113 27 2.1 1.3 to 3.4 .002 1.4 0.8 to 2.5 .21
D 139 14 0.9 0.5 to 1.5 .66 0.4 0.2 to 0.8 .01
E 33 24 1.8 0.8 to 4.1 .16 1.2 0.5 to 3.1 .69
F 49 12 0.8 0.3 to 1.9 .58 0.4 0.2 to 1.1 .08
G 81 28 2.2 1.3 to 3.8 .003 1.6 0.9 to 2.9 .13
H 194 18 1.2 0.8 to 1.9 .33 0.8 0.5 to 1.3 .37
Abbreviations: ACT, adjuvant chemotherapy; NOS, not otherwise specified; NSCLC, non–small-cell lung cancer; OR, odds ratio; Ref, reference group.
ⴱ
By quintiles 1-5 (Q1-Q5) based on community median household income reported in the 2001 Canadian census. Q1 represents the communities where the
poorest 20% of the Ontario population resided.
†Percentages may not add up to 100% given that data were not available for a small proportion of patients.
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16.2% in 2004 to 2006. This coincides with the reporting of pivotal adju-
vant chemotherapy trials and suggests that physicians are guided by and
are willing to adopt emerging evidence. However, the 16.2% uptake in the
elderly remains significantly lower than the 42.7% uptake in younger
patients. Furthermore, use of adjuvant chemotherapy among the elderly
remains substantially lower than among younger patients despite control-
ling for comorbidity. Our results are comparable to those of another
study
29
in which adjuvant chemotherapy was administered to 44% of
patients with NSCLC who were less than age 65 years, 18% age 65 to 75
years, and 9% older than 75 years. Disparities in the postoperative referral
of older patients with NSCLC, as well as elderly patients with other tumor
types, to medical oncology have been reported previously.
23,29,32,33
Inter-
estingly, patients frequently do not receive adjuvant chemotherapy be-
cause of patient refusal.
23
Because of the constraints of our data sources,
rates of patient refusal could not be analyzed.
We also show that the chemotherapy regimens used in the elderly
largely adhere to those validated by phase III trials, with cisplatin-
vinorelbine administered to approximately 70% of patients. Previous
studies have demonstrated survival benefits for adjuvant cisplatin-
vinorelbine in NSCLC, with absolute 5-year survival improvements
ranging from 8.6% to 15%.
12,13,34
However, the elderly represented
just 9% of patients in the LACE meta-analysis and ⱕ15% in other
studies. No elderly-specific adjuvant chemotherapy trials have been
reported. Nonetheless, retrospective subgroup analysis of JBR.10 con-
firmed a survival benefit for cisplatin-vinorelbine in patients older
than age 65 years (HR, 0.61; P⫽.04).
16
Elderly patients also were
shown to benefit from cisplatin-based chemotherapy in the LACE
meta-analysis of elderly patients.
17
The use of carboplatin-based regimens, particularly carboplatin-
paclitaxel, increased with advancing age. The only phase III study to
evaluate carboplatin in the adjuvant setting was Cancer and Leukemia
Group B (CALGB) 9633,
35
which compared carboplatin-paclitaxel to
observation in stage IB NSCLC. Although early results suggested a
significant survival advantage for chemotherapy, the benefit became
insignificant with longer follow-up (HR, 0.83; P⫽.12). Because of
early closure, CALGB 9633 with only 344 patients lacked the necessary
power to confirm that a 17% reduction in the risk of death was
statistically significant. Possibly, Ontario oncologists felt that with this
degree of potential survival benefit, using carboplatin-paclitaxel in the
elderly was justifiable in view of its favorable toxicity profile and
convenient administration schedule. In advanced NSCLC, meta-
analyses have shown that carboplatin-based regimens are inferior to
those containing cisplatin.
36,37
Although it is possible that a potential
trade-off of tolerability for response may translate to a survival benefit
for adjuvant carboplatin-based chemotherapy in the elderly by in-
creasing the number of patients treated, cisplatin-based regimens
must remain standard in other populations.
Concern regarding comorbidities and tolerability of treatment is
believed to underlie reluctance to recommend adjuvant chemotherapy in
the elderly.
23,38
Although we could not demonstrate statistically signifi-
cant differences, it appears that physicians were influenced by comorbid-
ity, with chemotherapy given to 17% of elderly patients without
comorbidities and only 9% of patients with at least three comorbidities
(P⫽.06). In a pooled analysis of trials conducted by the National Cancer
Institute of Canada (NCIC) Clinical Trials Group in NSCLC,
39
patients
with at least one comorbidity received lower median doses of chemother-
apy and experienced greater toxicity than those without comorbidities.
Furthermore, the presence of comorbid conditions was shown to be
prognostic of poorer outcome, independently of age.
Treatment appeared to be well tolerated across all age groups
with no significant differences observed in rates of modification of
chemotherapy drugs or dosages during subsequent cycles. These
findings contrast with the age-dependent decreased tolerability of
cisplatin-containing regimens observed in the retrospective re-
views of elderly patients in the LACE elderly meta-analysis and
JBR.10 trial.
16,17
When taking into account the increased use of
carboplatin-based chemotherapy in the elderly in our study, it ap-
pears that physicians are adapting their choice of chemotherapy
to the perceived tolerability in individual patients quite success-
fully in clinical practice.
Table 4. Summary of Chemotherapy Delivered Among 584 Patients Treated at Regional Cancer Centers From 2004 to 2006 by Age Group
Chemotherapy Characteristic
Age (years)
⬍70
(n ⫽454)
70-74
(n ⫽84)
75-79
(n ⫽39)
ⱖ80
(n ⫽7)
PNo. % No. % No. % No. %
Chemotherapy regimen
ⴱ
.005
Cisplatin-based 387 85 60 71 26 67 5 71
Carboplatin-based 62 14 22 26 13 33 2 29
No cisplatin or carboplatin 5 1 2 2 0 0 0 0
Specific regimens
ⴱ
.007
Cisplatin-vinorelbine 326 72 55 65 26 67 5 71
Carboplatin-vinorelbine 18 4 5 6 4 10 0 0
Carboplatin-paclitaxel 31 7 15 18 7 18 2 29
Cisplatin-etoposide 42 9 3 4 0 0 0 0
Other 37 8 6 7 2 5 0 0
Regimen modification
Cisplatin changed to carboplatin 8 2 0 0 2 5 0 0 .22
Change in drugs used 25 6 2 2 2 5 0 0 .63
Dose reduction† 110/406 27 23/76 30 11/34 32 0/4 0 .53
Omitted dose† 119/406 29 16/76 21 11/34 32 1/4 25 .48
ⴱ
Refers to regimen used in first cycle of adjuvant chemotherapy.
†Evaluated among the 520 patients for whom drug dosages were identifiable from existing data sources.
Cuffe et al
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
Our comparison of hospitalization rates pre- and postadoption,
suggests that uptake of adjuvant chemotherapy in the elderly does not
appear to be associated with an increase in severe toxicity. In fact, we
observed a significant reduction in the numbers of elderly patients
hospitalized within 6 months of surgery between 2001 to 2003 and
2004 to 2006, despite a corresponding increase in adjuvant chemother-
apy administration. Furthermore, there were no significant differences
in hospitalizations by age group 6 to 24 weeks postoperatively when
adjuvant chemotherapy was most likely to be delivered. In con-
trast, hospitalization in the 6-week postoperative period increased
significantly by age, suggesting more postoperative complications
in this population. Previous studies evaluating postoperative mor-
bidity in elderly patients with NSCLC have shown conflicting
results: some studies support an association between increased
postoperative complications and advancing age,
40,41
and others
do not.
8,42
B
012345
Overall Survival (%)
Time From Surgery (years)
20
40
60
80
100
2001-2003
2004-2006
A
012345
Overall Survival (%)
Time From Surgery (years)
20
40
60
80
100
2001-2003
Diagnosis Year Diagnosis Year
Diagnosis Year Diagnosis Year
HR, 0.85; 95% CI, 0.76 to 0.94; P ;79.0 ot 87.0 ,IC %59 ;78.0 ,RH6200. = P = .0123
HR, 0.83; 95% CI, 0.71 to 0.98; P ;00.1 ot 07.0 ,IC %59 ;48.0 ,RH1720. = P = .0517
2004-2006
D
Overall Survival (%)
Time From Surgery (years)
2001-2003
2004-2006
C
012345
Overall Survival (%)
Time From Surgery (years)
20
40
60
80
100
2001-2003
2004-2006
Diagnosis Year
HR, 1.00; 95% CI, 0.77 to 1.30; P = .9888
E
012345
Overall Survival (%)
Time From Surgery (years)
20
40
60
80
100
2001-2003
2004-2006
012345
20
40
60
80
100
Fig 1. Overall survival of patients with surgically resected non–small-cell lung cancer in Ontario between 2001 to 2003 and 2004 to 2006 by age group. (A) Younger
than age 70 years versus (B) ⱖ70 years; (C) 70 to 74 years; (D) 75 to 79 years; and (E) ⱖ80 years. HR, hazard ratio.
Adjuvant Chemotherapy for NSCLC in the Elderly
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Most importantly, elderly patients appear to derive significant
survival benefit from adjuvant chemotherapy, with a 2.8% absolute
improvement in survival at 4 years between the pre- and postadoption
cohorts. Since only 16.2% of elderly patients received chemotherapy
in 2004 to 2006, this figure may underestimate the true benefit of
adjuvant chemotherapy in this population. Indeed, compared with
younger patients, the magnitude of difference in survival among the
elderly in 2001 to 2003 and in 2004 to 2006 was larger than expected,
based on lower adjuvant chemotherapy uptake. It remains a possibil-
ity, therefore, that other factors may be contributing to improved
survival of elderly patients in 2004 to 2006. We did not observe any
obvious changes in demographic or disease-related factors over the
study period, and in our previous report, we did not detect any sub-
stantial difference in use of diagnostic imaging.
30
In contrast to patients age 70 to 79 years, there was no survival
improvement among patients age ⱖ80 years (HR, 1.00 between pre-
and postadoption cohorts). Unfortunately, it was not possible to ana-
lyze lung cancer–specific mortality, which may be a more accurate
reflection of chemotherapy benefit. Concern regarding benefit of ad-
juvant chemotherapy in the very elderly has also has been raised by the
JBR.10 age analysis, which revealed an HR of mortality of 2.41 for
patients older than 75 years, despite no significant interaction between
chemotherapy effect and age for the entire study population (P⫽
.41).
16
The results of the Adjuvant Navelbine International Trialist
Association 02 study, which compared single-agent vinorelbine to
observation in the elderly and in patients with poor performance
status, may elucidate the relative benefits of adjuvant chemotherapy in
this population and are eagerly awaited.
43
Several aspects of our methodology deserve mention. A strength of
this study is its large population size, which resulted in ample power to
detect even small differences in outcomes. Furthermore, by avoiding se-
lection and referral biases, this province-wide evaluation of the entire
population provides a more realistic reflection of the management of
early-stage NSCLC than traditional institution-based observational stud-
ies. Finally, the well-defined temporal difference in practice allowed com-
parison of outcomes in the overall population before and after adoption of
the new treatment rather than focusing on outcomes in the treated sub-
population alone. In contrast, incumbent on the integrity of this observa-
tional study is an inherent assumption that the underlying population
and/or other treatments did not change significantly. Although we
acknowledge that the modified Charlson index may underestimate
comorbidity, we have shown previously
30
that there were no substan-
tial differences in important prognostic variables, including comor-
bidity, between the pre- and postadoption cohorts. Although an
apparent variation in stage distribution was observed, this likely was ex-
plained by the increased number of early-stage patients referred to re-
gional cancer centers for adjuvant therapy after 2004. Concomitant with
an increase in the proportion of patients referred, we observed a propor-
tional decrease in the number of patients with unknown stage. Moreover,
it is highly unlikely that any significant variation in the mix of patients
could have occurred during the short interval over which changes to both
practice and outcome were observed.
Nonetheless, the large proportion of patients without pathologic
staging data represents a limitation of this study. Finally, we are not aware
of any significant changes to treatment practices of early-stage NSCLC in
Ontario from 2001 to 2006. Although stage migration as a result of en-
hanced use of computed tomographic scanning may have contributed to
the reduction in surgical resections seen in the late 1990s, we have shown
previously that this effect had stabilized by 2001.
30
Furthermore, positron
emission tomography imaging was not routinely used in clinical practice
in Ontario between 2001 and 2006.
30
Thus, although we cannot exclude
the possibility that there may be unidentified factors contributing to the
greater-than-expected improvement in survival seen among elderly pa-
tients across the study period, adoption of adjuvant chemotherapy ap-
pears to be a major contributing factor.
In conclusion, adoption of adjuvant chemotherapy for NSCLC
in the elderly appears to be associated with a significant survival benefit
and with an acceptable tolerability and toxicity profile, confirming
that the benefits of adjuvant chemotherapy suggested by clinical trials
are being realized in general practice. However, the benefit of adjuvant
chemotherapy in patients age ⱖ80 years remains unclear and war-
rantsfurther investigation. Although adoptionof adjuvant chemother-
apy for NSCLC has increased in the elderly, it continues to lag behind
that of younger patients. Significant efforts are therefore necessary to
improve understanding of the reasons underlying this apparent low
use in the elderly and to promote referral of such patients to medical
oncology to ensure that fit elderly patients are not denied potentially
curative therapy on the basis of age alone.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Sinead Cuffe, Christopher M. Booth, Gail E. Darling,
Gavin Li, Weidong Kong, William J. Mackillop, Frances A. Shepherd
Financial support: Christopher M. Booth, William J. Mackillop
Administrative support: Christopher M. Booth, William J. Mackillop
Provision of study materials or patients: Christopher M. Booth,
William J. Mackillop
Collection and assembly of data: Sinead Cuffe, Christopher M. Booth, Gail E.
Darling, Gavin Li, Weidong Kong, William J. Mackillop, Frances A. Shepherd
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Table 5. Summary of Hospital Admissions Within 6 Months of Surgery for Surgical Cases From 2004 to 2006 by Age Group
Toxicity
Age (years)
⬍70 70-74 75-79 ⱖ80
PNo. % No. % No. % No. %
Admissions within 6 weeks of surgery 203 11.1 81 12.1 90 17.2 46 17.7 ⬍.001
Admissions between 6 and 24 weeks of surgery 494 28.0 167 26.6 135 27.6 76 31.5 .54
Cuffe et al
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130.15.12.96
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
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