VOLUME 22 䡠 NUMBER 16 䡠 AUGUST 15 2004

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

Phase III Study of Adjuvant Chemotherapy and

From the North Central Cancer Treat-
ment Group; Mayo Clinic, Rochester,
MN; Radiation Therapy Oncology
Group, Philadelphia, PA; Missouri Valley
Cancer Consortium, Omaha, NE; South-
west Oncology Group, San Antonio, TX;
National Cancer Institute of Canada—
Clinical Trials Group, Kingston, Ontario,
Canada; Eastern Cooperative Oncology
Group, Boston, MA; Cancer and Leuke-
mia Group B, Chicago, IL.
Submitted January 8, 2004; accepted
April 16, 2004.
Supported in part by Public Health Ser-
vice grants CA 25224, CA 37404, CA
15083, and CA 63849; CA 21661, CA
37422, and CA 32115 (Radiation Ther-
apy Oncology Group); CA 32102 and
CA 22433 (Southwest Oncology
Group); CA 21115 (Eastern Cooperative
Oncology Group); CA 31946 and CA
774400 (Cancer and Leukemia Group
B); and a grant from the National Can-
cer Institute of Canada (NCIC 4448).
Presented in part at the 35th Annual
Meeting of the American Society of Clini-
cal Oncology, Atlanta, GA, May 15, 1999.
Radiation Therapy Compared With Chemotherapy
Alone in the Surgical Adjuvant Treatment of Colon
Cancer: Results of Intergroup Protocol 0130
James A. Martenson Jr, Christopher G. Willett, Daniel J. Sargent, James A. Mailliard, John H. Donohue,
Leonard L. Gunderson, Charles R. Thomas Jr, Barbara Fisher, Al Bowen Benson III, Robert Myerson,
and Richard M. Goldberg
A B S T R A C T
Purpose
Some patients with colon cancer have a high risk of local recurrence postoperatively. This trial was
undertaken to determine whether radiation therapy added to an adjuvant chemotherapy regimen
improves outcome in high-risk patients.
Patients and Methods
Patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or with
T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive
fluorouracil and levamisole therapy with or without radiation therapy. Patients who received chemother-
apy and radiation therapy (chemoRT) received 45 to 50.4 Gy in 25 to 28 fractions beginning 28 days after
starting chemotherapy. Patient enrollment was terminated because of slow accrual after 222 patients
enrolled (original goal was 700 patients); 187 patients were assessable.
Results
Overall 5-year survival was 62% for chemotherapy patients and 58% for chemoRT patients (P ⬎ .50);
5-year disease-free survival was 51% for both groups (P ⬎ .50). Toxicity (ⱖ grade 3) occurred in 42% of
chemotherapy patients and 54% of chemoRT patients (P ⫽ .04). Leukopenia (ⱖ grade 3) occurred in
10% of chemotherapy patients and 22% of chemoRT patients (P ⫽ .02). No significant difference in
nonhematologic toxicity (ⱖ grade 3) was observed between chemoRT and chemotherapy patients
(35% v 44%; P ⫽ .26).
Conclusion
Patients who received chemotherapy or chemoRT had similar overall survival and disease-free survival.
Toxicity was higher among chemoRT patients. These results must be interpreted with caution because
of the high number of ineligible patients and the limited power of the study to detect potentially
meaningful differences.

Authors’ disclosures of potential con- J Clin Oncol 22:3277-3283. © 2004 by American Society of Clinical Oncology
flicts of interest are found at the end of
this article.

Address reprint requests to James A. of local-regional recurrence among 41 pa-

Martenson, MD, Mayo Clinic, 200 First
St SW, Rochester, MN 55905; e-mail:
jmartenson@mayo.edu.
© 2004 by American Society of Clinical
Oncology
0732-183X/04/2216-3277/$20.00
DOI: 10.1200/JCO.2004.01.029
INTRODUCTION
Studies of patients who have had a second
operation1 and autopsy findings2-4 after a
potentially curative operation for colon can-
cer suggest that the risk of local-regional
recurrence is substantial for patients with
tumor adherence to surrounding structures
or with involvement of regional lymph
nodes. The Minnesota reoperation series,
for example, documented a 37% incidence
tients with tumor penetration through the
wall of the colon, and involvement of lymph
nodes. Among 24 patients with tumor ad-
herence to, or invasion of, surrounding
structures, the incidence of local-regional
recurrence was 67%. In an analysis of au-
topsy findings from the University of Wash-
ington, local recurrence was documented
among 69% of patients who had tumor ad-
herence to, or invasion of, surrounding

3277

Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015

Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
 Martenson et al
structures at the time of their initial operation, and among
30% of patients with involvement of regional lymph nodes
and penetration of tumor through the bowel wall.2
Analyses of patterns of recurrence in clinical series
support the hypothesis that the risk of local-regional recur-
rence is potentially clinically significant in specific sub-
groups of patients after curative resection for colon
cancer.5-9 At University Hospital in Boston, for example, in
33% of the patients with cecal cancer and tumor adherence
or invasion of surrounding structures, local-regional recur-
rence developed after a potentially curative operation. Sim-
ilarly, local-regional recurrence developed in 33% of the
patients with regional lymph node involvement and tumor
penetration through the large bowel.7 At Massachusetts
General Hospital, local-regional recurrence was observed
after a potentially curative operation in at least 30% of the
patients with tumor adherence to surrounding structures or
with tumor penetration through the bowel wall and in-
volvement of regional lymph nodes.5
Prospective and retrospective studies of patients with
large bowel cancer have suggested a possible role for radiation
therapy in selected patients with colon cancer. Several ran-
domized clinical trials with rectal cancer patients who have
tumor penetration through the bowel (T3 or T4) or positive
nodes have shown that, when compared with no adjuvant
treatment or radiation therapy alone, postoperative pelvic
radiation therapy in combination with fluorouracil-based
chemotherapy improved freedom from local recurrence,
disease-free survival, and overall survival.10-13 More recently,
results from a phase III clinical trial have suggested that the
major contribution of radiation therapy to the postoperative
adjuvant treatment of rectal cancer may be improved local
control rather than improved survival.14 Retrospective studies
of patients with colon cancer have suggested that the potential
role of adjuvant radiation therapy should be evaluated in a
prospective randomized clinical trial.15-22 A nonrandomized
study from Massachusetts General Hospital, for example, sug-
gested that postoperative adjuvant radiation therapy might
result in decreased local recurrence for patients with resected
colon cancer who had tumor adherence to surrounding struc-
tures or tumor penetration through the bowel wall and in-
volvement of regional lymph nodes. In the subgroup of
patients with tumor adherence to surrounding structures and
positive nodes, for example, the local control rate was 47%
with surgery alone and 69% with surgery and postoperative
radiation therapy.19
A landmark phase III study provided the first unequiv-
ocal evidence that systemic therapy using fluorouracil and
levamisole improved survival among patients with com-
pletely resected lymph node–positive colon cancer.23,24 Af-
ter publication of this study, the use of adjuvant fluorouracil
and levamisole became the standard of care for this group of
patients. Many oncologists also began to give adjuvant che-
motherapy to patients with node-negative colon cancer
3278
Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
who had unfavorable prognoses, such as patients with non-
diploid tumors, high proliferative indexes,25 or unfavorable
clinical features such as obstruction.26
The availability of effective adjuvant systemic therapy
created an opportunity to design a study of selected patients
with colon cancer that had a high risk of local recurrence,
comparing postoperative fluorouracil and levamisole ther-
apy with fluorouracil, levamisole, and radiation therapy
(chemoRT). Before initiation of this study, it was deter-
mined that chemoRT could be safely administered.27
PATIENTS AND METHODS
The primary goal of this study was to determine whether the
addition of radiation therapy to an adjuvant chemotherapy regi-
men would improve survival among patients considered at high
risk of local-regional recurrence after complete resection of colon
cancer. Secondary objectives included evaluation of disease-free
survival, patterns of recurrence, and toxicity.
To be eligible for this study, patients had to have a history of
completely resected colon cancer that was at high risk of local-
regional recurrence. Specifically, patients were eligible if they met
the following criteria: (1) The tumor was at any site in the colon
with adherence to, or invasion of, surrounding structures, as de-
termined by either the surgeon or the pathologist (tumors desig-
nated as T4 only on the basis of peritoneal invasion were not
included), or the tumor involved the ascending or descending
colon with penetration through the wall of the colon (T3) and
involvement of metastatic regional lymph nodes. For T3 node-
positive patients with ascending or descending colon cancer, the
protocol initially required evidence of gross tumor penetration
through the entire bowel wall, or invasion more than 2 mm be-
yond the bowel wall. In December 1994, the protocol was modified
to allow all T3 node-positive ascending or descending colon can-
cer patients to participate without regard to the degree of tumor
penetration beyond the bowel wall. (2) Their surgical procedure
occurred within the previous 21 to 36 days, there were no active
complications, and the patient was receiving adequate oral nutri-
tion without significant nausea or vomiting. (3) Laboratory test
results were as follows: WBC count ⱖ 4,000 cells/mm3; platelet
count ⱖ 130,000 cells/mm3; creatinine no more than 20% above
the upper limit of the reference range; total bilirubin no more than
twice the upper limit of the reference range; AST less than 3⫻ the
upper limit of the reference range; and alkaline phosphatase no
more than 3⫻ the upper limit of the reference range. (4) Bilateral
renal function was demonstrated by an abdominal computed
tomography (CT) scan with a contrast or excretory urogram. (5) A
consultation with medical and radiation oncologists had occurred.
Consultation with the radiation oncologist was required for
confirmation that there was sufficient information about the pre-
operative tumor volume to design the radiation fields (eg, infor-
mation from the operative note, surgical clips, or preoperative
imaging studies). Written informed consent from patients, and
institutional review board approval were required before entry
onto the study.
Ineligible patients included those with incompletely resected
tumor, those with coexistent medical conditions that would pre-
clude protocol therapy, those with a history of prior radiation
therapy to the abdomen or pelvis, or those who had previous
chemotherapy or levamisole therapy. Additional contraindica-
JOURNAL OF CLINICAL ONCOLOGY
 Adjuvant Radiation Therapy in Colon Cancer
tions included age younger than 18 years, an Eastern Cooperative
Oncology Group performance status of 2 to 4, current pregnancy
or lactation, a history of invasive cancer in the preceding 5 years, or
distant metastases or metastatically involved lymph nodes along a
named vascular trunk (N3 nodes).
Patients were stratified by tumor extent (T3 or T4) and
number of lymph nodes involved (0, 1-3, or ⬎ 3) and were then
randomly assigned to receive either fluorouracil and levami-
sole23,24 or chemoRT.
Protocol therapy for all patients included administration
of levamisole at a dosage of 50 mg orally three times daily for 3
days, to be repeated every 14 days for 1 year. Therapy with
fluorouracil 450 mg/m2 administered as an intravenous bolus
on 5 consecutive days was initiated concurrently with the first
day of levamisole therapy.
Patients who were assigned to receive chemotherapy without
radiation therapy received weekly doses of fluorouracil 450 mg/m2
intravenously, beginning 28 days after the first dose of chemother-
apy, until therapy had been given for a total of 1 year.
Patients assigned to receive chemoRT began radiation ther-
apy 28 days after the first fluorouracil dose. A total dose of 45 Gy in
25 fractions was given to fields designed to encompass the preop-
erative tumor volume and regional lymph nodes, including the
adjacent para-aortic or pelvic lymph nodes. An additional three
fractions of 1.8 Gy each were given to the preoperative tumor
volume if all small bowel could be excluded from this boost field.
The protocol required that two-thirds of the liver receive less than
30 Gy, that at least two-thirds of one kidney receive less than 20 Gy
(as assessed by excretory urography done at simulation or CT
scan), and that the maximal dose to the spinal cord be less than 50
Gy. Systemic treatment during radiation therapy consisted of flu-
orouracil 450 mg/m2 given intravenously on the days of the first,
second, and third radiation fractions, and again on the days of the
23rd, 24th, and 25th radiation fractions. During radiation therapy,
levamisole 50 mg by mouth was given three times daily for 3 days
approximately every 2 weeks, beginning with the day of the first,
11th, and 23rd radiation fractions. Weekly treatment with flu-
orouracil was initiated 28 days after completion of radiation ther-
apy according to the same schedule and dose as the weekly
treatment administered to the patients assigned to receive chemo-
therapy alone. As with those patients, treatment continued until
therapy had been given for a total of 1 year.
According to the protocol, patients were evaluated at 12, 15,
18, and 21 months after initiation of treatment. Subsequent to this,
patients were followed up every 6 months, until the patient had
been followed up for 5 years, and then annually until the patient
had been followed up for 8 years. Routine evaluations at each
follow-up visit included history, physical examination, complete
blood count, liver function tests, and chest radiography. A barium
enema or colonoscopy was required at 18, 38, and 60 months after
study entry. CT scans of the abdomen and pelvis at 12 months after
study entry and at the time of tumor recurrence were considered
optional, to be done at the discretion of the patient’s physician.
Enrollment began in October 1992 with an accrual goal of
700 patients, which was estimated to provide 82% power for
detecting a 33% decrease in the death rate. Accrual was lower than
expected, and in March 1996, the goal was decreased to 400 pa-
tients, which, by extending the duration of follow-up, would have
provided 81% power to detect a 33% decrease in the death rate.
Enrollment ended in December 1996 because of slow accrual. Of
the 222 accrued patients, 187 were eligible and assessable. The
www.jco.org
Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
resulting study had 80% power to detect a 75% decrease in the
death rate for patients assigned to the chemoRT group, using a
one-sided log-rank test with a significance level of .05.
Survival was defined as the time from random assignment to
death or last contact. The disease-free interval was defined as the
time from random assignment to the date of the earliest of the
following: last evaluation for disease status if no recurrence was
evident, recurrence, or death. Patients who withdrew before the
study treatment or who were declared ineligible (n ⫽ 35) were
excluded from the primary analyses of study end points, including
disease-free survival, overall survival, and toxicity.
Frequency tables and summary statistics (eg, mean and me-
dian) were used to describe the distributions of patient character-
istics and toxicity. Parametric and ␹2 tests were used to test for
significant differences in patient characteristics and toxicity by
treatment arm. The Kaplan-Meier method28 was used to estimate
the distributions of disease-free and overall survival. Cox propor-
tional hazards models29 were used to explore the associations of
patient characteristics (eg, age and number of lymph nodes) with
patient outcome (eg, survival). Graphical methods were used to
verify model assumptions. The score statistic was used to test for a
significant difference in patient outcome on the basis of a single
covariate (eg, sex). The likelihood ratio test was used to test for the
significance of a single covariate in the presence of (or adjusting
for) other covariates. All analyses were conducted using SAS (SAS
Institute, Cary, NC) version 8.0 (SAS/STAT User’s Guide, Version
6; SAS Institute), and P values less than .05 were considered
statistically significant.
RESULTS
Between October 16, 1992, and December 17, 1996, a total
of 222 patients were enrolled onto this study. Subsequent
review determined that 34 patients were ineligible (Table 1),
and one patient withdrew before receiving any protocol
treatment. The remaining 187 patients were the subject of
the primary analyses of study end points. Information
about pathologic radial margin status was requested but
was not reliably provided and was not used in the deter-
mination of protocol eligibility. Six of the 94 eligible
patients assigned to receive chemoRT refused radiation
therapy, but all 94 patients were included in the primary
analysis of the chemoRT arm results. No significant dif-
ferences in baseline characteristics were observed be-
tween the treatment arms (Table 2).
Table 1. Reasons for Patient Ineligibility by Treatment Arm
No. of Patients
Reason ChemoRT Chemotherapy
Disease too extensive 8 8
Inadequate evaluation or 6 8
documentation
Wrong primary tumor or other 2 2
concurrent primary tumor
Total 16 18
Abbreviation: ChemoRT, chemotherapy and radiation therapy.
3279
 Martenson et al

Table 2. Characteristics of Eligible Patients by Treatment Arm

Treatment Arm
ChemoRT Chemotherapy
(n ⫽ 94) (n ⫽ 93)
No. of No. of
Characteristic Patients % Patients % P

Age, years .86

Median 62.5 62.0
Range 31-83 27-77
Sex .41
Male 49 52 54 58
Female 45 48 39 42
Tumor extentⴱ† .88
T3 18 19 17 18
Fig 2. Disease-free survival according to treatment. There was no signifi-
T4 76 81 76 82
cant difference between patients treated with or without radiation therapy.
No. of lymph nodes involvedⴱ .94 Chemo, chemotherapy; chemoRT, chemotherapy and radiation therapy.
0 38 40 40 43
1-3 37 39 35 38
⬎3 19 20 18 19
ECOG performance status .61
ilar (data not shown). Of the 187 eligible patients, 18 in each
0 57 61 53 57 study arm experienced local recurrence (defined as recur-
1 37 39 40 43 rence at the initial site of disease progression).
Abbreviations: ChemoRT, chemotherapy and radiation therapy; ECOG, Results of an analysis of prognostic factors are summa-
Eastern Cooperative Oncology Group.
ⴱ
rized in Table 4. In univariate analyses, an increased num-
Stratification factor.
†Staging criteria were based on those in the Manual for Staging ber of positive lymph nodes was the only factor significantly
of Cancer.30 associated with reduced survival, with hazard ratios for
overall survival of 1.7 (95% CI, 1.0 to 2.8) for patients with
one to three positive nodes and 2.7 (95% CI, 1.5 to 4.7) for
patients with more than three positive nodes, as compared
The median duration of follow-up of living patients
with patients with 0 positive nodes (P ⫽ .003; Table 4). A
was 6.6 years. Overall survival (Fig 1) and disease-free
test for interaction between the assigned treatment and each of
survival (Fig 2) were similar for the two treatment arms
the protocol-specified stratification factors did not show a
(P ⬎ .50 for both analyses). The 5-year disease-free survival
differential treatment effect between patient subsets and sur-
was 52% for the chemotherapy-only arm and 51% for the
vival, disease-free survival, or local control (data not shown).
chemoRT arm. Overall survival at 5 years was 58% for
There were two treatment-related deaths, one in each
the chemoRT patients and 62% for patients assigned to
arm of the study. A patient assigned to the chemotherapy
receive only chemotherapy. Table 3 presents the estimated
group died of sepsis after experiencing severe leukopenia. A
5-year rates and hazard ratios for overall and disease-free
patient assigned to the chemoRT group died of liver failure,
survival by treatment arm. In a secondary analysis of all 222
which was believed to be caused by fluourouracil and le-
patients entered in the study, results were substantially sim-
vamisole. A summary of toxicity that was grade 3 or worse is
provided in Table 5. A significantly higher rate of toxicity
(ⱖ grade 3) was observed in patients assigned to receive

Table 3. Time-to-Event Analysis by Treatment Arm

5-Year (%) Hazard Ratio
Event Rate 95% CI Value 95% CIⴱ P†

Disease-free survival 1 0.7 to 1.6 .85

Chemotherapy 52 42 to 63
ChemoRT 51 42 to 62
Survival 1.1 0.7 to 1.7 .60
Chemotherapy 62 53 to 73
ChemoRT 58 49 to 69

Abbreviation: ChemoRT, chemotherapy and radiation therapy.

ⴱ
Fig 1. Overall survival according to treatment. There was no significant Hazard ratio of chemoRT, relative to chemotherapy alone.
difference between patients treated with or without radiation therapy. †Score statistic.
Chemo, chemotherapy; chemoRT, chemotherapy and radiation therapy.

3280 JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015

Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
 Adjuvant Radiation Therapy in Colon Cancer

Table 4. Univariate Associations of Clinical Characteristics With Outcome

Survival Disease-Free Survival
5-Year (%) Hazard Ratio 5-Year (%) Hazard Ratio
ⴱ
Characteristic Rate 95% CI Value 95% CI P Rate 95% CI Value 95% CI Pⴱ

Age (increased) Not applicable† 1.02 1 to 1.04 .09 Not applicable† 1.02 1 to 1.04 .10
Sex 1.2 0.8 to 1.9 .31 1.4 0.9 to 2.1 .14
Male‡ 58 49 to 69 45 36 to 57
Female 62 52 to 74 58 48 to 70
Extent of invasion 1.1 0.6 to 1.9 .73 1.1 0.6 to 1.9 .72
T3 65 51 to 83 56 42 to 76
T4‡ 59 51 to 67 50 42 to 59
No. of positive nodes .003 ⬍ .001
0 70 60 to 81 64 54 to 76
1-3‡ 54 43 to 67 1.7 1 to 2.8 45 34 to 59 1.8 1.1 to 3.1
⬎ 3‡ 50 36 to 69 2.7 1.5 to 4.7 35 23 to 54 2.7 1.5 to 4.7
ⴱ
Score statistic.
†Continuous variable.
‡Risk factor (eg, the hazard ratio for death, comparing males and females, is 1.2).

chemoRT than in those assigned to receive chemotherapy in 32% of the patients assigned to receive chemotherapy
(54% v 42%; P ⫽ .04). Most of this difference was attributable (P ⫽ .48). A significantly higher rate of hematologic toxicity
to a significantly higher rate of hematologic toxicity in the (ⱖ grade 3) was observed in the patients assigned to receive
patients assigned to the chemoRT group (23% v 11%; P ⫽ .01). chemoRT than in the patients assigned to receive chemo-
No significant difference was observed in symptomatic, non- therapy (23% v 12%; P ⫽ .04).
hematologic toxicity between the two groups (44% for Review of the radiation therapy quality assurance for
chemoRT v 35% for chemotherapy; P ⫽ .26). The most com- this study showed that the dosimetry and radiation fields, as
mon nonhematologic toxicity was diarrhea, which occurred in defined by the marked tumor volume on the simulation
20% of patients assigned to receive chemoRT and 13% of those film and protocol guidelines, were satisfactory. One critical
assigned to receive chemotherapy (P ⫽ .17). caveat is related to the method of determining the tumor
Because of the large number of ineligible patients, a volume to guide radiation therapy planning. Ideally, ra-
secondary analysis of toxicity (ⱖ grade 3) was performed diopaque clips would be positioned around the surgical bed
for all 222 patients in this study. In this analysis, there was and preoperative radiologic imaging (ie, barium enema or
no significant difference in overall toxicity between the two abdominal pelvic CT scan) would be used to accurately
arms (57% for chemoRT v 42% for chemotherapy; P ⫽ .09). define the tumor volume, thus aiding in the design of the
Symptomatic nonhematologic toxicity was observed in radiation fields. Although use of clips was encouraged in the
37% of the patients assigned to receive chemoRT and protocol, clip placement was performed in only 18 (19%) of
94 patients. Preoperative radiologic imaging (ie, barium
enema or abdominal and pelvic CT scan) was used to facil-
Table 5. Acute Toxicity Among Patients by Treatment Arm itate treatment planning for 45 patients (48%). For 17 pa-
ChemoRT Chemotherapy tients (18%), the tumor volume was defined by clinical means
(n ⫽ 94) (n ⫽ 93) (by review with the surgeon or by review of operative reports
No. of No. of without clips or imaging). It was unclear whether preoperative
Toxicity ⱖ Grade 3 Patients % Patients % P
radiologic imaging was obtained for 14 of the patients.
Any 51 54 39 42 .04
Nonhematologic 41 44 33 35 .26
Hematologic 22 23 10 11 .01 DISCUSSION
Leukopenia 20 21 9 10 .02
Diarrhea 19 20 12 13 .17
Survival, disease-free survival, and local control were simi-
Nausea 5 5 2 2 .25
Stomatitis 1 1 2 2 .55
lar in this study for patients assigned to receive chemoRT as
Vomiting 2 2 2 2 .99 compared with those assigned to receive chemotherapy
Skin 2 2 4 4 .39 alone. Although this clinical trial did not meet its accrual
Lethargy 3 3 1 1 .31 objective, it is one of the largest studies of adjuvant radia-
Abbreviation: ChemoRT, chemotherapy and radiation therapy. tion therapy in colon cancer. The number of patients in
most previous studies has been 40 to 150.15-19,21,22,30 Only

www.jco.org 3281

Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015

Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
 Martenson et al

the retrospective study from Massachusetts General Hospi-
tal, which described results in 203 patients, was larger.20
Our study is also the only published randomized clinical
trial that addresses the role of adjuvant radiation therapy for
colon cancer.
The results of this study must be interpreted with cau-
tion because of several limitations. The study fell dramati-
cally short of its accrual objective and therefore lacked the
power to detect potentially clinically significant differences
in outcome. With 187 eligible patients, the study had 80%
power to detect a 75% decrease in the death rate for patients
treated with chemoRT. This degree of improvement in the
death rate is more than has been demonstrated in any
positive surgical adjuvant trial of chemotherapy for colon
cancer.23,24,31-35 The 95% CI for the hazard ratio for overall
survival, comparing chemotherapy with chemoRT, is large
(0.7 to 1.7). Because of this, a possible meaningful advan-
tage for chemoRT cannot be excluded.
Radiopaque surgical clips to guide the design of radia-
tion therapy fields were used in a minority of patients, and
preoperative imaging was not available for most patients.
Because of the lack of reliable information about radial
surgical margins, it is virtually certain that some patients
with microscopic residual disease were included in this
study. The local control data must be interpreted with cau-
tion because CT scans were not required for patient follow-
up. The large number of ineligible patients indicates that
physicians often had difficulty selecting appropriate pa-
tients for this trial. For these reasons, the results of this study
cannot be considered definitive.
Our study did demonstrate significant differences in
toxicity between patients treated with chemoRT and those
treated with chemotherapy alone (Table 5). Overall, signif-
icantly more chemoRT patients than chemotherapy pa-
tients experienced toxicity of grade 3 or worse (54% v 42%;
P ⫽ .04). Most of the overall differences in toxicity between
the two treatment arms can be accounted for by the higher
rate of leukopenia observed among patients treated with
chemoRT than among those treated with chemotherapy alone
(21% v 10%; P ⫽ .02). There was no significant difference in
overall symptomatic nonhematologic toxicity (ⱖ grade 3) be-
tween the two treatment arms (44% v 35%; P ⫽ .26).
In conclusion, similar outcomes were observed be-
tween patients treated with chemoRT and patients treated
with chemotherapy alone. Our study demonstrated poten-
tial issues that may be encountered in clinical trials of adju-
vant therapy, which require close cooperation among
surgeons, pathologists, medical oncologists, and radiation
oncologists. It is possible that a different result might
have been observed with a larger number of patients if
preoperative imaging had been consistently available; if
radiopaque clips had been consistently placed at the time
of surgery to guide design of radiation therapy fields; and
if more reliable pathologic details had been available to
better identify appropriate patients for consideration of
adjuvant radiation therapy. Our experience suggests that
any future investigation of adjuvant radiation therapy for
patients with colon cancer should be considered only at
institutions with a high degree of commitment and ex-
pertise in multiple specialties, so that patient selection
criteria and treatment parameters can be optimized. One
possible area for future investigation would be the role of
preoperative chemotherapy and radiation therapy in pa-
tients found to have unresectable disease at the time of
initial diagnosis.
■ ■ ■
Appendix
The appendix is included in the full-text version 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.

REFERENCES
1. Gunderson LL, Sosin H, Levitt S: Extrapel-
vic colon: Areas of failure in a reoperation se-
ries—Implications for adjuvant therapy. Int J
Radiat Oncol Biol Phys 11:731-741, 1985
2. Russell AH, Pelton J, Reheis CE, et al:
Adenocarcinoma of the colon: An autopsy study
with implications for new therapeutic strategies.
Cancer 56:1446-1451, 1985
3. Welch JP, Donaldson GA: The clinical cor-
relation of an autopsy study of recurrent colorec-
tal cancer. Ann Surg 189:496-502, 1979
4. Cass AW, Million RR, Pfaff WW: Patterns
of recurrence following surgery alone for adeno-
carcinoma of the colon and rectum. Cancer 37:
2861-2865, 1976
5. Willett CG, Tepper JE, Cohen AM, et al:
Failure patterns following curative resection of
colonic carcinoma. Ann Surg 200:685-690, 1984
6. Minsky BD, Mies C, Rich TA, et al: Poten-
tially curative surgery of colon cancer: Patterns
of failure and survival. J Clin Oncol 6:106-118,
1988
7. Simanovsky M, Feldman MI: Adenocarci-
noma of the cecum: Analysis of 106 cases.
Cancer 58:1766-1769, 1986
8. Russell AH, Tong D, Dawson LE, et al:
Adenocarcinoma of the retroperitoneal ascend-
ing and descending colon: Sites of initial dissem-
ination and clinical patterns of recurrence
following surgery alone. Int J Radiat Oncol Biol
Phys 9:361-365, 1983
9. Tong D, Russell AH, Dawson LE, et al:
Adenocarcinoma of the cecum: Natural history and
clinical patterns of recurrence following radical sur-
gery. Int J Radiat Oncol Biol Phys 9:357-360, 1983
10. Gastrointestinal Tumor Study Group: Pro-
longation of the disease-free interval in surgically
treated rectal carcinoma. N Engl J Med 312:
1465-1472, 1985
11. Douglass HO Jr, Moertel CG, Mayer RJ, et
al: Survival after postoperative combination treat-
ment of rectal cancer. N Engl J Med 315:1294-
1295, 1986
12. Krook JE, Moertel CG, Gunderson LL, et
al: Effective surgical adjuvant therapy for high-
risk rectal carcinoma. N Engl J Med 324:709-715,
1991
13. Tveit KM, Guldvog I, Hagen S, et al: Ran-
domized controlled trial of postoperative radio-
therapy and short-term time-scheduled
5-fluorouracil against surgery alone in the treat-

3282 JOURNAL OF CLINICAL ONCOLOGY

Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015

Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

ment of Dukes B and C rectal cancer. Br J Surg
84:1130-1135, 1997
14. Wolmark N, Wieand HS, Hyams DM, et al:
Randomized trial of postoperative adjuvant che-
motherapy with or without radiotherapy for car-
cinoma of the rectum: National Surgical Adjuvant
Breast and Bowel Project Protocol R-02. J Natl
Cancer Inst 92:388-396, 2000
15. Kopelson G: Adjuvant postoperative radia-
tion therapy for colorectal carcinoma above the
peritoneal reflection, I: Sigmoid colon. Cancer
51:1593-1598, 1983
16. Kopelson G: Adjuvant postoperative radia-
tion therapy for colorectal carcinoma above the
peritoneal reflection, II: Antimesenteric wall as-
cending and descending colon and cecum. Can-
cer 52:633-636, 1983
17. Brenner HJ, Bibi C, Chaitchik S: Adjuvant
therapy for Dukes C adenocarcinoma of colon.
Int J Radiat Oncol Biol Phys 9:1789-1792, 1983
18. Shehata WM, Meyer RL, Jazy FK, et al:
Regional adjuvant irradiation for adenocarcinoma
of the cecum. Int J Radiat Oncol Biol Phys
13:843-846, 1987
19. Willett CG, Tepper JE, Skates SJ, et al:
Adjuvant postoperative radiation therapy for co-
lonic carcinoma. Ann Surg 206:694-698, 1987
20. Willett CG, Fung CY, Kaufman DS, et al:
Postoperative radiation therapy for high-risk co-
lon carcinoma. J Clin Oncol 11:1112-1117, 1993
21. Willett CG, Goldberg S, Shellito PC, et al:
Does postoperative irradiation play a role in the
adjuvant therapy of stage T4 colon cancer? Can-
cer J Sci Am 5:242-247, 1999
www.jco.org
Downloaded from ascopubs.org by 181.208.182.15 on March 6, 2018 from 181.208.182.015
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
Adjuvant Radiation Therapy in Colon Cancer
22. Duttenhaver JR, Hoskins RB, Gunderson
LL, et al: Adjuvant postoperative radiation ther-
apy in the management of adenocarcinoma of
the colon. Cancer 57:955-963, 1986
23. Moertel CG, Fleming TR, Macdonald JS,
et al: Levamisole and fluorouracil for adjuvant
therapy of resected colon carcinoma. N Engl
J Med 322:352-358, 1990
24. Moertel CG, Fleming TR, Macdonald JS,
et al: Fluorouracil plus levamisole as effective
adjuvant therapy after resection of stage III colon
carcinoma: A final report. Ann Intern Med 122:
321-326, 1995
25. Witzig TE, Loprinzi CL, Gonchoroff NJ, et
al: DNA ploidy and cell kinetic measurements as
predictors of recurrence and survival in stages
B2 and C colorectal adenocarcinoma. Cancer
68:879-888, 1991
26. Burdy G, Panis Y, Alves A, et al: Identifying
patients with T3–T4 node-negative colon cancer
at high risk of recurrence. Dis Colon Rectum
44:1682-1688, 2001
27. Martenson JA Jr, Schutt AJ, Grado GL, et
al: Prospective phase I evaluation of radiation
therapy, 5-fluorouracil, and levamisole in locally
advanced gastrointestinal cancer. Int J Radiat
Oncol Biol Phys 28:439-443, 1994
28. Kaplan E, Meier P: Nonparametric estima-
tion for incomplete observations. J Am Stat
Assoc 53:457-481, 1958
29. Cox DR: Regression models and life ta-
bles. J R Stat Soc B 34:187-202, 1972
30. American Joint Committee on Cancer:
Manual for Staging of Cancer (ed 3), in Beahrs
OH, Henson DE, Hutter RVP, et al: (eds). Phila-
delphia, PA, JB Lippincott Co, 1988
31. Fabian CJ, Reddy E, Jewell W, et al: Phase
I-II pilot of whole abdominal radiation and con-
comitant 5-FU as an adjuvant in colon cancer: A
Southwest Oncology Group Study. Int J Radiat
Oncol Biol Phys 15:885-892, 1988
32. Staib L, Link KH, Beger HG, et al: Toxicity
and effects of adjuvant therapy in colon cancer:
Results of the German prospective, controlled
randomized multicenter trial FOGT-1. J Gastro-
intest Surg 5:275-281, 2001
33. O’Connell MJ, Laurie JA, Kahn M, et al:
Prospectively randomized trial of postoperative
adjuvant chemotherapy in patients with high-
risk colon cancer. J Clin Oncol 16:295-300,
1998
34. O’Connell MJ, Mailliard JA, Kahn MJ, et al:
Controlled trial of fluorouracil and low-dose leu-
covorin given for 6 months as postoperative
adjuvant therapy for colon cancer. J Clin Oncol
15:246-250, 1997
35. Wolmark N, Rockette H, Fisher B, et al:
The benefit of leucovorin-modulated fluorouracil
as postoperative adjuvant therapy for primary
colon cancer: Results from National Surgical
Adjuvant Breast and Bowel Project protocol
C-03. J Clin Oncol 11:1879-1887, 1993
36. Porschen R, Bermann A, Löffler T, et al:
Fluorouracil plus leucovorin as effective adjuvant
chemotherapy in curatively resected stage III
colon cancer: Results of the trial adjCCA-01.
J Clin Oncol 19:1787-1794, 2001
3283