CANCER TREATMENT REVIEWS (2006) 32, 18

www.elsevierhealth.com/journals/ctrv

ANTI-TUMOUR TREATMENT

Treatment of colorectal cancer in the elderly: A

review of the literature
Vassilis Golfinopoulos, George Pentheroudakis, Nicholas Pavlidis

School of Medicine, Department of Medical Oncology, University Hospital of Ioannina, GR-45110 Ioannina,
Greece

KEYWORDS

Summary Although major progress has been achieved in the treatment of colorectal cancer, there are still several questions open for discussion concerning the management of elderly colorectal cancer patients. We conducted a review of the
available literature concerning the use of adjuvant chemotherapy, palliative chemotherapy and surgery in elderly patients with colorectal cancer, using data from
meta-analyses, non-systematic reviews and individual trials. All report similar survival benefits with adjuvant and palliative chemotherapy in elderly patients in comparison with younger age groups. Data on treatment-related side effects did not
reveal a different toxicity profile for elderly patients. Efficacy and safety data were
similar but more difficult to interpret concerning surgery, so this review is inconclusive about the proper use of this treatment modality in the elderly population. It is
demonstrated that there is significant gain from chemotherapy in the adjuvant and
palliative management of colorectal cancer patients irrespective of age. We, therefore, conclude that all patients should receive the most intensive treatment thought
to be effective and safe, according to their biological age and comorbidities.
c 2005 Elsevier Ltd. All rights reserved.

Colorectal cancer;
Elderly;
Chemotherapy;
Surgery


Introduction

Cancer is mostly a disease of old people, and this is

definitely true for colorectal cancer. The median
age of presentation is in the seventh decade of life,
with advanced age being a major risk factor for
developing the disease. In view of the improving
general population life expectancy, physicians are

* Corresponding author. Tel./fax: +30 26510 99394.

E-mail address: npavlid@cc.uoi.gr (N. Pavlidis).

likely to face more often elderly patients with

colorectal cancer who are both willing and able
to tolerate optimal antineoplastic therapy. Still,
there are several questions open for discussion concerning the management of elderly people with
colorectal cancer. Adjuvant chemotherapy, palliative chemotherapy, and surgery for advanced-stage
disease, all represent treatment modalities without a clearly defined role in the elderly patient
population, while the addition of new cytotoxic
drugs and biological agents in our armamentarium
impacts on both outcome and safety issues.

0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2005.10.002

V. Golfinopoulos et al.

To answer the above, we conducted a review of

the available literature concerning the multidisciplinary treatment of colorectal cancer in elderly
patients.

Methods
We searched PubMed for English-language articles
containing the terms colorectal, cancer, and elderly. As our aim was not to perform a systematic
review, the keyword search was limited to the titles and abstracts, encompassing all treatment
modalities: chemotherapy, surgery, and palliative
care. An emphasis on reviews and meta-analyses
was placed, with clinical trial reports included only
if contributory to significant information.
The acquired articles were reviewed for evidence concerning the efficacy and toxicity of the
treatment of colorectal cancer in elderly patients.
The areas covered included adjuvant chemotherapy, palliative chemotherapy and surgery for advanced-stage disease, including metastasectomy.

tions, except one of the Colorectal Cancer

Collaborative Group studies, which reviewed surgical options. The reviews of Folprecht et al. and the
chemotherapy Colorectal Cancer Collaborative
Group study referred to metastatic colorectal cancer; no limits according to disease stage were set in
the other reviews. Not all articles retrieved represent systematic reviews; Folprecht et al. and
Kohne et al. do not claim to have performed a systematic search of the literature. It is interesting to
note that the definition of old age is arbitrary in the
various articles; there is no universally accepted
age limit.
All of the above-mentioned reviews refer to 5FU-based chemotherapy. No systematic reviews
have been conducted concerning the application
of newer but already widely used agents, such as
capecitabine, irinotecan, and oxaliplatin. Therefore, data from individual trials were used where
appropriate, including published reports in abstract form concerning the use of new biological
agents, as there are scant relevant data published
to date (Table 2).

Adjuvant chemotherapy

Results
Several reviews relevant to the subject were retrieved (Table 1). All reviewed chemotherapy op-

Table 1

Two reviews, from Au et al. and Kohne et al.,

examined the clinical experience with 5-FU-based
adjuvant chemotherapy in elderly patients. Both

Selected reviews concerning the treatment of colorectal cancer in elderly patients

Reference

Elderly patients (%) and sample size

Study design

Folprecht et al.1

16.4% P 70 y out of 3825

Au et al.2

N/A

Kohne et al.3
CCCGa4

1438% P 70 y out of 2151208

(metastatic)
35% P 75 y out of 34,194

CCCGa, 20005

2.5% P 75 y out of 1365

Sargent et al.6

15.1% > 70 y out of 3351

Popescu et al.7

22.4% P 70 y out of 1387

Brower et al.8

N/A

Temple et al.19

54.5% > 75 y out of 9011

(overall population P 65 y)

Review of prospective randomized trials of 5-FUbased chemotherapy in elderly patients with

metastatic colorectal cancer
Systematic review of the management of colorectal
cancer in elderly patients
Review of chemotherapy in elderly patients with
colorectal cancer
Systematic review of prospective studies of surgery
for colorectal cancer in elderly patients
Systematic review of prospective randomized trials
comparing chemotherapy with supportive care alone
for advanced colorectal cancer
Review of prospective randomized trials comparing
adjuvant chemotherapy vs. surgery alone for
resectable colorectal cancer
Review of single-institution prospectively recorded
data concerning chemotherapy for colorectal cancer
Population-based review of adjuvant chemotherapy
for elderly patients with colorectal cancer (abstract)
Population-based retrospective review of surgery in
elderly patients with advanced colorectal cancer

Colorectal Cancer Collaborative Group.

Treatment of colorectal cancer in the elderly: A review of the literature

Table 2

Selected trials contributory to information about the treatment of colorectal cancer in elderly patients

Reference
Scheithauer et al.

Elderly patients (%) and sample size

Study design

41.1% P 65 y out of 1967

Capecitabine vs. 5-FU-based adjuvant

chemotherapy for colon cancer, safety results of
a prospective randomized phase III trial
Capecitabine vs. 5-FU-based chemotherapy for
advanced colorectal cancer, toxicity analysis of
two prospective randomized phase III studies
Irinotecan monotherapy in previously treated
advanced colorectal cancer patients, prospective
phase II trial
Irinotecan monotherapy in previously treated
elderly advanced colorectal cancer patients,
prospective phase II trial
5-FU/leucovorin Oxaliplatin in first-line
advanced colorectal cancer patients, prospective
randomized phase III trial
Subgroup analysis of the IFLa bevacizumab in
first-line advanced colorectal cancer patients,
prospective randomized phase III trial (abstract)

Cassidy et al.10

27.5% P 70 y out of 596

(Capecitabine arm)

Rothenberg et al.11

N/A out of 166

Chau et al.12

N/A out of 339

De Gramont et al.13

38.1% > 65 y out of 420

Fyfe et al.15

33% P 65 y out of 813

Hurwitz et al.14
Puig-La Calle et al.17

15% P 75 y out of 1,120

Chiappa et al.18

14.7% P 80 y out of 346

Retrospective review of individual data of

consecutive patients who underwent surgery for
rectal cancer
Retrospective review of individual data of
consecutive patients who underwent surgery for
colorectal cancer

Bolus irinotecan/5-fluorouracil/leucovorin.

cited a meta-analysis of seven studies comparing

either 5-FU and leucovorin (five studies), or 5-FU
and levamisole (two studies), with observation
alone, as adjuvant treatment in 3351 elderly patients with resected stage II and III colon cancer.6
They found similar time to progression and overall
survival across all age groups (defined groups were
below 50, 5160, 6170, and over 70 years). As expected, death without cancer was more frequent in
the elderly, occurring in 13% of patients older than
70 years (n = 506), compared with 7% in the 6170
age group (n = 1269), 4% in the 5160 age group
(n = 1012), and 1% in patients below 50 years of
age (n = 564). Kohne et al. also presented evidence
suggesting similar efficacy and toxicity of adjuvant
5-FU-based regimens in all age groups. However, a
higher frequency of stomatitis was observed in elderly patients with bolus 5-FU (19% vs. 11%) in
one study, although this was not the case when patients receiving infusional 5-FU were analyzed.7
Similarly, the combination of 5-FU with levamisole
proved more toxic than the combination of 5-FU
with folinic acid, leading to increased frequency
of grade 3 or greater leucopenia to patients older
than 70 years in one meta-analysis,6 and to decreased administered dose-intensity in patients

older than 75 years in another study (71% vs. 84%

for those younger than 70 years).8
The safety results of the X-ACT study, a randomized phase III trial comparing oral capecitabine
with 5-fluorouracil-based adjuvant therapy for
stage III colon cancer patients, provide some information concerning the effect of age on the toxicity
of this agent.9 Although the study posed an upper
age limit of 75 years, patients up to 82 years old
were enrolled. The safety profile of both arms
was analyzed in patients younger than 65 and 65
years or older. The analysis concentrates on the
more favorable toxicity profile that capecitabine
demonstrates in both age groups as compared to
bolus 5-FU plus leucovorin (Mayo Clinic regimen),
with less treatment-related diarrhea, nausea, vomiting, stomatitis and neutropenia, but more hand
foot syndrome, thus improving on the tolerability
of the intravenous regimen. Moreover, it was
shown that capecitabine was as safe in elders as
in younger patients, as there were no major differences between the two age groups. It must be
acknowledged that although it is currently accepted that infusional 5-FU regimens result in lower
toxicity than bolus schedules of administration,
thus potentially altering the conclusions of the

4
study if such a schedule was used, the authors state
that at the time of study planning bolus 5-FU was
the standard regimen in the adjuvant setting.

Chemotherapy for advanced disease

All of the reviews retrieved covered the subject of
palliative chemotherapy for metastatic or recurrent colorectal cancer in the elderly population.
Folprecht et al.1 carried out a retrospective analysis using source data of 3825 patients who received
5-fluorouracil-containing treatment in 22 European
phase II and phase III trials, and identified 629 patients aged 70 years or older. Twenty-eight percent
of elderly patients in the analyzed trials received
infusional 5-FU, with the rest receiving bolus regimens. The authors found no statistically significant
difference in response rate (23.9% vs. 21.1%,
p = 0.14) and overall survival (10.8 vs. 11.3 months,
p = 0.31) between these patients and those younger than 70 years. They found statistically but not
clinically significant longer progression-free survival in elderly patients (5.5 vs. 5.3 months,
p = 0.01). Overall survival was longer in patients
receiving infusional rather than bolus 5-FU (12.3
vs. 10.7 months, p < 0.0001), with all age groups
receiving equal benefit.
Kohne et al. undertook a narrative approach in
their analysis, citing several studies relevant to
the subject. The results consistently support the
conclusion that patients over 70 years with advanced colorectal cancer receive similar benefit
from palliative chemotherapy, concerning response and overall survival, with younger age
groups. The evidence concerning toxicity presented in this review is inconclusive, as the data
were inconsistent across the various trials
analyzed.
The Colorectal Cancer Collaborative Group performed a systematic review and meta-analysis of
randomized controlled trials comparing palliative
chemotherapy with supportive care alone in patients with locally advanced or metastatic colorectal cancer.5 Overall, median survival was 11.7
months in the chemotherapy group, with a median
progression-free survival of 10 months, vs. a median survival of eight months, and a median progression-free survival of four months in the control
group. The authors point out the fact that elderly
patients were under-represented in these trials,
as only 2.5% of the 1365 patients reviewed were
over 75 years of age. Nevertheless, they performed
a subgroup analysis of overall survival by age group
(younger than 50, 5064, and over 64 years), using
individual patient data from seven randomized tri-

V. Golfinopoulos et al.
als. They found no relation between age and the
effect of treatment on overall survival or time to
progression, suggesting that elders derived from
palliative chemotherapy a benefit similar to younger patients. Again, the effect of chemotherapy
on quality of life and toxicity could not be assessed, as data were not sufficient in quantity
and quality to allow reliable evaluation.
The safety analysis performed by Cassidy et al.10
using data from two large phase III studies randomizing 1207 patients to receive oral capecitabine vs.
intravenous 5-fluorouracil/leucovorin as first-line
chemotherapy for metastatic colorectal cancer, is
the best source of evidence so far concerning the
efficacy and toxicity of this oral fluoropyrimidine
in the elderly population. Initial analysis according
to 5-year age intervals revealed a poor safety
profile in patients aged more than 80 years, mainly
because of a higher incidence of grade 34 gastrointestinal events, whereas differences were modest in the younger age categories. However,
multivariate analysis demonstrated that age did
not have an additional statistically significant impact on the safety profile of capecitabine over creatinine clearance. Therefore, the conclusion was
reached that the increased toxicity of capecitabine
in older patients was caused mostly by the expected age-related decline in renal function, as is
evident by the calculated value of creatinine
clearance.
Much caution is usually exercised regarding the
use of irinotecan in elderly patients with colorectal
cancer. There is contradicting evidence to support
this notion. In a phase II study by Rothenberg
et al.11 including 166 patients aged up to 84 years,
patients aged P65 years were twice as likely
(38.6% vs. 18.8%) to develop grade 34 diarrhea,
compared to younger patients when all courses of
therapy were evaluated. However, this was not
the case for diarrhea presenting during the first
course of treatment (25.0% vs. 14.7%, not statistically significant). Chau et al.12 recently reported
the results of a trial where all advanced colorectal
cancer patients received second-line irinotecan
monotherapy at the full recommended tri-weekly
dose of 350 mg/m2 irrespective of their age. The final analysis of the 339 patients included in the
study, revealed no differences in irinotecan-specific toxicity (defined as the occurrence of grade
3 or 4 diarrhea, neutropenia, febrile neutropenia,
fever, infection, or nausea and vomiting), objective responses or median survival between the
two age groups (younger than 70 vs. 70 or older).
In the phase III study of De Gramont et al.13
demonstrating the superior time-to-progression
experienced by patients treated with oxaliplatin

Treatment of colorectal cancer in the elderly: A review of the literature

combined with infusional 5-fluorouracil/leucovorin
over 5 fluorouracil/leucovorin alone in the first-line
metastatic setting, patients up to 76 years old were
enrolled. In the efficacy analysis, age was not
found to represent an individual predictive factor
for response to chemotherapy. The 160 patients
over 65 years old who were enrolled in the study,
did not experience increased toxicity compared
with younger patients, except for grade 34 diarrhea (18% vs. 8%, p = 0.034). However, although
sensory neuropathy was the cumulative dose-limiting toxicity of oxaliplatin and reversible paresthesia interfering with function was observed in
16.3% of the patients, no specific data are reported
concerning the incidence or the duration of the
neurotoxicity experienced by the elderly patients
included in the study. Moreover, no analysis was
performed to further age-specific groups, notably
those 70 years or older.
Hurwitz et al.14 explored in a phase III trial the
efficacy and toxicity of adding bevacizumab, a
monoclonal antibody against the vascular endothelial growth factor, to bolus irinotecan, 5-FU and
leucovorin chemotherapy (IFL) as first-line treatment of colorectal cancer patients. They showed
increased median survival to the bevacizumab plus
IFL group (20.3 vs. 15.6 months, p < 0.001) compared with the IFL-only group. A subgroup analysis
of that trial showed this favorable effect on survival to be consistent across the age groups analyzed (22.8 vs. 15.6 months, p = NS for the <40
group, 19.6 vs. 15.8 months, p < 0.05 for the 40
64 group and 24.2 vs. 14.9 months, p < 0.05 for
the P65 group).15 A recent analysis of data from
1745 patients with metastatic breast, colorectal
and non-small-cell lung cancer who received bevacizumab plus chemotherapy in five randomized
controlled trials showed that in addition to bevacizumab administration, a history of atherosclerosis and age of 65 years or older were independent
risk factors for the development of arterial thrombotic events, thus raising some concern over the
tolerability of this agent in the elderly
population.16

Surgery
One systematic review covering the subject of surgery in elderly patients with colorectal cancer,
conducted by the Colorectal Cancer Collaborative
Group, was retrieved.4 The authors identified 60
relevant studies, and were able to obtain aggregate
data broken down by age from 28 studies, with a
total enrolment of 34,194 patients. Twenty of
these studies were prospective series of surgical

cases. They analyzed surgical outcome data from

patients divided according to the following age
groups: younger than 65, 6574, 7584 and 85
years or older. Patients were almost equally distributed among the first three groups, with 8%
belonging to the older than 85 years group. The
analysis of a series of studies including patients
who underwent curative, palliative, emergency
and elective surgery, showed that the relative risk
of postoperative death compared to the reference
incidence of the younger than 65 group was 1.8 for
the 6574 group, 3.2 for the 7584 group and 6.2
for the older than 85 group. A similar trend was
demonstrated concerning postoperative morbidity,
when data on respiratory complications, cardiovascular complications, cerebrovascular accident and
thromboembolism were analyzed, with all of these
events being more frequent with advancing age.
The odds of survival at two years post-surgery relative to the reference odds of the under-65 age
group were 0.91 for the 6574 age group, 0.77
for the 7584 age group and 0.62 for the over 85
group. This was less clear for the subgroup of patients who underwent curative resection, as in
some studies patients had similar survival rates
among the different age groups whereas in others
survival seemed to decrease with age, with the
odds of survival at two years being 0.92, 0.82,
and 0.65, respectively, for the three over-65 age
groups. Moreover, cancer-specific median five-year
survival rates were similar in all age groups, for patients who underwent curative surgery, i.e. 74% for
the younger than 65 age group, 69% for the 6574
group, 70% for the 7584 group, and 61% for the
older than 85 years group.
Puig-La Calle et al.17 identified 1120 consecutive
patients who underwent major pelvic surgery for
rectal cancer and compared the short- and longterm surgical outcome of the 157 patients aged
75 years or older with the outcome of a random
sample of 174 younger patients. Perioperative
complications did not differ between the two age
groups (34 vs. 36%, p = NS). Overall survival was
lower in the elderly group (5-yr survival 51 vs.
66%, p = 0.02), although the disease-specific survival rate was similar between the two age groups
(5-yr survival 69 vs. 71%, p = 0.75). Similarly, Chiappa et al.18reported equal 5-year survival rates
according to age (85% for the <65 age group, 76%
for the 6579 group and 69% for the P80 group,
p = 0.3) in the 346 consecutive colorectal cancer
patients analyzed who underwent surgery.
None of the reviews retrieved covered the prognosis and complications of metastasectomy in elderly patients. Most of the relevant search results
were reports of small series of patients, with little

6
information concerning advanced age. This is in
fact supported by the literature. Temple et al.19
conducted a review to evaluate the patterns of
cancer treatment for 9011 Medicare beneficiaries
presenting with stage IV colorectal cancer from
1991 to 1999. They reported that although elderly
patients with metastatic colorectal cancer were
likely to undergo palliative surgery (69% for the
over-75 group), only 3.9% of patients underwent
metastasectomy. Still, the percentage of patients
who had resectable metastases and, therefore,
were eligible for such a procedure was not
specified.

Discussion
Despite the fact that elderly people represent a
major proportion of colorectal cancer patients,
they are being frequently undertreated both for
early and advanced-stage disease.20,21 An explanation can be found in both the patients and the physicians attitudes. Patient preference is often the
main reason for not receiving adequate treatment,
as fatalism may play a more prominent role in the
decision-making process in elderly people. On the
other hand, physicians often tend to evaluate patients according to their chronological rather than
their biological age. This is not completely unjustified: most clinical trials impose an upper age limit
(usually 75 years) on the inclusion criteria, leading
to the absence of evidence-based guidelines for
treating older patients. However, it has been demonstrated by numerous reports, including the ones
in this review, that there is significant gain from
chemotherapy and surgery in the adjuvant and palliative setting, irrespective of patient age.
The reviewed reports consistently support the
notion that elderly patients have equal potential
gains with younger patients from adjuvant and palliative chemotherapy. The toxicity profile of most
regimens was mostly unchanged at older-age
groups, although some differences were reported
for specific drug combinations. Nevertheless, in
all reports the evidence was inconclusive concerning toxicity.
It is of value to note that all the retrospective
analyses concerning chemotherapy included in this
review refer to 5-FU-based chemotherapy. No attempt is made to distinguish among the various bolus and infusional 5-FU delivery schedules in use.
However, it should be noted that there is evidence
supportive of the fact that different schedules exhibit different toxicity profiles, with similar efficacy concerning survival.22,23 No claim can be
made from the data analyzed in the selected re-

V. Golfinopoulos et al.
views concerning the age-dependent toxicity profile that specific regimens may demonstrate.
Newer agents, such as irinotecan, oxaliplatin,
and capecitabine, were not included and data from
individual trials were used. We only tried to include
the most representative trials regarding the use of
these agents and not every single relevant report,
since our initial aim was to include reviews and
meta-analyses. The inclusion of additional trials
was not expected to alter the overall conclusion.
This somewhat limited experience does not demonstrate that age is an independent predictive factor
as far as efficacy and toxicity of these agents in the
elderly population are concerned. Irinotecan has
received much more attention than the other drugs
examined in this review. The recently published
trial of Sastre et al.,24 for the Spanish Cooperative
Group for the Treatment of Digestive Tumors, provides proof that irinotecan combined with infusional 5-FU/leucovorin is an active and well
tolerated combination in patients over 72 years of
age in good general condition. However, we think
that our review demonstrates that the resources
reserved for such trials may be better utilized with
the elimination of the upper age-limit in future relevant studies. Concern has been expressed regarding the gastrointestinal and cardiovascular toxicity
of irinotecan coupled with bolus 5-FU-based regimens, although this has been attributed to the specific schedule of administration interacting with
irinotecan and not the camptothecin per se. Attempts to individualize the dose of irinotecan have
been made, the most notable being the one of Van
Cutsem et al.,25 who proposed an algorithm using
three dose levels for single-agent three-weekly irinotecan (250, 350, and 500 mg/m2) for individual
dose escalation based on patient tolerance, thus
permitting optimal dose intensity without unacceptable toxicity in individual patients. Similarly,
the trial of Comella et al.26 attempts to individualize the doses of oxaliplatin and capecitabine when
the XELOX regimen is used to treat the elderly population. The incorporation of biological compounds
such as vascular endothelial growth factor (VEGF)
or epidermal growth factor receptor (EGFR) inhibitors in chemotherapy regimens, has been shown to
enhance effectiveness without appreciably
increasing toxicity.14,27 These offer promise for
rationally intensifying the treatment of elderly patients with specific data just emerging15 and more
being eagerly awaited from age subgroup analyses
of ongoing studies.
Evidence concerning the use of surgery was
harder to interpret. It is more common for elderly
people to have comorbid conditions not allowing a
surgical procedure to be performed, or not allow-

Treatment of colorectal cancer in the elderly: A review of the literature

ing rapid and uneventful recovery after surgery. Elderly people also frequently postpone medical consultation, leading to a greater proportion of
advanced-stage disease and therefore, more
extensive or frequently emergency operation. Indeed, in the systematic review of the Colorectal
Cancer Collaborative Group, 11% of patients younger than 65 years underwent emergency surgery, as
opposed to 15% in the 6574 age group, 18% in the
7584 age group, and an alarming 29% in the older
than 85 years group. Another disquieting statistic
from the same review is the proportion of unstaged
cancers in the different age groups, i.e. 3.9% in the
younger than 65 years group, 6.1% in the 6574 age
group, 9.0% in the 7584 age group, and 17.3% in
the older than 85 years group, showing that elderly
patients may have received substandard medical
care. However, the data reviewed suggest that surgery may be of benefit to selected patients, after
thorough medical evaluation from the surgical
team. There were not enough data to conclude if
there is any difference in the outcome of metastasectomy operations between younger and older age
groups.
It seems rational to conclude from this review
that no further trials are needed to evaluate agerelated differences in the activity and toxicity of
therapeutic interventions for colorectal cancer. It
may be proper to eliminate the age limit for inclusion in randomized controlled trials and simply rely
on performance status eligibility. The percentage
of elderly patients participating in the trials reviewed by the retrieved reports varies from 2.5%
to 35%, which is not representative of the actual
demographic characteristics of colorectal cancer
patients. A shift in colorectal cancer clinical research to represent the actual patient population
of the disease treated, may therefore be appropriate. Until further data are available, it seems wise
for the physician and the patient to jointly reach
therapeutic decisions on an individual basis, taking
into account the patients preferences and biologic, rather than chronological age.

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