Download Controlled Trial of Fluorouracil and Low-Dose

Controlled Trial of Fluorouracil and Low-Dose
Leucovorin Given for 6 Months as Postoperative
Adjuvant Therapy for Colon Cancer
By Michael J. O'Connell, James A. Mailliard, Michael J. Kahn, John S. Macdonald, Daniel G. Hailler,
Robert J. Mayer, and Harry S. Wieand
Purpose: The goal of this study was to determine the
efficacy-of intensive-course fluorouracil (5FU) plus lowdose leucovorin given for 6 months following potentially
curative resection of colon cancer.
Patients and Methods: Three hundred seventeen patients with high-risk stage IIor stage IIIcolon cancer were
randomly assigned 3 to 4 weeks following surgery to
receive either (1) chemotherapy with six cycles of 5FU
(425 mg/m 2) plus leucovorin (20 mg/m 2 ) by rapid intravenous injection daily for 5 consecutive days every 4 to
5 weeks, or (2) observation.
Results: The median follow-up duration is 72 months
for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant im-
E
XPERIMENTAL STUDIES from a variety of preclinical model tumor systems have established the
ability of leucovorin to enhance the cytotoxicity of fluorouracil (5FU).' -3 Early controlled clinical trials demonstrated improved tumor response rates when the combination of 5FU and leucovorin, given in various dosage
administration schedules, was compared with singleagent 5FU in patients with metastatic colorectal cancer. 4 5
Some of these studies also demonstrated short-term survival improvement with SFU/leucovorin4 '5 in the palliative treatment of metastatic colorectal cancer.
With this background, a prospectively randomized clinical trial was initiated in 1988 to test the value of intensive-course 5FU combined with low-dose leucovorin as
postoperative adjuvant therapy in patients with high-risk
primary colon cancer. We desired to determine whether
the use of this chemotherapy regimen, which had been
shown to be more active than 5FU alone in patients with
advanced disease, could improve long-term survival when
provement in time to relapse (P < .01) and survival (P =
.02) compared with control patients treated with surgery
alone. Stomatitis, diarrhea, and leukopenia were the
predominant chemotherapy toxicities. There were no
treatment-related deaths.
Conclusion: These results indicate that intensivecourse 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients
with high-risk colon cancer. These benefits were seen
with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient
for outpatient administration.
1997 by American SoJ Clin Oncol 15:246-250.
ciety of Clinical Oncology.
given as adjuvant therapy in the minimal residual disease
setting following surgical removal of the primary tumor.
We elected to give chemotherapy for 6 months.
As originally conceived, this study had an untreated
control arm, since it had not been established that adjuvant chemotherapy was effective in patients with colon
cancer when the trial was started. We believed that it was
no longer appropriate to randomize high-risk colon cancer
patients to observation without adjuvant chemotherapy
when the emerging results of a national intergroup trial
clearly demonstrated that relapse-free and overall survival
were significantly improved with the use of 5FU plus
levamisole given for 1 year following surgery. 9 Our trial
was thus prematurely discontinued after the entry of 317
patients.
The preliminary results of this study were reported at
the American Society of Clinical Oncology Meeting in
1993.' ° This report presents the mature results of our
clinical trial.
PATIENTS AND METHODS
Eligibility Criteria
From the North Central Cancer Treatment Group, Rochester, MN.
Submitted February 20. 1996; accepted June 25, 1996.
Supported by thefollowing grantsfrom the National Cancer Institute, Bethesda, MD: U10 CA 25224 (North Central Cancer Treatment Group), U10 CA 32102 (Southwest Oncology Group), U10 CA
21115 (Eastern Cooperative Oncology Group), and U1O CA 31946
(Cancer and Leukemia Group B).
Address reprint requests to Michael J. O'Connell, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN
55905; Email [email protected].
© 1997 by American Society of Clinical Oncology.
0732-183X/97/1501-0015$3.00/0
246
Patients must have had histologic proof of adenocarcinoma of the
colon and have undergone complete resection of the primary tumor
without gross or microscopic evidence of residual disease. All known
tumor had to be resected en bloc. Only patients at high risk for
tumor relapse following surgery were eligible, as indicated by one
or more of the following features of the primary colon cancer: (1)
regional lymph node metastases; (2) transmural penetration of the
muscular wall of the bowel with evidence of bowel obstruction,
perforation, adherence, or invasion of adjacent organ(s); and (3)
regional peritoneal or mesenteric implants resected en bloc. The
inferior margin of the tumor had to be above the peritoneal reflection.
Patients had to be ambulatory and maintaining adequate oral nutri-
Journal of Clinical Oncology, Vol 15, No 1 (January), 1997: pp 246-250
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Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved.
COLON CANCER SURGICAL ADJUVANT THERAPY
tion; patients were randomized into the study between 21 and 30
days postoperatively. Informed consent was required.
The following factors were contraindications to participating in
this trial: WBC count less than 3,500/L, platelet count less than
100,000/giL, prior or concurrent radiation or chemotherapy for colon
cancer, concurrent or previous second malignant disease within the
preceding 3 years (except superficial squamous or basal cell skin
cancer, or in situ carcinoma of the uterine cervix), pregnancy, or
lactation.
Patient Eligibility and Follow-Up
Patients underwent a history and physical examination, complete
blood cell count, and liver function tests at weeks 4. 8, 13, 18, and
23 during chemotherapy, or at weeks 13 and 23 if randomized to
observation. Chest x-ray was performed at week 13, and proctoscopic examination and colon x-ray (or colonoscopy) were performed within the first 6 months for all patients. All patients were
subsequently evaluated at 9 months, 12 months, and every 6 months
to 5 years with a history and physical examination, complete blood
cell count, liver function tests, and chest x-ray. Proctoscopic examination and colon x-ray (or colonoscopy) were performed annually.
Testing for serum carcinoembryonic antigen (CEA) was optional.
Chemotherapy Dosage Administration Schedule
5FU was given by rapid intravenous infusion (push) at a dose of
425 mg/m 2 /d for 5 consecutive days. Leucovorin was also given by
rapid intravenous infusion at dose of 20 mg/m immediately preceding each dose of 5FU. Courses were repeated at 4 weeks, 8 weeks,
and then every 5 weeks for a total of six cycles.
Randomization Procedures
Before randomization, patients were stratified according to the
following criteria: extent of invasion by the primary tumor, presence
or absence of intestinal obstruction, presence or absence of regional
peritoneal metastases resected en bloc, and extent of regional lymph
node metastases.
Patients were then randomized to receive six courses of 5FU/
leucovorin chemotherapy, or to be monitored without the use of
adjuvant chemotherapy.
StatisticalMethods
Statistical analyses were performed using the statistical language
S-plus1 and SAS.' 2 Relapse-free and survival curves were calculated
using standard Kaplan-Meier methodology." The log-rank statistic
was used to compare survival distributions. 4 Proportional hazards
models were used for all multivariate analyses 5 to identify factors
significantly related to relapse and survival times. Factors were retained in the models if the corresponding estimates had a two-sided
P value less than .05. To adjust for covariates when evaluating
treatments, we forced the variable that indicated the patients' treatment regimens into the model and used a backward-selection regression method to identify which of the remaining covanates were
significantly associated with the end point.
RESULTS
Administrative Data
Three hundred seventeen patients entered the study between February 1988 and August 1989. Patients were
247
Table 1. Patient Characteristics
Vaorable
No. of patients
Age, years
Median
Range
%of patients
Sex (male/female)
Regional implants (yes/no)
Obstruction* (yes/no)
Extent of invasion
Bowel wall
Into or through serosa
Perforation
Adjacent organs-adhesion
Adjacent organs-invasion
Nodal involvement
0
1-4
>4
Surgery Alone
Surgery + Chemotherapy
151
158
64.1
29.1-81.7
62.7
22 4-79.4
62/38
13/87
35/65
52/48
13/87
37/63
15
67
3
12
3
13
70
4
9
4
18
58
24
19
56
25
*Bowel obstruction determined by preoperative symptoms; or endoscopic, surgical, or pathologic findings indicating definite narrowing of
bowel lumen and producing at least partial obstruction.
entered from 17 individual institutions, including 106
from the North Central Cancer Treatment Group, 86 from
the Southwest Oncology Group (SWOG), 70 from the
Eastern Cooperative Oncology Group (ECOG), and 55
from Cancer and Leukemia Group B (CALGB). Eight
patients (2.5%) were ineligible: five from the chemotherapy arm and three from the observation arm. Statistical
analyses have used data from the 309 eligible patients.
The median patient follow-up duration is 72 months,
while 195 of 205 patients who are still alive have at
least 4 years of follow-up evaluation. Baseline patient
characteristics are listed in Table 1. There were no significant differences between the two groups.
Tumor Relapse
Among 309 eligible patients, 105 have relapsed: 62 of
151 (41%) in the control group and 43 of 158 (27%)
in the chemotherapy group. The proportion of patients
relapse-free at 5 years was 0.74 for those who received
chemotherapy and 0.58 for those treated with surgery
alone. These data provide strong evidence that chemotherapy patients had a significantly better time to relapse
than control patients (Fig 1) as seen by the two-sided P
values (.004 before adjusting for other covariates and .001
after adjusting for covariates). When the stratification factors plus sex and age were combined with treatment in a
multivariate proportional hazards model, only age, extent
of nodal involvement (zero, one to four, or > four), and
whether the patient had regional implants (yes/no) re-
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O'CONNELL ET AL
248
100 -
80 a>
a)
C:
It
n=158
__
60 -
40 -
for other covariates and .01 after adjusting for covariates).
When the stratification factors plus sex and age were
combined with treatment in a multivariate proportional
hazards model, only extent of nodal involvement and
--
_ _,
cc
presence of regional implants were significantly associated with an increased risk of death. There were no significant interactions between treatment and any of the
prognostic variables. The 95% confidence interval for the
relative risk of death for control patients versus chemotherapy patients was 1.06 to 2.31 with no covariate adjustment and 1.12 to 2.45 after covariate adjustment.
n=151
Surgery plus chemotherapy
- - Surgery alone
P values.
Log-rank 0.004
Covanate mod el0001
20 -
1
2
3
4
6
5
Years since randomization
Fig 1.
Toxicity
Time-to-relapse.
sected en bloc were significantly associated with an increased risk of tumor relapse. Increased nodal involvement, the presence of regional implants, and older ages
were significantly associated with an increased risk of
relapse. There were no significant interactions between
treatment and any of the prognostic variables. The 95%
confidence interval for the relative risk of relapse for
control patients versus chemotherapy patients was 1.19
to 2.60 with no covariate adjustment and 1.29 to 2.82
after covariate adjustment.
Survival
One hundred of 309 eligible patients have died: 60 of
151 (40%) in the control group and 44 of 158 (28%) in
the chemotherapy group. The proportion of patients alive
at 5 years was 0.74 for patients who received chemotherapy and 0.63 for patients treated with surgery alone. These
data also provide strong evidence that chemotherapy patients had longer survival times than control patients (Fig
2) as seen by the two-sided P values (.02 before adjusting
100 80-
.,
60_>
40-
t--_
Surgery plus chemotherapy
- - Surgery alone
n=158
.
-n= 151
There were no deaths associated with chemotherapy.
Toxicities were generally tolerable and were manageable
with reduction of 5FU dose on subsequent cycles. Table
2 lists the percentages of chemotherapy patients who experienced grade 3 or 4 toxicities. Table 3 lists the amount
of 5FU chemotherapy actually administered, relative to
the targeted dose, according to treatment cycle.
DISCUSSION
This study provides strong evidence that 6 months of
postoperative adjuvant chemotherapy with intensivecourse 5FU combined with low-dose leucovorin can substantially reduce rates of tumor relapse and death in patients with high-risk colon cancer. This favorable outcome
was observed with a regimen that had only a modest
effect on short-term survival, and no impact whatsoever
on long-term survival, in patients with metastatic colorectal cancer. 5 '16 A recent meta-analysis of clinical trials
that used other dosage schedules of 5FU and leucovorin
in combination for advanced colorectal cancer confirmed
a significant improvement in tumor response rates, but no
improvement in survival.'7 The 5FU/low-dose leucovorin
regimen used in this study has been directly compared
with two other schedules of 5FU/leucovorin in metastatic
colorectal cancer, 6 ' 8 with no significant differences in
treatment efficacy observed. Taken together, these data
demonstrate that chemotherapy with definite but modest
cytoreductive capability in colorectal cancer patients with
a large tumor burden may be curative when applied in a
minimal residual disease setting.
P values:
Log-rank 0 02
Covariate model 0.01
20-
0
Years
randomizaton6
since
Years since randomization
Fig 2.
Survival.
7
Table 2. Severe Chemotherapy Toxicities
8
Toxicity
Grade 3 %}
Stomatitis
Diarrhea
Leukopenia
Nausea
33
20
14
7
Grade 4 (%1
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3
4
0
0
COLON CANCER SURGICAL ADJUVANT THERAPY
249
Table 3. 5FU Dose Administration as a Function of Ideal Full Dose
Cycle
No
1
2
3
4
5
6
No of
Patients
157
146
142
141
138
134
5FU Dose
Administered/
Target Median, %)
99
80
78
77
76
76
*
PatientsReceiving
2 80% of Target
5FU Dose (%)'
95
51
44
36
31
35
*Numbers in these columns indicate the median percent of 5FU actually
administered as a function of targeted dose for all patients beginning a
given cycle of treatment, and the percent of patients receiving at least 80%
of the targeted dose for that cycle, respectively. For example, 50% of 142
patients who received cycle 3 were given at least 78% of the target dose
on that cycle, and 44% of these patients received at least 80% of the targeted
5FU dose.
It is important to observe from this study that a significant improvement in outcome resulted from just six cycles
of postoperative adjuvant chemotherapy in patients with
colon cancer. Previous clinical trials have documented
the effectiveness of 5FU plus levamisole given for 1
year,9 and weekly 5FU plus high-dose leucovorin (500
mg/m 2) given for I year."9 More recently, a pooled analysis of 1,526 patients from three separate randomized clinical trials of intensive-course 5FU (370 to 400 mg/m 2)
plus leucovorin (200 mg/m 2) demonstrated significant improvement in event-free and overall survival with 6
months of adjuvant therapy.2 0 These data provide complementary evidence that administration of adjuvant chemotherapy with intensive-course 5FU/leucovorin regimens
for only 6 months is sufficient to have a favorable impact
on patient survival when used as postoperative adjuvant
treatment for colon cancer.
There were too few patients entered onto this study to
allow definitive analyses of treatment effect according to
stage. However, exploratory analyses of survival within
node-positive and node-negative patients were undertaken. The majority of patients in our trial had evidence
of regional lymph node metastases at the time of surgery
(82%), and it was within this subgroup that the survival
benefit of treatment with chemotherapy was most clearly
seen (P = .06 unadjusted; .03 with covariate adjustment).
There was a trend toward fewer deaths in the node-negative patients who received chemotherapy (three deaths
among 30 patients) compared with those treated with surgery alone (seven deaths among 27 patients), although the
difference in survival distributions was not statistically
significant (P = .15 unadjusted; covariate modeling could
not be appropriately performed in this small subset).
The side effects associated with the intensive-course
5FU/low-dose leucovorin regimen were clinically tolerable and consisted primarily of stomatitis and diarrhea.
The incidence and severity of stomatitis associated with
5FU-based chemotherapy has been demonstrated to be
reduced through the use of oral ice chips given for 30
minutes at the time of 5FU administered by bolus injection.2 The routine application of this ancillary technique
may help to reduce the dose-limiting side effect of this
chemotherapy regimen.
Intensive-course 5FU combined with low-dose leucovorin significantly improves relapse-free and overall survival in patients with high-risk colon cancer. It can be
conveniently administered in the outpatient setting and is
safe and clinically tolerable. It is also relatively inexpensive. The current cost for a 5-day course of treatment
with this regimen, including chemotherapy drug charges
and nursing administration fees, is $696 at the Mayo
Clinic in Rochester, MN.
An intergroup colon cancer surgical adjuvant study
(INT-0089) conducted by ECOG, SWOG, and CALGB
directly comparing the chemotherapy regimen used in this
study with the same regimen plus levamisole, a weekly
5FU/high-dose leucovorin regimen, and a standard 5FU/
levamisole regimen is currently in the follow-up phase.
This large multicenter trial will help to place the intensive-course 5FU/low-dose leucovorin regimen into further clinical perspective.
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