VOLUME 22 NUMBER 16 AUGUST 15 2004

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Adjuvant Therapy for Stage II Colon Cancer: A

From the Hamilton Regional Cancer
Centre; Department of Clinical Epidemiol-
ogy and Biostatistics, McMaster Univer-
sity, Hamilton; and Ottawa Regional
Cancer Centre, Ottawa, Ontario, Canada.
Submitted March 13, 2003; accepted
March 16, 2004.
Supported by Cancer Care Ontario and
the Ontario Ministry of Health and
Long-Term Care.
Authors disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to Melissa C.
Brouwers, PhD, Department of Clinical
Epidemiology and Biostatistics,
McMaster University, 1280 Main St W,
T-27, 3rd Floor, Hamilton, Ontario,
Canada L8S 4L8; e-mail: mbrouwer@
mcmaster.ca.
2004 by American Society of Clinical
Oncology
0732-183X/04/2216-3395/$20.00
DOI: 10.1200/JCO.2004.03.087
Systematic Review From the Cancer Care Ontario
Program in Evidence-Based Cares Gastrointestinal
Cancer Disease Site Group
Alvaro Figueredo, Manya L. Charette, Jean Maroun, Melissa C. Brouwers, and Lisa Zuraw
A B S T R A C T
Purpose
To develop a systematic review that would address the following question: Should patients with stage
II colon cancer receive adjuvant therapy?
Methods
A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy
to observation.
Results
Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes
primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing
fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or
overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit
for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free
survival benefits appeared to extend to stage II patients; however, no P values were provided. A
meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and
overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients
where data were available (n 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P .07).
Conclusion
There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival
benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated
with improved overall survival. Patients should be made aware of these results and encouraged to
participate in active clinical trials. Additional investigation of newer therapies and more mature data from
the presently available trials should be pursued.

J Clin Oncol 22:3395-3407. 2004 by American Society of Clinical Oncology

III disease (lymph node metastases): 40% to

INTRODUCTION
Colon cancer is second only to lung cancer as a
leading cause of death from cancer. The prog-
nosis of the newly diagnosed colon cancer pa-
tient is determined by the clinicopathologic
stage of the disease. In stage II disease there is
tumor penetration through the bowel wall be-
yond the submucosa, but there is no involve-
ment of the regional lymph nodes or distant
sites. The overall survival in this group of pa-
tients is 70% to 80% 5 years after surgery.1
High-risk stage II disease is associated with an
outcome similar to that of patients with stage
50% overall survival at 5 years. These high-risk
patients are identified by tumors that not only
penetrate the bowel wall, but also show evi-
dence of adhesion to or invasion of surround-
ing structures, free perforation, obstruction,
or aneuploidy.2 Adjuvant therapy has been
recommended for stage III colon cancer pa-
tients because decreases in relapse and mortal-
ity rates by 30% to 40% were observed
compared with observation after surgery.3 A
systematic review of the literature was under-
taken to determine the value of adjuvant ther-
apy in stage II colon cancer.

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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
 Figueredo et al
METHODS
Development of Systematic Review
In 1997, the Gastrointestinal Cancer Disease Site Group of
the Cancer Care Ontario Program in Evidence-Based Care
(CCOPEBC) published an evidence-based practice guideline on
the use of adjuvant therapy for stage II colon cancer after complete
resection4 using the methodology outlined in the practice guide-
lines development cycle of Browman et al.5 Oncologists and meth-
odologists developed the practice guideline that comprises a
systematic review, evidence synthesis, interpretation, and external
review by practitioners in Ontario, Canada. Since the publication
of the original practice guideline in 1997, new evidence relating
to adjuvant therapy for stage II colon cancer has been pub-
lished. This document is an update of the original systematic
review included in the original practice guideline produced by
the CCOPEBC,4 and includes literature published since 1997.
Literature Search Strategy
The MEDLINE (1966 through July 2003), CANCERLIT
(1983 through October 2002), and Cochrane Library (through
issue 2, 2003) databases were searched using the medical subject
headings colonic neoplasms, colorectal neoplasms, adjuvant
chemotherapy, adjuvant radiotherapy, and immunotherapy,
and the text words colon cancer and colonic neoplasms. These
terms were then combined with the search terms for the following
study designs: practice guidelines, systematic reviews or meta-
analyses, and randomized controlled trials. In addition, proceed-
ings from the annual meetings of the American Society of Clinical
Oncology (1998 to 2003) and the American Society for Therapeu-
tic Radiology and Oncology (1998 to 2002) were searched for
reports of newly completed trials. Personal reprint files and refer-
ence lists of relevant studies were also searched.
Inclusion Criteria
Articles were selected for inclusion in this systematic review
of the evidence if they met the following criteria: randomized
controlled trials (RCTs) or meta-analyses of RCTs involving pa-
tients with stage II colon cancer who had undergone surgery with
curative intent that compared adjuvant therapy with observation;
and the main outcome of primary interest was survival, but
disease-free survival was also considered. Because of the inconsis-
tent reporting of treatment toxicities and quality of life, these data
were not considered.
Exclusion Criteria
This review considered clinical trials published after 1987.
Buyse et al6 summarized the results of randomized trials of adju-
vant therapy for colorectal cancer up to that year. The results of
this meta-analysis are reviewed at the beginning of Results. Trials
comparing different adjuvant treatment regimens without an ob-
servation arm were originally reviewed, but have been omitted
from this report; they did not contribute to the main review
question. A list of the trials reviewed is available on request.
Synthesis of the Evidence
Individual patient data were not available for review. When
pooling of data is to be undertaken and individual patient data are
not available, two methods can be used to extract data from
primary studies to perform meta-analysis: estimating the number
of events from survival curves (when actual numbers of events are
not reported), or using the method outlined by Parmar et al,7
which describes ways of calculating hazard ratios estimates. Al-
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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
though the latter has many benefits, appropriate data must be
available. Data on stage II colon cancer patients were available for
pooling from 18 studies using survival curves to estimate the
number of events. In most of these studies, insufficient informa-
tion was available (in either the published reports or follow-up
with the authors) to proceed with the Parmar method. In weighing
the pros and cons of each option, we decided on the strategy that
would maximize the sample size for the analysis. Data on specific
subgroups of stage II patients (ie, high-risk v low-risk) were not
available. Data on survival were combined at the time of follow-up
reported in each study, but it should be noted that the length of
follow-up differed across studies. Combining data in this way
assumes a constant hazard ratio of risks between the groups
being compared. The data did not allow for statistical adjust-
ments of covariates such as length of follow-up when pooling
was undertaken.
Data across studies were combined using the meta-analysis
software, Metaview Update Software (The Cochrane Collabora-
tion, Oxford, UK). Results are expressed as relative risks (also
known as risk ratios; RR) with 95% CIs, where an RR less than 1.0
favors the experimental treatment,8 indicating that patients in the
experimental treatment group (adjuvant therapy) experienced few
deaths compared with those receiving control treatment (observa-
tion). Data were analyzed using the random effects models.9 For
calculation of the RR and the 95% CI for survival data, the denom-
inator used was the number of patients randomly assigned to
treatment rather than those at risk at the time of follow-up, which
will overestimate the precision of the confidence limits. These
narrower limits do not alter the conclusions in this case.
RESULTS
Original Meta-Analysis of Adjuvant Therapy
(RCTs to 1987)
In 1988, Buyse et al6 conducted a meta-analysis of
all English trials of adjuvant therapy for colorectal cancer
(all stages included). Seventeen trials compared adjuvant
chemotherapy with surgery alone in patients with colorectal
cancer (6,791 patients). The pooled results detected no
significant difference in the odds of death between treat-
ment and control (odd ratio [OR], 0.96; 95% CI, 0.87 to
1.06). Stage could not be examined because of the lack
of standardization of staging methods. For the subgroup of
patients treated with fluorouracil (FU) for at least 1 year, a
significant decrease in the odds of death was detected (OR,
0.83; 95% CI, 0.70 to 0.98; P .03) when compared with
untreated controls.
Summary of Randomized Controlled Trials
(after 1987)
The literature search identified 37 randomized con-
trolled trials and 11 meta-analyses published after 1987. The
literature reviewed in this report has been grouped into
categories according to the type of treatment tested.
In all of the RCTs reviewed, patients with stage II colon
cancer had undergone surgery with curative intent and were
randomly assigned to receive adjuvant therapy or observa-
tion. Most systemic adjuvant therapy started within 5 to 6
JOURNAL OF CLINICAL ONCOLOGY
 Adjuvant Therapy for Stage II Colon Cancer

Table 1. Adjuvant Therapy Trials Including Patients With Stage II Colon Cancer: Number of Patients and Proportion With Stage II Disease According to
Adjuvant Therapy Used
No. of No. of % Stage No. Colon Cancer % Stage No. Colorectal % Stage
Adjuvant Therapy Trials Patients (total) II Patients II Cancer Patients II

FU-Sem 2 1,674 36 1,113 43 561 23

FU-Lev 4 1,887 54 325 100 1,562 45
FU FA-IV 5 2,082 49 2,082 49 NA NA
IP-FU 3 486 52 385 55 101 43
PVI-FU 14 9,520 32 1,585 36 7,935 31
HAI-FU 1 286 NR 286 NR NA NA
Oral FU 3 3,158 39 984 NR 2,174 39
Immuno 5 1,224 74 1,043 81 181 33
Total 37 20,317 NA 7,803 NA 12,514 NA

Abbreviations: FU, fluorouracil; FU-Sem, FU plus semustine; FU-Lev, FU plus levamisole; FU FA-IV, FU plus folinic acid (leucovorin) intravenously; IP-FU,
FU by intraperitoneal infusion; PVI-FU, FU by portal vein infusion either alone or with mitomycin; HAI-FU, hepatic artery infusion of FU; Immuno,
immunotherapy; NA not applicable; NR not reported; oral FU, oral fluoropyrimidines either alone or combined with mitomycin.

weeks postoperatively. For portal vein infusion (PVI), treat-
ment began immediately after surgery. The backbone of
most adjuvant regimens was intravenous (IV; systemic) FU,
often combined with semustine,10,11 levamisole,12-15 or fo-
linic acid (leucovorin).16-18 In some trials, FU or an analog
of this drug was administered by PVI,19-32 by intraperito-
neal (IP)33-35 hepatic artery infusion,36 or orally.37-39
Immunotherapy was either nonspecific with Bacillus
Calmette-Guerin (BCG)10,11 or prepared from autologous
tumor cells.40-42 Eligible patients were those with good per-
formance status or general health; no active comorbidity or
previous malignancy except skin cancer; and good hemato-
logic, renal, and hepatic functions. The median age of pa-
tients included in the trials was in the mid-60s, and the
proportion of males and females was similar. Compliance
with treatment was well described. Stratification before ran-
domization was performed in most trials, especially for
stage and tumor location. Stratification for stage was not
possible in trials using chemotherapy by PVI.
Overall, 20,317 patients were included in 37 trials (Ta-
ble 1). These trials included 7,803 patients with colon can-
cer and 12,514 patients with colorectal cancer. The
proportion of patients with stage II disease ranged from
23% to 100%. Results of adjuvant treatment for stage II
colon cancer, therefore, derive mainly from clinical trials
that also included patients with stage III colon cancer, oc-
casionally stage I, and patients with rectal cancer. Results for
stage II colon cancer are based mainly on subgroup analysis
and thus, the generalizability of results is open to some
interpretation. These circumstances require consideration
of the overall trial result, along with subgroup analysis of
patients with stage II colon cancer. For a summary of overall
results across all patients as well as subgroup analyses of
stage II patients, readers are referred to Tables 2 to 7. For the

Table 2. Randomized Adjuvant Trials in Stage II Colon Cancer: FU Combined With Semustine Versus Observation
Number of Patients
Randomized (eligible)
Months Colon Median All Trial Patients Stage II Patients
Receiving Follow-Up
Trial Treatment Allocation Therapy Rectal II III (years) DFS% OS% DFS% OS%
10
SWOG, 1988 Obs NR (14) NR (80) 7.0 44 51 NR 61
FU m-CCNU 12.0 NR (28) NR (213) 45 51 57
FU m-CCNU BCG 12.0 NR (36) NR (190) 40 47 53
P NS P NS P NS
11
NSABP C-01, 1988 Obs NR (169) NR (214) 6.4 (mean) 51 59 NR NR
BCG 20.0 NR (154) NR (221) 56 67
MOF 20.0 NR (154) NR (201) 58 67

Abbreviations: FU, fluorouracil; DFS, disease-free survival; OS, overall survival; SWOG, Southwest Oncology Group; Obs, observation; m-CCNU,
methyl-CCNU (semustine); BCG, Bacillus Calmette-Gurin; NR, not reported; NS, not significant; NSABP, National Surgical Adjuvant Breast and Bowel
Project; MOF, semustine vincristine FU.

Numbers may include patients with rectal cancer.
Patients in this trial were randomly assigned in two phases. Data marked with this symbol reflect only patients randomly assigned in the second phase
of the trial (n 279, total; n 56, stage II).
P .05 (compared with observation).

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 Figueredo et al

Table 3. Randomized Adjuvant Trials in Stage II Colon Cancer: Systemic Therapy With Levamisole and FU
Number of Patients
Randomized (eligible)
Months Colon Median All Trial Patients Stage II Patients
Receiving Follow-Up
Trial Treatment Allocation Therapy Rectal II III (years) DFS% OS% DFS% OS%
12
Windle et al, 1987 Obs NR (19) NR (26) NR 56 NR NR
FU 6.0 NR (16) NR (26) 5.0 48
FU Lev 6.0 NR (20) NR (25) 68
13
NCCTG, 1989 Obs NR (8) NR (127) 45 53 59 76
Lev 12.0 NR (8) NR (122) 7.8 53 59 67 76
FU Lev 12.0 NR (12) NR (124) 57 61 73 76
14
INT-0035, 1995 Obs 161 (159) 7.0 NA NA 71 72
FU Lev 12.0 164 (159) 79 72
P .10 P .83
15
NACCP, 2001 Obs 150 (NR) 365 (NR) 4.7 51 58 65 70
FU Lev 12.0 149 (NR) 365 (NR) 58 68 71 78

Abbreviations: FU, fluorouracil; DFS, disease-free survival; OS, overall survival; Obs, observation; Lev, levamisole; NR, not reported; NCCTG, North Central
Cancer Treatment Group; INT, Intergroup of US Clinical Trial Groups; NA, not applicable; NACCP, Netherlands Adjuvant Colorectal Cancer Project.

P .05 (compared with observation).
Values estimated from survival curves.
May include patients with rectal cancer.

purposes of this report, the text focuses on the survival and
disease-free survival results from studies where data on
stage II patients were reported separately. Adverse effects
are discussed only in cases where stage II patient data
were available.
Systemic adjuvant chemotherapy: FU combined with se-
mustine. Two trials compared adjuvant chemotherapy
plus FU and semustine with observation10,11 (Table 2). The
Southwest Oncology Group trial included a third arm in-
vestigating the addition of BCG to FU and semustine.10 No
significant differences in disease-free or overall survival
were reported for the entire group, or the subset of stage II
colorectal cancer patients. The National Surgical Adjuvant
Breast and Bowel Project (NSABP) trial C-01 added vincris-
tine to FU and semustine (MOF) and also included a third
treatment arm investigating BCG alone.11 No separate data
were provided for stage II patients, although it was stated
that there was no significant interaction between treatment
effect and stage, despite significant improvements in
disease-free and overall survival favoring adjuvant chemo-
therapy when all patients were considered.
Systemic adjuvant chemotherapy: FU and levamisole.
Four randomized trials compared the combination of FU
plus levamisole with observation12-15 (Table 3). Two of the
trials also included a third arm consisting of either single-
agent FU12 or single-agent levamisole.13 One trial did not
report a separate analysis by stage and is not discussed
further.12 Two trials included colon and rectal cancer pa-
tients and reported separate analyses for stage II disease.13,15
The North Central Cancer Treatment Group trial reported
no statistically significant improvements in disease-free or
overall survival for single-agent levamisole or levamisole
plus FU when compared with observation for the subset of
patients with stage II disease (Table 3), despite reported
improvements in disease-free survival when all patients
were considered.13 In the Netherlands Adjuvant Colorectal
Cancer Project trial, significant disease-free and overall sur-
vival benefits favoring FU plus levamisole compared with
observation were reported in subgroup analysis of stage II
patients, but the P values were not provided.15 Similar ben-
efits for both outcomes were reported for all patients.
The Intergroup 0035 study included only patients with
stage II colon cancer (n 325).14 Adjuvant therapy was
found to reduce the recurrence rate by 31%, but this did not
reach levels of statistical significance (P .10). No differ-
ences in overall survival were detected (P .83). To inves-
tigate possible prognostic factors in patients with stage II
colon cancer, data from this trial were pooled with data
from stage II patients included in the North Central Cancer
Treatment Group trial (403 patients total).13 The analysis
did not detect any interactions between treatment effect and
any of the prognostic factors examined (sex, age, adhesion,
invasion, obstruction, perforation, location, or days since
surgery). When the pooled data on recurrence were ad-
justed for perforation and location of primary tumor (the
significant variables in the multivariate analysis), there was
a 38% reduction in the rate of recurrence for treatment
when compared with observation (P .02). There was
no corresponding improvement in survival when the
data were adjusted for location of primary tumor and age
(the significant variables in the multivariate analysis of
survival; P .91).
Systemic adjuvant chemotherapy: FU and folinic acid
(leucovorin). Five trials have tested the combination of FU

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 Adjuvant Therapy for Stage II Colon Cancer

Table 4. Randomized Adjuvant Trials in Stage II Colon Cancer: Systemic Therapy With Folinic Acid (leucovorin) and FU
Number of Patients
Randomized (eligible)
All Trial
Months Colon Median Patients Stage II Patients
Receiving Follow-Up
Trial Treatment Allocation Therapy Rectal II III (years) DFS% OS% DFS% OS%
16
NCCTG, 1997 Obs NR (27) NR (124) 6.0 58 63 NR NR
FU FA 6.0 NR (30) NR (128) 74 74
17
Francini et al, 1994 Obs 61 (60) 60 (58) 4.5 59 65 77 86
FU FA 12.0 60 (59) 58 (57) 74 79 83 89
P NR P NR
18
GIVIO-SITAC, 1998 Obs NR (228) NR (218) 5.0 54 65 68 77
FU FA 6.0 NR (223) NR (200) 66 72 76 80
P NS P NS
43
IMPACT 1, 1995 Obs NR (423) NR (334) 3.0 62 78 76 90
FU FA 6.0 NR (418) NR (318) 71 83 79 88
P NR P NR
44
IMPACT 2, 1999 Obs NR (509) 5.8 NA NA 73 80
FU FA 6.0 or 12.0 NR (507) 76 82
P .06 P .06

Abbreviations: FU, fluorouracil; DFS, disease-free survival; OS, overall survival; NCCTG, North Central Cancer Treatment Group; Obs, observation; FA, folinic
acid (leucovorin); NR, not reported; GIVIO-SITAC, Gruppo Italiano Valutazione Interventi in OncologiaStudio Italiano Terapia Adiuvante Colon; NS, not
significant; IMPACT, International Multicentre Pooled Analysis of Colon Cancer Trials.

Included in the IMPACT 2 study as part of a meta-analysis of stage II colon cancer patients using individual patient data.
Indicates a statistically significant difference (P .05 compared with observation).
Included in the IMPACT 1 study as part of a meta-analysis of stage II and III colon cancer patients using individual patient data.
Event-free survival data.

modulated by folinic acid (leucovorin) compared with ob-
servation (Table 4). Only three of these trials have been
published individually.16-18 The most compelling analysis
of these trials comes from the International Multicenter
Pooled Analysis of Colon Cancer Trials (IMPACT). These
investigators initially pooled data from three trials.43 More
recently, they performed a meta-analysis using individual
patient data of patients with stage II colon cancer partici-
pating in all five trials.44 This pooled analysis yielded no
significant difference in 5-year event-free survival (hazard
ratio [HR], 0.83; 90% CI, 0.72 to 1.07) or overall survival
(HR, 0.86; 90% CI, 0.68 to 1.07) for FU plus folinic acid
compared with observation.
The IMPACT investigators reported one death as a
result of septic shock.43 Grade 3 to 4 toxicities observed in
stage II patients included stomatitis in 11% of patients,
diarrhea in 8% of patients, leukopenia in 2% of patients,
thrombocytopenia in 2% of patients, and nausea and vom-
iting in 4% of patients.44
Regional chemotherapy: PVI. The fourth group of tri-
als (Table 5) investigated the role of chemotherapy admin-
istered by PVI. Fourteen randomized trials19-32 and two
meta-analyses45,46 were located. Data specific to stage II
patients was reported in only six of the reports.19-21,23,29,32
An initial trial by Taylor et al19 reported a significant
improvement in 5-year overall survival for PVI of FU com-
pared with observation in the subgroup of patients with
stage II colon cancer (95% v 65%; P .002), and for all
subgroups combined (78% v 58%; P .002). A seven-day
PVI of FU and heparin was tested in eight subsequent
trials.20-27 Data on stage II patients were reported separately
in three trials,20,21,23 none of which reported significant
differences in overall or disease-free survival. In contrast,
when all patients were considered, PVI chemotherapy was
associated with significantly improved overall survival
compared with observation (P .037) and IV FU (P
.026) in one of the eight trials23 and a significant improve-
ment in disease-free survival at 4 years for PVI versus ob-
servation (74% v 64%; P .02) in a second trial.24
The addition of mitomycin C to the standard PVI
regimen was tested in four trials.28-31 No significant differ-
ences in disease-free or overall survival were reported in the
trials that provided separate data on stage II patients28,29
and only one trial reported a significant improvement in
disease-free (57% v 48%; P .05) and overall survival
(66% v 55%; P .05) for PVI versus observation across
all patients.29
Adjuvant floxuridine delivered by PVI was compared
with observation in one additional trial; no significant
differences were reported in overall or disease-free survival
in the subgroup of stage II colon cancer patients, or across
all patients.32
A meta-analysis of the published literature reported in
1991 including data from six randomized trials19,21-24,28
detected an overall 31% decrease in deaths for PVI com-
pared with observation (P .0002).45 A separate analysis

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 Figueredo et al

Table 5. Randomized Adjuvant Trials in Stage II Colon Cancer: PVI Therapy

Number of Patients Randomized (eligible)
Colon Median All Trial Patients Stage II Patients
Treatment Days Follow-Up
Trial Allocation Receiving PVI Rectal I II III (years) DFS% OS% DFS% OS%
PVI of FU With/Without Heparin
19
Taylor et al, 1985 Obs NR (66) NR (6) NR (34) NR (20) 5.0 NR 58 NR 65
PVI-FU/hep 7.0 NR (54) NR (5) NR (38) NR (19) 78 95
20
LBCP-UK, 1992 Obs NR (68) NR (77) 5.0 NR 77 NR 93
PVI-hep 7.0 NR (66) NR (57) 73 81
PVI-FU/hep 7.0 NR (69) NR (61) 82 90
ENR NR (88) NR (114) 74 87
P NS P NS
21
NCCTG, 1990 Obs NR (3) NR (106) 5.5 67 68 NR 79
PVI-FU/hep 7.0 NR (7) NR (103) 73 68 79
P .57 P .61 P .73
22
Rotterdam, 1990 Obs NR (44) NR (6) NR (30) NR (22) 3.7 NR 58 NR NR
PVI-urokinase 1.0 NR (38) NR (11) NR (30) NR (24) 58
PVI-FU/hep 7.0 NR (46) NR (6) NR (24) NR (23) 65
P NR
23
ANZ, 1987 Obs 372 (232) NR 58 62 79 78
IV-FU 7.0 64 65 82 75
PVI-FU 7.0 67 81 68 83
P NS P NS P NS
NSABP C-02 Obs NR (114) NR (202) NR (143) 3.5 (mean) 64 73 NR NR
24
1990 PVI-FU/hep 7.0 NR (96) NR (189) NR (157) 74 81
25
EORTC, 1997 Obs NR (6) NR (41) NR (23) 9.0 56 69 NR NR
PVI-hep 7.0 NR (5) NR (32) NR (19) 56 61
PVI-FU/hep 7.0 NR (8) NR (42) NR (19) 65 71
Plus 4 with unknown stage P NS P NS

Rougier et al, Obs NR (232) NR (367) 5.3 67 73 NR NR

26
1998 PVI-FU/hep 7.0 NR (230) NR (365) 65 72
P NS P NS
UKCC R AXIS, Obs 4.0 NR NR NR NR
27
1999 (abstr) PVI-FU/hep 7.0 1,541 (NR) 2,042 (NR)

PVI of FU Plus Mitomycin With/Without Heparin

28
Ryan et al, 1988 Obs
(abstr) PVI-hep 5.0 63 (NR) 169 (NR) 1.8 NR NR NR NR
PVI-MIFU/hep 5.0 P NS P NS
29
SAKK 1995 Obs NR (92) NR (174) 8.0 48 55 63 69
PVI-MIFU/hep 7.0 NR (93) NR (174) 57 66 68 77
P NS P NS

30
SAKK 40/87 1998 Obs 5.0 63 72 NR NR
(abstr) PVI-MIFU/hep 7.0 277 (NR) 492 (NR) 60 68
IV-MIFU/hep 7.0 64 74
P NS P NS
31
Focan, 2000 Obs 48 81 4.5 70 74 NR NR
PVI-MIFU/hep 7.0 46 84 68 76

PVI of Other Agents

Schlag et al, Obs NR (34) NR (21) 3.9 80 81 NR NR
32
1990 PVI-FUDR/ 7.0 NR (36) NR (22) 80 81 P .89 P .40
hep
P .95 P .3

Abbreviations: PVI, portal vein infusion; DFS, disease-free survival; OS, overall survival; Obs, observation; FU, fluorouracil; hep, heparin; NR, not reported;
LBCP-UK, Large Bowel Cancer Project; ENR, eligible patients not randomized; NS, not significant; NCCTG, North Central Cancer Treatment Group; IV,
intravenous; ANZ, Australia and New Zealand; NSABP, National Surgical Adjuvant Breast and Bowel Project; EORTC, European Organization for Research and
Treatment of Cancer; UKCCCR, United Kingdom Coordination Committee on Cancer Research; MIFU, mitomycin FU; SAKK, Swiss Group for Clinical
Cancer Research; FUDR, floxuridine; Lev, levamisole; FA, folinic acid (leucovorin).

Statistically significant difference (P .05 compared with observation).
May include patients with rectal cancer.
Values estimated from survival curves.
Patients in this trial were involved in a second randomization to a comparison of FU Lev v FU FA Lev following PVI.

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 Adjuvant Therapy for Stage II Colon Cancer

Table 6. Randomized Adjuvant Trials in Stage II Colon Cancer: Intraperitoneal Chemotherapy

Number of Patients
Randomized (eligible)
Time Colon Median All Trial Patients Stage II Patients
Receiving Follow-Up
Trial Treatment Allocation Therapy Rectal II III (years) DFS% OS% DFS% OS%
33
Vaillant et al, 2000 Obs NR (77) NR (57) 4.8 62 69 73 79
FU-IP 6.0 days NR (74) NR (59) 68 74 89 88
P .26 P .30 P NS
34
Scheithauer et al, 1995 Obs NR (31) NR (29) 4.6 58 63 NR NR
FU FA-IV IP 6.0 months NR (29) NR (29) 75 78 P NS P NS
35
Graf et al, 1994 Placebo 6.0 days 13 NR (38) NR NR NR NR NR
FU-IP FA-IV 6.0 days 10 NR (40)

Abbreviations: DFS, disease-free survival; OS, overall survival; Obs, observation; FU, fluorouracil; IP, intraperitoneal; IV, intravenous; NR, not reported; NS,
not significant.

P .05 (compared with observation).
Difference is significant only when those who received the full dose of FU were compared with those receiving no adjuvant treatment.

on stage II patients was not performed. In 1997, a second
meta-analysis was published using individual patient data
from nine published trials19-25,28,29 and one unpublished
trial of PVI in colorectal cancer.46 An 18% and 13.6%
(P .006) reduction in the annual odds of death emerged
for stage II and all patients, respectively. Patients with early-
stage disease (Dukes A and B) experienced a 5% absolute
improvement in survival at 5 years (70.5% [control] v
75.5% [PVI]; P .01) when data from nine trials, excluding
the trial by Taylor et al,19 were analyzed.
Regional chemotherapy: IP chemotherapy. Chemother-
apy delivered by the IP route has been tested in three trials of
adjuvant therapy33-35 (Table 6). Two trials used no-
treatment control groups,33,34 one trial used a placebo.35
Clinical outcomes related to recurrence and survival were
reported in two trials.33,34
Vaillant et al33 reported improved 5-year disease-free
survival in the treatment group in patients with stage II
cancer (89% v 73%; P .05) when patients who had re-
ceived the full dose of intraperitoneal FU (n 58) were
compared with those in the surgery-alone group (n 77).
The difference was not significant when all stage II patients
were considered. No improvements in overall survival were
observed in stage II patients.
No significant differences in disease-free or overall sur-
vival in stage II patients were reported in the study by
Scheithauer et al,34 despite an observed benefit for treat-
ment in overall survival when all patients were considered.
Regional chemotherapy: hepatic arterial infusion. Sada-
hiro et al36 reported on a trial of 286 stage II and III colon
cancer patients randomized to a control arm consisting of
observation only following surgery, or to chemotherapy
consisting of FU delivered by a 21-day hepatic arterial infu-
sion beginning on postoperative day 7. Three-year disease-
free (86% v 76%; P .002) and overall survival (91% v
83%; P .03) were significantly improved in the patients
receiving chemotherapy compared with patients in the
observation arm. Results of this trial have been reported
in abstract form only, and there was no separate analysis
by stage. No serious toxicities were observed with hepatic
arterial infusion.
Oral FU or analogs. Three trials were located that
investigated an oral preparation of FU37-39 (Table 7). One
trial compared oral FU to observation37; the other two
compared a combination of mitomycin and FU to observa-
tion.38,39 Data specific to stage II patients were available for
one trial only.39 No significant differences in disease-free or
overall survival were reported for the subgroup of stage II
patients, or for all study patients.
Japanese investigators performed a meta-analysis using
individual patient data from three randomized trials of oral
FU and its prodrugs (tegafur, carmofur) versus observation
in 4,960 patients with curatively resected colorectal cancer
(Dukes A, B, and C).47 Two of the included trials were
included in this systematic review,37,39 wheras the third was
published in Japanese and therefore did not meet the inclu-
sion criteria. A total of 185 patients were excluded from the
final analysis because of violations in the randomization
procedure. After a median follow-up of almost 5 years,
subgroup analysis of patients with Dukes B colon cancer
demonstrated no significant difference in overall survival
(P .721) or disease-free survival (P .296) for adjuvant
chemotherapy compared with surgery alone. This meta-
analysis has been updated in abstract form to include 9,819
patients with colorectal cancer from six trials.48 It is not
clear from the abstract which trials were included. Overall,
the results for the six trials detected an advantage in disease-
free survival (RR, 0.84; 95% CI, 0.79 to 0.91; P .0001) and
overall survival (RR, 0.91; 95% CI, 0.84 to 0.99; P .022)
for oral agents versus surgery alone. This benefit was also
detected for stage II patients for disease-free (RR, 0.78; 95%

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 Figueredo et al

Table 7. Randomized Trials in Stage II Colon Cancer: Oral FU Therapy

Number of Patients
Randomly Assigned
Months Colon Median All Trial Patients Stage II Patients
Receiving Follow-Up
Trial Treatment Allocation Therapy Rectal II III (years) DFS% OS% DFS% OS%
37
Ito et al, 1996 Obs 40 (NR) 45 (NR) NR 63 NR NR NR
HCFU 12.0 37 (NR) 51 (NR) 77 P NS
38
Watanabe et al, 2000 Obs NR NR (405) NR 72 78 NR NR
(abstr) MIFU HCFU NR (579) 78 82
P NS
39
CCCSG-Japan, 1995 Obs 335 (293) 315 (279) NR 76 80 88 90
MIFU-1 6.0 323 (297) 354 (327) 81 82 89 88
MIFU-2 6.0 346 (316) 328 (293) 77 80 84 84
P NS P NS P NS P NS

Abbreviations: FU, fluorouracil; DFS, disease-free survival; OS, overall survival; Obs, observation; HCFU, 1-hexylcarbamoyl-fluorouracil; NR, not reported; NS,
not significant; MIFU, mitomycin fluorouracil; CCCSG, Colorectal Cancer Chemotherapy Study Group of Japan.

A statistically significant difference (P .05).
Includes patients with stage I, II, and III disease.

CI, 0.68 to 0.88; P .001) and overall survival (RR, 0.84;
95% CI, 0.72 to 0.97; P .017).
Immunotherapy. Passive immunotherapy with BCG,
with or without chemotherapy, has been tested in early
trials,10,11 although no benefit compared with chemother-
apy alone has been observed (Table 2). More recently,
Isenberg et al49 tested preoperative immunostimulation
with bacterial products compared with a no-treatment con-
trol in 101 patients with colon and rectal cancer. At 6.3 years
of follow-up for all patients, immunostimulation was asso-
ciated with improved overall survival (54% v 34%), includ-
ing 22 stage II patients (90% v 45%). Formal significance
tests were not reported, and the sample size was small.
Three trials compared vaccination with autologous tu-
mor cells and BCG with observation.40-42 Hoover et al40
included 80 patients with high-risk stage II and III colon
and rectal cancer; only a subanalysis of colon cancer pa-
tients (all stages) yielded a survival benefit in favor of treat-
ment (83% v 52%; P .02). Vermorken et al41 included 254
patients with stage II and III colon cancer. Analysis by stage
at a median follow-up of 5.3 years detected a significant
recurrence-free survival benefit for patients with stage II
colon cancer favoring immunotherapy (42% risk reduction
for recurrence or death; 95% CI, 0% to 68%; P .023).
There was no significant difference in overall survival in
stage II patients (P .15). The Eastern Cooperative Oncol-
ogy Group trial randomly assigned 412 patients with colon
cancer (297 stage II, 115 stage III) to adjuvant immunother-
apy consisting of an autologous tumor cell and BCG vaccine
(n 205; 148 stage II) or no adjuvant treatment (n 207;
149 stage II) after surgery.42 After a median follow-up of 7.6
years, there were no statistically significant differences be-
tween the two treatment arms in disease-free (64% [vac-
cine] v 66% [observation]) or overall survival (69%
[vaccine] v 71% [observation]) for stage II patients. Similar
results were obtained in the overall analysis of all patients.
In a trial reported in abstract form, Dencausse et al50
randomly assigned 377 stage II colon cancer patients to
treatment with edrecolomab, a murine monoclonal anti-
body, or observation following surgery. After a median
follow-up of 1.1 years, the overall disease-free rate was 93%
in the edrecolomab and 92% with observation (P .50).
No difference in overall survival was observed.
Other Literature
Since the publication of the Buyse et al6 meta-
analysis, several meta-analyses of adjuvant therapy (all
types of chemotherapy),51-55 and one evidence-based
practice guideline including a meta-analysis of adjuvant
therapy4 have been published. These publications are
described below.
Meta-analyses of adjuvant therapy (all types). In addi-
tion to the therapy-specific meta-analyses of FU plus folinic
acid,43,44 chemotherapy by PVI,45,46 and oral FU47 dis-
cussed in previous sections of the systematic review, there
have been other meta-analyses reported which combined
results of trials using several different adjuvant chemo-
therapy regimens compared with observation. Three of
the meta-analyses did not report on stage II colon cancer
patient outcomes51-53 and will not be discussed further.
Two meta-analyses referred specifically to stage II colon
cancer patients.54,55
Mamounas et al54 pooled data from four trials (proto-
cols C-01, C-02, C-03, and C-04) by the NSABP that com-
pared different adjuvant chemotherapy regimens with each
other or with no adjuvant therapy for patients with Dukes
B and C colorectal cancer. The pooled groups were formed
by combining the study arms with the inferior overall and

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 Adjuvant Therapy for Stage II Colon Cancer
recurrence-free survival versus the study arms with the
superior results for each of these outcomes. The inferior
treatment group included the surgery group in C-01 and
C-02, the MOF group in C-03, and the FU plus levamisole
group in C-04. The superior treatment group included the
MOF group in C-01, perioperative PVI of FU in C-02, and
FU plus leucovorin in C-03 and C-04. Among 1,565 pa-
tients with Dukes B colon cancer, there was a 30% RR
reduction in mortality for the superior treatment group
compared with the inferior treatment group. A graph of the
pooled ORs indicated that the reduction in the odds of
death, recurrence, and disease-free survival events was sta-
tistically significant for Dukes B patients. There was a sta-
tistically significant reduction in mortality for patients with
Dukes B colon cancer who presented without adverse clin-
ical prognostic factors, but the survival benefit was not
statistically significant for Dukes B patients with high-risk
prognostic factors.
A pooled analysis of trials comparing adjuvant therapy
with FU combined with levamisole13,14 or folinic acid16,17,43
compared with observation for patients with stage II and III
colon cancer was recently published in abstract form.55
Using the database developed by Sargent et al53 with indi-
vidual patient data from 3,341 patients with stage II and III
colon cancer in seven RCTs, these investigators performed
an analysis based on a Cox proportional hazards model.
Prognostic factors considered were adjuvant treatment, age,
sex, tumor location, T stage, nodal status, and tumor grade.
In a multivariate analysis adjusted for T stage, nodal status,
and grade, adjuvant therapy was associated with a signifi-
cant beneficial treatment effect for recurrence (35% reduc-
tion in risk of recurrence; HR, 0.65; 95% CI, 0.58 to 0.73)
and mortality (30% reduction in risk of death; HR, 0.73;
95% CI, 0.63 to 0.79). The authors reported that these
benefits associated with adjuvant therapy occurred across
all subsets. The authors tabulated the estimates of 5-year
disease-free survival for subgroups according to T stage,
nodal status, and tumor histologic grade, demonstrating
that patients attain similar proportional benefit from adju-
vant therapy regardless of T stage, nodal status, or grade.
However, neither the total number of patients in each sub-
group, nor the P values of the differences in 5-year disease-
free survival were provided in the abstract. However, the
trend is quite striking and the fully published results of this
analysis are awaited.
Evidence-based practice guidelines. In 1997, the
CCOPEBC published an evidence-based practice guideline
on adjuvant therapy in stage II colon cancer based on a
systematic review of 25 randomized controlled trials and
one meta-analysis.4 The group did not recommend adju-
vant therapy for patients with stage II colon cancer, but
encouraged the enrollment of stage II patients onto clinical
trials comparing adjuvant therapy with observation. In view
of uncertainty about the role of adjuvant therapy in stage
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II colon cancer, the CCOPEBC practice guideline in-
cluded a pooled analysis of stage II patients where data
were available.4 The meta-analysis did not indicate a
significant reduction in the odds of death for adjuvant
treatment compared with observation (OR, 0.83; 95%
CI, 0.62 to 1.10). The OR for patients receiving PVI was
0.62 (95% CI, 0.35 to 1.11).
Updated meta-analysis. An update of the 1997
CCOPEBC meta-analysis of trials comparing adjuvant
therapy to observation is shown in Figure 1. Survival data
were available for 4,187 patients with stage II disease across
18 trials.10,11,13-15,19-21,24,29,39,41,42,44 Using the more con-
servative random effects model,9 the mortality RR across
the trials was 0.87 (95% CI, 0.75 to 1.01; P .07). This
overall result must be interpreted cautiously because this
was a selected group of trials using a variety of adjuvant
therapies. Of more interest are the pooled results of studies
of commonly used adjuvant treatments. Pooling the results
of three trials investigating FU plus levamisole led to a
mortality RR of 0.90 (95% CI, 0.71 to 1.13; P .35).
Combining these results with those of the five trials of FU
plus folinic acid included in the IMPACT B2 analysis re-
sulted in an RR of 0.86 (95% CI, 0.73 to 1.01; P .07). A
pooled analysis of five trials investigating adjuvant therapy
by PVI resulted in an RR of 0.70 (95% CI, 0.44 to 1.11; P
.13). It should be noted that significant heterogeneity was
detected in the pooled analysis of the PVI trials (Fig 1).
DISCUSSION
In 1988, Buyse et al6 conducted a meta-analysis of clinical
trials of adjuvant therapy for colorectal cancer. A significant
difference in the odds of death was not detected between
adjuvant therapy and observation. In the subgroup of pa-
tients treated with FU for 1 year, a small but significant
benefit for adjuvant therapy was detected. Additional sub-
group analyses were impossible due to the lack of standard-
ization of surgery, staging, and distinction between rectum
and colon, and due to the poor description of treatment
compliance. The authors of the meta-analysis stressed the
need for larger clinical trials with improved methodology to
provide definitive answers regarding the benefits of adju-
vant therapy.
In 1990, the National Institutes of Health reviewed the
available evidence on adjuvant therapy for colon and rectal
cancer.3 Adjuvant therapy with FU and levamisole was rec-
ommended for patients with stage III colon cancer because
clinical trials had shown disease relapse and mortality de-
creased by 30% to 40% at 5 years. The panel did not recom-
mend any specific therapy outside of a clinical trial for
patients with stage II disease.
Since the publication of the meta-analysis by Buyse et
al6 and the National Institutes of Health Consensus Confer-
3403
 Figueredo et al

Fig 1. The Netherlands Central Cancer Treatment Group (NACCP), North Central Cancer Treatment Group (NCCTG), Large Bowel Cancer Project (LBCP) -UK,
NCCTG (protal vein infusion [PVI]), and Swiss Group for Clinical Cancer Research (SAKK) trials include rectal cancer patients. Data for the LBCP-UK, NCCTG (PVI),
and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 and C-02 were estimated from survival curves or tables. Data on stage II patients for
the NSABP C-01 and C-02 trials were located in the pooled analysis by Mamounas et al,54 and the numbers of patients are slightly different from the original
publications detailed in Tables 2 and 5. IMPACT, International Multicenter Pooled Analysis of Colon Cancer Trials; FU, fluorouracil; SWOG, Southwest Oncology
Group; ECOG, Eastern Cooperative Oncology Group; CCCSG, Colorectal Cancer Chemotherapy Study Group of Japan.

ence recommendations,3 a significant number of trials have abandoned an observation arm in favor of FU plus levami-
investigated varied forms of adjuvant therapy. Unfortu- sole as the control treatment. Many trials also have included
nately, a large number of recently published trials have both stage II and III patients in the same trial, and not all

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 Adjuvant Therapy for Stage II Colon Cancer
have provided a separate subgroup analysis of stage II pa-
tients. The backbone of adjuvant therapy has been FU. Its
administration has been mainly by the peripheral IV route,
but perioperative PVI, intraperitoneal, and oral prepara-
tions have been evaluated. IV FU has been tested rarely as a
single-agent, but has been added with other drugs including
semustine, mitomycin, immune stimulants such as levami-
sole and monoclonal antibody 17A, and folinic acid, a bio-
chemical modulator of FU.
Many of these trials have continued to show benefits
for adjuvant therapy in patients with stage III disease,
whereas its value has remained doubtful for stage II pa-
tients. None of the individual trials reviewed has shown a
significant benefit in overall survival for stage II colon can-
cer for adjuvant treatment compared with observation. The
Netherlands Adjuvant Colorectal Cancer Project trial did
demonstrate a benefit for stage II colon and rectal cancer
combined and showed survival curves for stage II and III
colon cancer depicting the benefit of adjuvant therapy, but
neither the number of patients nor P values for the differ-
ences were given.15 The pooling of data of five trials using
adjuvant FU plus folinic acid detected a small 2% absolute
survival benefit (P .057, one sided) for stage II patients.44
Similar lack of benefit was noted in meta-analyses of oral
fluoropyrimidines.47 However, three other meta-analyses
demonstrated beneficial effects of adjuvant therapy in stage
II patients. A meta-analysis of individual patient data in-
cluding trials of FU by PVI showed an 18% reduction in the
annual odds of death (P .006), translating into a 5%
absolute 5-year survival for stage II patients.46 An analysis of
four consecutive trials by NSABP showed similar rates of
RR reduction of 18% to 20% for patients with stage II and
III disease.54 More recently, Gill et al55 reported on an
analysis of patients with stage II and III colon cancer
participating in seven trials of FU combined with either
levamisole or folinic acid compared with observation.
The investigators observed disease-free survival benefits
for all subsets of curatively resected colon cancer. How-
ever, the data are currently only available in abstract
form, and the number of patients in each subset and the
P values were not provided.
In a recent article, Buyse and Piedbois56 provide a
statistical perspective to the question, Should Dukes B
patients receive adjuvant chemotherapy? The authors at-
tribute the lack of survival benefit in the individual trials to
the insufficient number of patients, to the relatively good
prognosis of this group of patients (80% survival at 5 years),
and to the competing noncancer deaths in this population.
They also add statistical approaches that can be used to
investigate the benefits of adjuvant therapy. The first ap-
proach is to consider that the overall effect of the treatment
should be similar for all stages of the disease. This consid-
eration is possible because there are no a priori biologic
reasons for the treatment effect to be different in stage II and
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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
III colon cancer. A second approach, which we have fol-
lowed in this overview, is to estimate the treatment benefits
in a meta-analysis of stage II patients. The problem with this
approach is the lack of significant data in the publications
and the relative inefficiency of the procedure because it
eliminates patients with other stages of the disease in the
analysis. A third approach compares the RR reduction of
patients with different stages of the disease. Mamounas et
al54 used this approach comparing the results of four con-
secutive NSABP trials of adjuvant therapy. Their analysis
showed similar relative risk reductions for stage II and III
colon cancer. Finally, a fourth approach is to perform tests
of interaction between treatment effect and stage of the
disease. This procedure is the most sensitive and efficient
because it uses the information from all stages of the disease.
The investigators of two NSABP trials, C-0111 and C-02,24
have reported lack of significant interaction between
treatment effect and stage, suggesting similar relative risk
reduction in different stages of the disease. Buyse and
Piedbois56 conclude their article by outlining the number
of patients required to detect a significant treatment
benefit in stage II colon cancer.
So far, no trial has enrolled the 4,000 assessable patients
required. An alternative approach will be to perform a
meta-analysis of trials including stage II colon cancer pa-
tients. We have attempted this task; unfortunately the pub-
lished data are incomplete for this subgroup of patients.
Certainly, such an investigation can be done with updated
individual patient data provided by the trialists. Gill et al55
have done this analysis on a database originally developed
by Sargent et al.53 The analysis of seven trials using systemic
FU plus levamisole or folinic acid has demonstrated similar
relative risk reductions in recurrences and deaths for stage II
and III disease. This is the most direct evidence that adju-
vant therapy is effective in stage II colon cancer. This anal-
ysis has not been published in full and details on the number
of patients in each subgroup, as well as the P values, were
not provided in the abstract. The absolute risk difference
for disease-free survival ranged from 5% for T3N0 stage
to 15% for T3-4N2 stage. Overall survival differences are
likely to be smaller, as indicated by results of the individ-
ual trials analyzed.
A question that should be posed is how large does a
benefit in overall survival (or disease-free survival) have to
be to become not only statistically significant, but most
importantly, clinically relevant? If adjuvant treatment were
completely nontoxic and nondemanding, then a minimal
benefit would be sufficient to recommend such treatment.
Most adjuvant effective treatments such as systemic FU plus
levamisole or folinic acid, however, are associated not only
with measurable side effects, but often with nonmeasured
symptoms such as fatigue, anorexia, loss of taste, and med-
ical dependence, which affect quality of life. Measurement
of these subtle changes should be a priority for future clin-
3405
 Figueredo et al

ical trials. Present improvements in disease-free and, per-
haps, in overall survival are modest: at best, only one of
eight to 20 treated patients will benefit, whereas the remain-
der will receive treatment with no benefit. Additional trials
are required to improve treatment, testing either potentially
more effective therapies such as combinations of FU with
folinic acid and oxaliplatin, or those with lesser toxicity
such as the use of FU by continuous infusion or the mono-
clonal antibody. In the meantime, the advice for adjuvant
therapy in stage II colon cancer should be cautious. Patients
should be given objective facts of benefit and harm, so that
the decision for or against treatment is arrived at mutually.
Patients should also be offered the participation in clinical
trials that test potentially more effective and/or less toxic
treatments and measure quality of life.
In summary, there is no compelling evidence to advise
standard use of systemic adjuvant therapy for patients with
stage II resected colon cancer. There is probably a small
survival benefit for adjuvant treatment that present trials
have not detected as significant. The important question is
whether this small benefit might prove to be clinically sig-
nificant for recommendation as standard therapy. Addi-
tional investigation of newer therapies and more mature
data from the presently available trials should be pursued.
Acknowledgment
The acknowledgment is included in the full-text ver-
sion of this article, available online at www.jco.org. It is not
included in the PDF (via Adobe Acrobat Reader) version.
Authors Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.

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