Impact of Age on the Efficacy of Newer Adjuvant Therapies in Patients With Stage II/III Colon Cancer: Findings From the ACCENT Database

Article (PDF Available)inJournal of Clinical Oncology 31(20) · June 2013with53 Reads
DOI: 10.1200/JCO.2013.49.6638 · Source: PubMed
Abstract
PURPOSEPrior studies have suggested that patients with stage II/III colon cancer receive similar benefit from intravenous (IV) fluoropyrimidine adjuvant therapy regardless of age. Combination regimens and oral fluorouracil (FU) therapy are now standard. We examined the impact of age on colon cancer recurrence and mortality after adjuvant therapy with these newer options. PATIENTS AND METHODS We analyzed 11,953 patients age < 70 and 2,575 age ≥ 70 years from seven adjuvant therapy trials comparing IV FU with oral fluoropyrimidines (capecitabine, uracil, or tegafur) or combinations of fluoropyrimidines with oxaliplatin or irinotecan in stage II/III colon cancer. End points were disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).ResultsIn three studies comparing oxaliplatin-based chemotherapy with IV FU, statistically significant interactions were not observed between treatment arm and age (P interaction = .09 for DFS, .05 for OS, and .36 for TTR), although the stratified point estimates suggested limited benefit from the addition of oxaliplatin in elderly patients (DFS hazard ratio [HR], 0.94; 95% CI, 0.78 to 1.13; OS HR, 1.04; 95% CI, 0.85 to 1.27). No significant interactions by age were detected with oral fluoropyrimidine therapy compared with IV FU; noninferiority was supported in both age populations. CONCLUSION Patients age ≥ 70 years seemed to experience reduced benefit from adding oxaliplatin to fluoropyrimidines in the adjuvant setting, although statistically, there was not a significant effect modification by age, whereas oral fluoropyrimidines retained their efficacy.

Figures

Impact of Age on the Efficacy of Newer Adjuvant Therapies
in Patients With Stage II/III Colon Cancer: Findings From
the ACCENT Database
Nadine J. McCleary, Jeffrey A. Meyerhardt, Erin Green, Greg Yothers, Aimery de Gramont, Eric Van Cutsem,
Michael O’Connell, Christopher J. Twelves, Leonard B. Saltz, Daniel G. Haller, and Daniel J. Sargent
Nadine J. McCleary and Jeffrey A.
Meyerhardt, Dana-Farber Cancer Insti-
tute, Boston, MA; Erin Green, Michael
O’Connell, and Daniel J. Sargent, Mayo
Clinic, Rochester, MN; Greg Yothers,
University of Pittsburgh, Pittsburgh;
Daniel G. Haller, University of Pennsyl-
vania, Philadelphia, PA; Aimery de
Gramont, Hoˆ pital Saint Antoine, Paris,
France; Eric Van Cutsem, University
Hospital Gasthuisberg, Leuven,
Belgium; Christopher J. Twelves,
University of Leeds and St James’s
Institute of Oncology, Leeds, United
Kingdom; and Leonard B. Saltz, Memo-
rial Sloan-Kettering Hospital, New York,
NY.
Published online ahead of print at
www.jco.org on June 3, 2013.
Written on behalf of the ACCENT (Adju-
vant Colon Cancer End Points) Collabor-
ative Group.
Supported in part by the American Soci-
ety of Clinical Oncology Young Investi-
gator Award cosponsored by the
Hartford Foundation, North Central
Cancer Treatment Group (National
Cancer Institute [NCI] Grant No.
CA25224), and Dana-Farber Cancer
Institute/Harvard Cancer Center SPORE
(Specialized Programs of Research
Excellence; NCI Grant No. P50
CA127003).
Presented at the 45th Annual Meeting
of the American Society of Clinical
Oncology, Orlando, FL, May 29-June 2,
2009.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Nadine J.
McCleary, MD, MPH, Dana-Farber
Cancer Institute, 450 Brookline Ave,
Boston, MA 02215; e-mail:
nj_mccleary@dfci.harvard.edu.
© 2013 by American Society of Clinical
Oncology
0732-183X/13/3120w-2600w/$20.00
DOI: 10.1200/JCO.2013.49.6638
ABSTRACT
Purpose
Prior studies have suggested that patients with stage II/III colon cancer receive similar benefit
from intravenous (IV) fluoropyrimidine adjuvant therapy regardless of age. Combination regimens
and oral fluorouracil (FU) therapy are now standard. We examined the impact of age on colon
cancer recurrence and mortality after adjuvant therapy with these newer options.
Patients and Methods
We analyzed 11,953 patients age 70 and 2,575 age 70 years from seven adjuvant therapy
trials comparing IV FU with oral fluoropyrimidines (capecitabine, uracil, or tegafur) or
combinations of fluoropyrimidines with oxaliplatin or irinotecan in stage II/III colon cancer.
End points were disease-free survival (DFS), overall survival (OS), and time to
recurrence (TTR).
Results
In three studies comparing oxaliplatin-based chemotherapy with IV FU, statistically significant
interactions were not observed between treatment arm and age (P interaction .09 for DFS,
.05 for OS, and .36 for TTR), although the stratified point estimates suggested limited benefit
from the addition of oxaliplatin in elderly patients (DFS hazard ratio [HR], 0.94; 95% CI, 0.78
to 1.13; OS HR, 1.04; 95% CI, 0.85 to 1.27). No significant interactions by age were detected
with oral fluoropyrimidine therapy compared with IV FU; noninferiority was supported in both
age populations.
Conclusion
Patients age 70 years seemed to experience reduced benefit from adding oxaliplatin to
fluoropyrimidines in the adjuvant setting, although statistically, there was not a significant effect
modification by age, whereas oral fluoropyrimidines retained their efficacy.
J Clin Oncol 31:2600-2606. © 2013 by American Society of Clinical Oncology
INTRODUCTION
Colorectal cancer accounts for approximately 10%
of all new patient cases of cancer and cancer-related
deaths in the United States. In 2012, an estimated
143,460 new patient cases of colorectal cancer were
diagnosed.
1
Worldwide, the incidence of colorectal
cancer is 1,000,000 per year.
2
The probability of
developing colorectal cancer increases from 0.07%
in the first four decades of life to 4.5% to 5% in the
seventh decade of life.
3
The Adjuvant Colon Cancer End Points (AC-
CENT) group (Appendix, online only) originally as-
sembled individual patient data from 18 trials in the
United States, Canada, Australia, and Europe testing
fluoropyrimidine-based adjuvant therapy for patients
with stage II or III colon cancer. Previous analyses of
data from trials included in ACCENT comparing sur-
gery alone with surgery followed by fluorouracil (FU)
-based chemotherapy demonstrated that patients
age 70 years experienced a similar benefit from
chemotherapy compared with younger patients.
4
Recently, data from seven newer studies compar-
ing either intravenous (IV) combination regi-
mens with oxaliplatin or irinotecan or oral
fluoropyrimidine chemotherapy with IV FU and
leucovorin (LV) in stages II and III colon cancer
were added to ACCENT (Table 1).
5-10
These stud-
ies included 14,500 participants, of whom 18%
were age 70 years. We sought to determine the
impact of age on cancer recurrence and mortality
after combination chemotherapy or oral fluoro-
pyrimidines compared with single-agent IV FU as
adjuvant colon cancer treatment.
JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
VOLUME 31 NUMBER 20 JULY 10 2013
2600 © 2013 by American Society of Clinical Oncology
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Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
PATIENTS AND METHODS
Study Design and Trial Selection
The ACCENT group identifies and obtains individual patient data from
phase III adjuvant trials in patients with colon cancer. Our analysis used seven
phase III trials recently added to ACCENT that either compared standard IV
FU and LV with combination regimens or oral fluoropyrimidine therapy.
5-10
The trials accrued 14,528 patients between 1997 and 2004 (Table 1). Beyond
age, available data include patient sex, disease stage, treatment arm, survival
status, and recurrence status at last follow-up time point. Data on toxicity and
comorbidities were not consistently available across all studies and were there-
fore not included in this analysis.
Statistical Considerations
All patients were included in the analyses according to the intention-to-
treat principle. Disease-free survival (DFS) was defined as the time from
random assignment to either recurrent disease or death, whichever occurred
first. Overall survival (OS) was defined as the time from random assignment to
death resulting from any cause. Time to recurrence (TTR) was defined as the
time to colon cancer recurrence; deaths without recurrence were censored at
the time of death. Second primary colon or noncolon tumors were not
counted as events in the DFS and TTR analyses. The definitions of DFS and
TTR used in the primary analysis of each individual trial were not consistent
across the seven trials; thus, the definitions for our analyses may differ from
those used inthe original trials. The primary analyses pooled individual patient
data from the seven trials, stratified by the patient’s original trial, and consid-
ered age as a two-level dichotomous variable: age 70 versus 70 years.
Hazard ratios (HRs) were calculated using the Cox proportional hazards
regression model, adjusting for sex, treatment arm, and disease stage. Models
tested for an age-by-treatment interaction using the likelihood ratio test. Ad-
ditional models for age were explored using three age groups ( 70, 70 to 74,
and 75 years) and using age as a continuous variable. Age as a continuous
variable was modeled using a subpopulation treatment effect pattern plot
(STEPP) analysis, which plots treatment effects within a clinical trial by a
covariate (eg, age), allowing validation of cutoff points for treatment effects.
11
RESULTS
Patient Enrollment and Characteristics
In the seven trials included in our analyses, 11,953 patients were
age 70 years, and 2,575 were age 70 years. There were no appre-
ciable differences in sex, stage of disease, or treatment assignment by
age, although 4% more patients age 70 years had stage II disease
compared with those age 70 years (Table 2).
Efficacy
In analyses that combined data from all seven trials (Table 3; Fig
1), older patients did not experience statistically significant benefit
from combination therapy or oral fluoropyrimidines in terms of DFS
(HR, 1.05; 95% CI, 0.94 to 1.19), OS (HR, 1.08; 95% CI, 0.95 to 1.23),
or TTR (HR, 1.06; 95% CI, 0.93 to 1.22). In contrast, patients age 70
years experienced statistically significant improvements in all three end
points for the experimental regimens compared with standard IV FU and
LV. Tests for interaction between age and treatment were statistically
significant for all three end points (P interaction .001 for DFS, .004 for
OS, and .002 for TTR). Although rates of death within 6 months of
initiation of therapy were higher in older patients (2.80% v 0.85%), there
were no significant differences in death rates at 6 months comparing age
categories within experimental (age 70 v 70 years, 3.10% v 2.52%;
P .4) and control arms (age 70 v 70 years, 0.91% v 0.80%; P .5).
Thus, early deaths resulting from toxicity are unlikely to explain the sig-
nificant interaction between treatment and age observed for DFS and OS.
We then performed analyses by drug class, given that the current standard
Table 1. Adjuvant Colon Cancer Trials Included
Trial
Accrual
Period
No. of
Patients
Patients Age
70 Years (%)
Experimental
Treatment Arm
Stage III (%)†
Oxaliplatin
MOSAIC 1998 to 2001 2,246 14 FOLFOX4 60
NSABP-C07 2000 to 2002 2,434 16 FLOX 71
XELOXA 2003 to 2004 1,862 22 XELOX 100
Irinotecan
CALGB-89803 1999 to 2001 1,263 24 IFL 98
PETACC-3 2000 to 2002 3,186 13 FOLFIRI 71
Oral fluoropyrimidine
NSABP-C06 1997 to 1999 1,557 23 Uracil/tegafur 53
X-ACT 1998 to 2001 1,983 20 Capecitabine 100
Abbreviations: CALGB, Cancer and Leukemia Group B; FLOX, bolus intravenous fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, infusional fluorouracil, leucovorin, and irinotecan;
FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; IFL, bolus intravenous fluorouracil, leucovorin, and irinotecan; MOSAIC, Multicenter International Study of
Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; NSABP, National Adjuvant Breast and Bowel Project; PETACC, Pan-European Trials in Adjuvant Colon
Cancer; X-ACT, Xeloda in Adjuvant Colon Cancer Therapy; XELOX, Xeloda and oxaliplatin; XELOXA, Xeloda and Oxaliplatin in Adjuvant Colon Cancer Treatment.
Compared with control arm of intravenous flourouracil and leucovorin.
†Remaining patients had stage II disease or unknown stage.
Table 2. Overall Baseline Patient Characteristics
Characteristic
Age 70 Years
(%; n 11,953)
Age 70 Years
(%; n 2,575)
Sex
Female 45 45
Male 55 55
Stage
II 23 19
III 77 81
Treatment arm
Control 49 52
Experimental 51 48
Impact of Age on Adjuvant Therapy for Colon Cancer
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of care for adjuvant therapy is oxaliplatin-based chemotherapy, IV FU
and LV, or oral fluoropyrimidines.
Oxaliplatin-Based Trials
Three trials tested the addition of oxaliplatin to fluoropyrimi-
dines—two with IV FU and LV and one with oral capecitabine (Table
3). Patients age 70 years experienced significant improvements in
DFS, OS, and TTR, whereas those age 70 years did not experience
significant improvements for any of these end points. Older patients
also had an appreciably greater risk of dying in the first 6 months from
start of therapy, with or without oxaliplatin. There was, however, not a
significant interaction by age for OS (P .05), DFS (P .09), or TTR
(P .36). Thus, although the HRs suggest reduced benefit from
oxaliplatin in older patients, the P values for interactions .05 indi-
cate lack of significant effect modification by age for all three
end points.
To further explore the efficacy of oxaliplatin in older patients and
the smaller apparent gain in DFS and OS based on the subgroup HR
point estimates, we censored the analyses at 3, 4, 5, and 6 years after
study entry, presuming that the analyses with longer follow-up would
be affected more by non– cancer-related deaths (Fig 2). As shown in
Figure 2, the HRs for DFS remained consistent at each censoring time
point for younger patients but become increasingly closer to 1 (null
hypothesis) for elderly patients. For OS, the HRs for younger patients
demonstrated an increasingly stronger point estimate as time evolved,
but for older patients, they were 1 at each censoring year. These
analyses suggest that oxaliplatin may provide a short-term reduction
in the risk of recurrence in elderly patients, but by 3 years after surgery,
a sufficient proportion of elderly patients die as a result of other causes
so that no long-term DFS or OS benefit is present.
Irinotecan-Based Trials
Two adjuvant irinotecan trials were incorporated into the
ACCENT database, although the administration of FU and LV dif-
fered between the two trials (bolus regimen in CALGB-89803 [Cancer
and Leukemia Group B] and infusional regimen in PETACC-3 [Pan-
European Trials in Adjuvant Colon Cancer]). Older patients did not
benefit from the addition of irinotecan to FU and LV in DFS, OS, or
TTR (Table 3). However, patients age 70 years seemed to experience
significant improvement in DFS (HR, 0.89; 95% CI, 0.80 to 0.99) and
TTR (HR, 0.88; 95% CI, 0.79 to 0.98). There was a significant interac-
tion by age for DFS (P .02) and TTR (P .002) but not OS
(P .13). It should be noted that the definition of DFS used in these
analyses included time to disease recurrence, new primary colon can-
cer, or death resulting from any cause (which was the definition of
recurrence-free survival in PETACC-3).
Oral Fluoropyrimidines
For oral fluoropyrimidines, interaction testing between treat-
ment and age for DFS (P .13), OS (P .16), and TTR (P .09) were
not significant. Both oral fluoropyrimidine trials were designed to test
noninferiority compared with IV FU and LV. These data suggest that
the benefit of oral fluoropyrimidines is similar to that of IV FU regard-
less of age.
Stage III Disease
We tested whether older patients with stage III disease benefited
from newer therapies, excluding stage II patients. The point estimates
of the HRs for DFS for older patients, comparing experimental with
control arms, were all 1 (overall stage III population: HR, 1.06; 95%
CI, 0.94 to 1.21; oral fluoropyrimidines: HR, 1.19; 95% CI, 0.95 to
1.50; irinotecan-based therapy: HR, 1.21; 95% CI, 0.95 to 1.55); for
oxaliplatin-based therapy, it was slightly 1 (HR, 0.91; 95% CI, 0.74
to 1.11). The P value for interaction for DFS between age and treat-
ment arm was .15 when restricted to the three oxaliplatin-based ther-
apy trials; it was .002 for all seven trials. Although this analysis suggests
that there is a lack of DFS benefit among older patients with stage III
Table 3. Outcomes of Experimental (combination or oral FU) Versus Control Arm (IV FU) by Treatment and Age
Treatment Arm
DFS
OS
TTR
Deaths Within 6
Months,
Experimental Versus
Control
HR 95% CI HR 95% CI HR 95% CI % P
All trials
Age 70 years (n 11,953) 0.85 0.80 to 0.90 0.87 0.81 to 0.93 0.84 0.79 to 0.89 0.91 v 0.80 .5
Age 70 years (n 2,575) 1.05 0.94 to 1.19 1.08 0.95 to 1.23 1.06 0.93 to 1.22 3.10 v 2.52 .4
P interaction .001 .004 .002
Oxaliplatin based
Age 70 years (n 5,420) 0.78 0.71 to 0.86 0.83 0.74 to 0.92 0.77 0.69 to 0.85 0.88 v 0.82 .8
Age 70 years (n 1,119) 0.94 0.78 to 1.13 1.04 0.85 to 1.27 0.86 0.69 to 1.06 3.15 v 2.25 .4
P interaction .09 .05 .36
Irinotecan based
Age 70 years (n 3,750) 0.89 0.80 to 0.99 0.90 0.80 to 1.03 0.88 0.79 to 0.98 0.90 v 0.43 .1
Age 70 years (n 699) 1.19 0.95 to 1.49 1.11 0.87 to 1.42 1.35 1.04 to 1.76 3.96 v 2.43 .3
P interaction .02 .13 .002
Oral fluoropyrimidine
Age 70 years (n 2,783) 0.91 0.80 to 1.02 0.90 0.79 to 1.03 0.90 0.80 to 1.02 0.98 v 1.25 .5
Age 70 years (n 757) 1.14 0.92 to 1.41 1.13 0.90 to 1.41 1.20 0.93 to 1.54 2.24 v 3.00 .5
P interaction .13 .16 .09
Abbreviations: DFS, disease-free survival; FU, fluorouracil; HR, hazard ratio; IV, intravenous; OS, overall survival; TTR, Time to recurrence.
Values 1 favor experimental arm.
McCleary et al
2602
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disease for combination regimens, a significant P value for a treatment
interaction was not seen.
Alternative Models of Age
The lack of recurrence-free or OS benefit is not altered when
alternative modeling of age is used. In secondary analyses, we divided
age into three categories: 70 (n 11,953), 70 to 74 (n 1,989),
and 75 years (n 586); two of the trials (MOSAIC [Multicenter
International Study of Oxaliplatin/Fluorouracil/Leucovorin in the
Adjuvant Treatment of Colon Cancer] and PETACC-3) limited eligi-
bility to those age 75 years and thus contributed minimally to the
oldest category. For the overall population, the HRs for DFS for
experimental versus control treatment were 0.85 (95% CI, 0.80 to
0.90) for patients age 70, 1.09 (95% CI, 0.95 to 1.25) for patients age
70 to 74, and 0.97 (95% CI, 0.77 to 1.23) for patients age 75 years. In
analyses by chemotherapy regimen, for oxaliplatin-based chemother-
apy versus FU and LV, HRs for DFS were 0.78 (95% CI, 0.71 to 0.86)
for patients age 70, 0.91 (95% CI, 0.73 to 1.13) for patients age 70 to
74, and 1.01 (95% CI, 0.72 to 1.42) for patients age 75 years. For oral
versus IV FU chemotherapy, HRs for DFS were 0.91 (95% CI, 0.80 to
1.02) for patients age 70, 1.23 (95% CI, 0.96 to 1.57) for patients age
70 to 74, and 0.93 (95% CI, 0.61 to 1.41) for patients age 75 years.
Furthermore, we conducted analyses using the STEPP method.
12
This method estimates the treatment benefit for a sequence of patient
subgroups defined by a characteristic of interest (such as age) without
set cut points. For the oxaliplatin cohort, improved DFS was estimated
by the STEPP method for patients age 50 to 65 years, with no benefit
estimated for the experimental versus control treatment for patients
age approximately 65 years (Fig 3).
DISCUSSION
In the ACCENT database, older patients (age 70 years) experienced
mixed benefit from newer adjuvant cytotoxic chemotherapy regi-
mens. When initially reported in 2009,
9
only two of the oxaliplatin-
based trials were available for analyses (MOSAIC and NSABP-C07
A
Hazard Ratio
Oral
Oxaliplatin
Irinotecan
Overall
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
B
Hazard Ratio
Oral
Oxaliplatin
Irinotecan
Overall
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
C
Hazard Ratio
Oral
Oxaliplatin
Irinotecan
Overall
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
Fig 1. Forest plots by drug class, all stages. (A) Disease-free survival; (B) overall
survival; (C) time to recurrence.
Censored
at 3 years
Censored
at 4 years
Censored
at 5 years
Censored
at 6 years
Censored
at 3 years
Censored
at 4 years
Censored
at 5 years
Censored
at 6 years
A
Hazard Ratio
Censored
at 3 years
Censored
at 4 years
Censored
at 5 years
Censored
at 6 years
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
B
Hazard Ratio
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
C
Hazard Ratio
0.40.2 0.6 0.8 1.0 1.41.2 1.6 1.8 2.0 2.2
Age < 70 years
Age 70 years
Fig 2. Oxaliplatin trials with censoring analyses of different time points. (A)
Disease-free survival; (B) overall survival; (C) time to recurrence.
Impact of Age on Adjuvant Therapy for Colon Cancer
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[National Surgical Adjuvant Breast and Bowel Project]), and there
were statistically significant P values for interaction in DFS and OS
comparing older and younger patients with the addition of oxalipla-
tin. With the addition of a third oxaliplatin-based treatment study,
XELOXA [Xeloda and Oxaliplatin in Adjuvant Colon Cancer Treat-
ment], the P value for interaction for age and oxaliplatin treatment
was no longer statistically significant for DFS, suggesting that older
patients may experience a DFS benefit from oxaliplatin in the adjuvant
setting. However, the lack of an OS benefit among older patients
receiving oxaliplatin in the adjuvant setting remains consistent with
prior analysis.
9
Recent studies have focused on combination regimens for pa-
tients with metastatic disease.
12,13
In a retrospective pooled analysis of
3,742 participants (16% age 70 years) enrolled onto four clinical
trials of FOLFOX (infusional FU, LV, and oxaliplatin; three metastatic
trials and one adjuvant trial), individuals age 70 years had similar
recurrence or relapse-free and OS as well as overall toxicity rates
compared with those age 70 years with oxaliplatin-based therapy.
12
Folprecht et al
13
published a combined analysis of four phase III
studies enrolling 2,691 patients (22% age 70 years) receiving first-
line irinotecan-based therapy in the metastatic setting. Combination
regimens with irinotecan were associated with a significant improve-
ment in progression-free survival and a trend toward improvement in
OS for older patients, compared with FU and LV alone. Our analysis
sought to test the impact of age in the adjuvant setting because benefits
of treatment in the metastatic setting do not always translate to the
adjuvant setting in colorectal cancer.
Initial studies in the adjuvant setting of fluoropyrimidine therapy
showed similar survival benefit regardless of age. One prior analysis of
the efficacy of adjuvant IV FU and either levamisole or LV therapy
compared with surgery alone in elderly patients using pooled data
from seven randomized trials found no significant interaction be-
tween age and efficacy of treatment.
4
Our current data do not contra-
dict those findings, because all studies in the current analysis involved
chemotherapy in both arms.
The seven trials included in this analysis were those with mature
data testing regimens beyond variations in dosing schedule of IV FU
and LV therapy. Five trials (MOSAIC, XELOXA, NSABP-C07,
CALGB-89803, and PETACC-3) were designed to demonstrate supe-
riority of the experimental regimen to IV FU and LV to significantly
improve DFS or OS. Two trials (X-ACT [Xeloda in Adjuvant Colon
Cancer Therapy] and NSABP-C06) were designed to demonstrate
noninferiority of oral fluoropyrimidine therapy compared with IV FU
and LV; the analyses presented here are supportive of the conclusion
that the effect of oral versus IV therapy is similar regardless of age.
In contrast to our initial report reflecting two adjuvant studies of
oxaliplatin, expansion of the data to include a third study, the
XELOXA trial, changed the Pvalueforage/oxaliplatinfromsignificant
(P .016)
9
to nonsignificant (P .09). It is important to note that the
XELOXA trial differed from MOSAIC because it used bolus instead of
infusional FU/LV for the control arm and oral fluoropyrimidine
(capecitabine) with oxaliplatin (instead of infusional FU/LV) for the
experimental arm. The age-by-treatment benefit interaction became
P .05 for OS, whereas that for TTR remained nonsignificant, sug-
gesting that oxaliplatin provides a reduction in the risk of recurrence in
a subset of elderly patients. However, after a period of time, a sufficient
number of elderly patients died as a result of other causes, diminishing
the OS benefit. The nonsignificant P interaction for age with oxalipla-
tin treatment suggests that a subset of elderly patients derives a DFS
benefit from oxaliplatin. This hypothesis is supported by exploratory
analyses in which the data from the three oxaliplatin trials were cen-
sored at different time points (Fig 2). If this is truly the explanation, it
raises the clinical question of whether increased toxicity from more
intensive therapy to delay recurrence is a clinically meaningful benefit,
given the competing risks of toxicity and death in older adults.
Our study did not include evaluation of biologic agents (bevaci-
zumab and cetuximab) among older patients in the adjuvant
setting.
14-19
However, given the lack of survival benefit noted in the
general adjuvant treatment setting, subgroup analyses by age may be
less relevant.
The ACCENT database provides the advantage of pooling large,
mature clinical trials to test hypotheses that are difficult or impossible
to test within individual trials. Given the fact that none of the included
trials had one quarter of the patients age 70 years, subset analyses
by age in the individual studies have limited power. Pooling of the data
from these seven trials resulted in 2,000 patients age 70 years to be
studied, larger than any subgroup analysis from individual studies.
Nonetheless, there are limitations to this analysis. First, the ACCENT
analysis lacks toxicity or comorbidity data. Given the potential benefit
of oxaliplatin DFS but not OS, consideration of the toxicity from
oxaliplatin should be weighed in decision making regarding the use of
oxaliplatin in elderly patients. Second, we do not have data on dose-
intensity or proportion of doses delivered compared with the total
dose planned. Thus, we were unable to comment on the extent to
which the amount of actual dose received may have accounted for this
lack of benefit among older patients receiving adjuvant therapy. How-
ever, in previously published analyses from the MOSAIC and XE-
LOXA trials, dose-intensity did not alter efficacy of treatment.
11,20
Also, only a minority of the elderly receive adjuvant therapy in prac-
tice, and an even smaller proportion of highly selected patients enter
clinical trials. Therefore, in an unselected population of patients who
may have been ineligible for such trials for many reasons, the degree of
benefit may be less than the results reported here. Our study suggests
that the competitive risk of dying as a result of other causes may be a
mechanism by which older patients do not experience a DFS or OS
benefit with combination therapy in the adjuvant setting, in contrast
to that noted in the metastatic setting. The age cutoff of 70 years was
3-Year DFS
Age (years)
100
80
60
40
20
0
4237 47 52 57 62 777267
Control
Experimental
Fig 3. Subpopulation treatment effect pattern plot of disease-free survival (DFS)
by age for oxaliplatin-based therapy.
McCleary et al
2604
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selected to be consistent with past studies evaluating the impact of
chemotherapy regimens in older patients with colorectal cancer and
was also supported using a STEPP analysis. However, other factors not
collected or evaluated in our study may explain the observed lack of
benefit for older patients. These factors may include measures of
comorbidity or functional decline collected in a comprehensive geri-
atric assessment that are not captured by Eastern Cooperative Oncol-
ogy Group performance status.
21-25
Such factors may directly or
indirectly lead to lower survival via competing mortality or modifica-
tion of dose-intensity or dose schedule.
23,26-30
In conclusion, our findings suggest that the benefit of oxaliplatin
compared with IV FU and LV is restricted to patients age 70 years
for OS. For patients age 70 years, oxaliplatin may provide a DFS
benefit for a subset of older adults; however, we cannot establish which
subsets of older adults experience benefit. For this reason, the data also
support fluoropyrimidine monotherapy as an appropriate treatment
option. Fluoropyrimidine monotherapy with either FU/LV or cape-
citabine is an appropriate adjuvant treatment option for patients
age 70 years. Clinical studies incorporating measures of factors
beyond physiologic age predicting response to treatment (eg, comor-
bid conditions, patient functional status, treatment duration, or dose-
intensity, as collected by the Cancer-Specific Geriatric Assessment
31
)
may guide clinicians in optimal treatment selection for older patients,
limiting the potential lack of benefit or harm to vulnerable or frail older
patients. Further studyis needed to identify which subsetsof older patients
derive potential benefit from oxaliplatin-based chemotherapy.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Aimery de Gramont, Roche (C), sanofi-aventis (C); Christopher J.
Twelves, Roche (C); Leonard B. Saltz, Pfizer (C), Roche (C),
sanofi-aventis (U); Daniel G. Haller, Roche (C), sanofi-aventis (C) Stock
Ownership: None Honoraria: Aimery de Gramont, Roche,
sanofi-aventis; Christopher J. Twelves, Roche; Daniel G. Haller,
sanofi-aventis Research Funding: Eric Van Cutsem, Pfizer,
sanofi-aventis; Leonard B. Saltz, Roche Expert Testimony: None
Patents: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Nadine J. McCleary, Jeffrey A. Meyerhardt,
Daniel G. Haller, Daniel J. Sargent
Financial support: Daniel J. Sargent
Administrative support: Greg Yothers, Daniel J. Sargent
Provision of study materials or patients: Eric Van Cutsem, Daniel
G. Haller
Collection and assembly of data: Erin Green, Greg Yothers, Aimery de
Gramont, Christopher J. Twelves, Leonard B. Saltz, Daniel G. Haller,
Daniel J. Sargent
Data analysis and interpretation: Nadine J. McCleary, Erin Green,
Aimery de Gramont, Eric Van Cutsem, Michael O’Connell, Daniel
J. Sargent
Manuscript writing: All authors
Final approval of manuscript: All authors
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Appendix
The ACCENT (Adjuvant Colon Cancer End Points) Collaborative Group includes: D.J. Sargent, E. Green, A. Grothey, S.R. Alberts,
Q. Shi, L. Renfro (Mayo Clinic, Rochester, MN); G. Yothers, M.J. O’Connell, N. Wolmark (National Surgical Adjuvant Breast and Bowel
Project Biostatistical and Operations Centers, Pittsburgh, PA); A. de Gramont (Hoˆpital Saint Antoine, Paris, France); R. Gray, D. Kerr
(Quasar Collaborative Group, Birmingham and Oxford, United Kingdom); D.G. Haller (Abramson Cancer Center, University of
Pennsylvania, Philadelphia, PA); J. Benedetti (Southwest Oncology Group Statistical Center, Seattle, WA); M. Buyse (International Drug
Development Institute, Louvain-la-Neuve, Belgium); R. Labianca (Ospedali Riuniti, Bergamo, Italy); J.F. Seitz (University of the
Mediterranean, Marseilles, France); C.J. O’Callaghan (National Cancer Institute of Canada Clinical Trials Group, Queens University,
Kingston, Ontario, Canada); G. Francini (University of Siena, Siena, Italy); P.J. Catalano (Eastern Cooperative Oncology Group Statistical
Center, Boston, MA); C.D. Blanke (British Columbia Cancer Agency, Vancouver, British Columbia, Canada); T. Andre (Groupe
Hospitalier Piti e-Salpetriere, Paris, France); R.M. Goldberg (University of North Carolina, Chapel Hill, NC); A. Benson (Northwestern
University, Chicago, IL); C. Twelves (University of Leeds, Leeds, United Kingdom); J. Cassidy (Genentech/Roche, Glasgow, United
Kingdom); F. Sirzen (Roche, Basel, Switzerland); L. Cisar (Pfizer, New York, NY); E. Van Cutsem (University Hospital Gasthuisberg,
Leuven, Belgium); L. Saltz (Memorial Sloan-Kettering Cancer Center, New York, NY); J. Meyerhardt, N.J. McCleary (Dana-Farber
Cancer Center, Boston, MA).
Impact of Age on Adjuvant Therapy for Colon Cancer
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    • "In addition, capecitabine (or infusional 5-FU) seems to be the favorable combination partner if an oxaliplatin-based adjuvant treatment is chosen. In contrast to prior data including bolus 5FU based regimen (FLOX), Haller and colleagues recently demonstrated an attenuated but sustained DFS and OS benefit in elderly patients with a modern fluoropyrimidine schedule in combination with oxaliplatin (CAPOX or FOLFOX)323334. Further oral fluoropyrimidines (S-1 or UFT) have been studied in localized or metastatic CRC, showing tolerability and efficacy as single agent or in different combinations (e.g., oxaliplatin – SOX/TEGAFOX regimen or irinotecan – IRIS/TEGAFIRI) without any apparent interaction with age3536373839. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The purpose of this observational study was to evaluate feasibility, efficacy results and toxicity observations of capecitabine in routine first line treatment of patients with metastatic colorectal cancer, with particular regard of elderly patients (>75 years of age). Methods Patients with colorectal cancer receiving capecitabine as part of their first-line treatment were recorded until detection of disease progression or up to a maximum of 12 cycles on standardized evaluation forms. Additional information on long-term outcomes, progression-free survival, and overall survival were retrieved at two follow-up time points. Obtained data were analyzed with regard to age up to 75 and >75 years of age. There were no specific requirements for patient selection and conduct of therapy, corresponding to the non-interventional nature of the study. Results In total, 1249 evaluable patients were enrolled in Germany. The median age of the study population was 74 years (range: 21–99). Capecitabine-based combination was administered in 56 % of patients in the overall population. The median treatment duration was about 5 months. Severe toxicities occurred rarely without any difference regarding age groups. The most common hematological toxicity was anemia. Gastrointestinal side effects and hand-food-syndrome (HFS) were the most frequent non-hematologic toxicities. Overall response rate (ORR) was significantly higher in the patient group <=75 years compared to patients >75 years of age (38 vs. 32 %, p=0.019). Median progression free survival (PFS 9.7 vs. 8.2 months, p=0.00021) and overall survival (OS 31.0 vs. 22.6 months, p<0.0001) was decreased in elderly patients. Conclusion Efficacy and tolerability of capecitabine treatment either as single drug or in various combination regimens, as proven in randomized studies, could be confirmed in a clinical routine setting. Patients older than 75 years may derive a relevant benefit by first line capecitabine-based treatment with good tolerability.
    Full-text · Article · Dec 2016
    • "Accurate clinical staging with MRI is more diffcult in the low rectum, at lower than 4 cm there is a 5–15 % risk of involved lateral pelvic lymph nodes, which are not resected at TME. A lack of evidence to suggest a benefit from oxaliplatin containing adjuvant chemotherapy for stage II colorectal cancer343536 and insufficient data to support a benefit from adjuvant chemotherapy in Stage III colorectal cancer in patients over 70 years has informed the decision to exclude patients over 70 years from this trial [33]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection. Methods/design: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy. Discussion: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial. Trial registration: Clinical trial identifier BACCHUS: NCT01650428.
    Full-text · Article · Oct 2015
    • "The addition of oxaliplatin provided a short-term reduction in the risk of recurrence, but after a period of time the OS benefit diminished as older patients died from other causes. It is therefore unclear as to which subset of older patients may derive benefit from oxaliplatin-based regimens [McCleary et al. 2013]. "
    [Show abstract] [Hide abstract] ABSTRACT: In a continuously aging population, the burden of colorectal cancer (CRC) is rising among older patients. Despite the fact that almost half of the cases occur in patients over 75 years, this age group is subjected to disparities regarding diagnostic and therapeutic options. So far, exclusion of older patients from randomized clinical trials has resulted in a lack of evidence-based guidelines. Nevertheless, newer data from studies specifically targeting older patients and subgroup analyses indicate that proper treatment planning and specific medical and geriatric assessment can achieve a safe and beneficial treatment result in older patients, often with similar outcomes to their younger counterparts. Resection of the primary tumour, if feasible, should be the primary goal of surgery aiming for cure, although it should be avoided under emergency conditions. Chronological age per se should not be an exclusion criterion for adjuvant or palliative chemotherapy, or targeted therapies. Careful patient selection, dose adjustments, close monitoring and early intervention in the event of side effects are essential. The benefits of treatment must be balanced with potential effects of treatment and patients' wishes.
    Full-text · Article · May 2014
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