Content uploaded by Norman Wolmark
Author content
All content in this area was uploaded by Norman Wolmark on Oct 01, 2023
Content may be subject to copyright.
Bevacizumab in Stage II-III Colon Cancer: 5-Year Update of
the National Surgical Adjuvant Breast and Bowel Project
C-08 Trial
Carmen J. Allegra, Greg Yothers, Michael J. O’Connell, Saima Sharif, Nicholas J. Petrelli, Samia H. Lopa,
and Norman Wolmark
Carmen J. Allegra, Greg Yothers,
Michael J. O’Connell, Saima Sharif,
Nicholas J. Petrelli, Samia H. Lopa,
Norman Wolmark, National Surgical
Adjuvant Breast and Bowel Project;
Greg Yothers, Samia H. Lopa, Univer-
sity of Pittsburgh; Saima Sharif,
Norman Wolmark, Allegheny Cancer
Center at Allegheny General Hospital,
Pittsburgh, PA; Carmen J. Allegra,
University of Florida, Gainesville, FL;
Nicholas J. Petrelli, Helen F. Graham
Cancer Center at Christiana Care,
Newark, DE.
Published online ahead of print at
www.jco.org on December 10, 2012.
Supported by Public Health Service
Grants No. U10-CA-12027, U10-CA-
69651, U10-CA-37377, and U10-CA-
69974 from the National Cancer
Institute, US Department of Health and
Human Services.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Clinical trial information: NCT00096278.
Corresponding author: Carmen J.
Allegra, MD, University of Florida, Divi-
sion of Hematology and Oncology,
1600 SW Archer Ave, Rm N-503,
Gainesville, FL 32610; e-mail:
Carmen.Allegra@medicine.ufl.edu.
© 2012 by American Society of Clinical
Oncology
0732-183X/13/3103-359/$20.00
DOI: 10.1200/JCO.2012.44.4711
ABSTRACT
Purpose
The National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the
safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for
the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary
and secondary end points of disease-free and overall survival, respectively, with 5 years median
follow-up time.
Patients and Methods
Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or
modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month
period (experimental group). The primary end point of the study was disease-free survival (DFS)
and overall survival (OS) was a secondary end point.
Results
Of 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median
follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall
significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P⫽.35). Exploratory
analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year
landmark (time-by-treatment interaction Pvalue ⬍.0001). The secondary end point of OS was no
different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P⫽.56) and
for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P⫽.99).
Conclusion
Bevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage
2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab.
A transient effect on disease-free survival was observed during bevacizumab exposure in the
study’s experimental arm.
J Clin Oncol 31:359-364. © 2012 by American Society of Clinical Oncology
INTRODUCTION
The combined use of fluorouracil, leucovorin, and
oxaliplatin for 6 months constitutes the standard of
care for the adjuvant treatment of patients with co-
lon cancer. In two large randomized studies, this
combination was established as superior to single-
agent therapy using leucovorin-modulated fluorou-
racil.
1,2
The National Surgical Adjuvant Breast and
Bowel Project (NSABP) trial C-07 and the Multicenter
International Study of Oxaliplatin/Fluorouracil-
Leucovorin in the Adjuvant Treatment of Colon
Cancer trials both demonstrated that 3-year DFS
was significantly prolonged in patients with stage 2
or 3 colon cancer by the addition of oxaliplatin to
fluorouracil and leucovorin, with hazard ratios of
0.80 and 0.77, respectively. Bevacizumab, a human-
ized monoclonal antibody directed against circulat-
ing vascular endothelial growth factor (VEGF), has
demonstrated clinical benefit in patients with ad-
vanced colorectal cancer when combined with fluo-
rouracil, leucovorin, and oxaliplatin in both
untreated and previously treated patients. A study
published by Giantonio et al
3
randomly assigned
577 previously treated patients with colorectal can-
cer to fluorouracil, leucovorin, and oxaliplatin
(FOLFOX) with or without bevacizumab. This trial
showed a significant increase in response rate (8.6%
v22.7%), progression-free survival (4.7 v7.3
months), and overall survival (OS; 10.8 v12.9
months) for patients treated without and with the
addition of bevacizumab, respectively. A second
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
VOLUME 31 䡠NUMBER 3 䡠JANUARY 20 2013
© 2012 by American Society of Clinical Oncology 359
randomized study of 1,401 previously untreated patients with ad-
vanced disease failed to demonstrate a significant difference in re-
sponse rate (38% v38%) or OS (19.9 v21.3 months) with the addition
of bevacizumab to FOLFOX; however, the addition of bevacizumab
did result in a significant improvement in progression-free survival
from 8.0 to 9.4 months (P⫽.0023).
4
These data, coupled with appar-
ent clinical benefit associated with the addition of bevacizumab to
oxaliplatin-based chemotherapy regimens from nonrandomized reg-
istry studies, underpin the rationale for testing the benefit of adding
bevacizumab to FOLFOX chemotherapy in the adjuvant colon can-
cer setting.
5,6
The primary goal of NSABP C-08 is to test the potential benefit
and safety associated with the addition of bevacizumab to modified
FOLFOX6 (using oxaliplatin at a dose of 85 mg/m
2
) in the adjuvant
colon cancer setting. This report summarizes the updated disease-free
survival (DFS), OS, and late adverse events associated with the addi-
tion of bevacizumab to standard chemotherapy in the adjuvant treat-
ment of patients with stage 2 and 3 colon cancer. The safety profile and
early DFS associated with the use of bevacizumab in combination with
chemotherapy as used in NSABP C-08 has been reported.
7,8
PATIENTS AND METHODS
Study Population
This study was approved by institutional review committees with assur-
ances approved by the Department of Health and Human Services, in accor-
dance with the Helsinki Declaration. Written informed consent was required
for participation.
Patients meeting the eligibility criteria with stage 2 or 3 colon adenocar-
cinoma were stratified by number of positive lymph nodes and institution and
were then randomly assigned 1:1 to receive either modified FOLFOX6 for 6
months or modified FOLFOX6 for 6 months plus bevacizumab for 12 months
beginning concurrently with chemotherapy. This was an open-label study
with no blinding of treatment assignment for patients, physicians, or investi-
gators. Patients with Eastern Cooperative Oncology Group (ECOG) perfor-
mance status of 0 or 1 were randomly assigned within a window of 21 to 50
days following surgical removal of the primary tumor, and treatment was
begun within 1 week of random assignment. Patients were excluded for any
history of cerebral vascular accident, transient ischemic attack, symptomatic
peripheral vascular disease, or an arterial thrombotic episode such as a myo-
cardial infarction within the 12 months before randomization.
Regimens
The modified FOLFOX6 (mFOLFOX6) regimen includes leucovorin
400 mg/m
2
intravenous (IV) on day 1, fluorouracil 400 mg/m
2
IV bolus day 1
followed by 2,400 mg/m
2
IV over 46 hours, and oxaliplatin 85 mg/m
2
IV day 1.
Bevacizumab is given in the experimental arm at a dose of 5 mg/kg IV day 1. All
therapy is given once every 2 weeks for 12 doses (for a period of 6 months) or,
for bevacizumab, 26 doses (for a period of 1 year).
Statistical Considerations
DFS was the primary end point defined as colon cancer recurrence,
second primary cancer of any type, or death from any cause. Secondary end
points included survival and toxicity related to study therapy. Random assign-
ment was performed centrally using a biased-coin minimization algorithm.
9
Protocol C-08 was designed to have 90% power to detect a 23.4%
reduction in the hazard of DFS event when 592 DFS events were observed
(approximately 3 years’ median follow-up). Time to an event was measured
from randomization. All Pvalues will be two-sided and evaluated as significant
at the .05 level. Time-to-event plots were prepared using the Kaplan-Meier
method.
10
Hazard ratios (HR) were calculated from Cox models,
11
and P
values for time to event are from the log-rank test stratified for nodal status
(N0, N1, N2).
12
Proportions were compared by Fisher’s exact method.
13
The
primary analysis of DFS is based on the intention-to-treat principle
14
exclud-
ing only patients with no follow-up and patients not at risk for the primary end
point at the time of randomization (metastases or positive surgical margins).
OS analyses include all patients with follow-up. The time-treatment interac-
tion was tested by adding a time-varying term for the product of the treatment
indicator and an indicator for DFS time more than 1.25 years to a Cox model
already including the treatment indicator and stratified by nodal status.
15
RESULTS
Patients
This analysis uses data collected by June 30, 2011, by which time
743 DFS and 442 OS events had occurred. During the 2-year period
between September 2004 and October 2006, 2,710 patients were ac-
crued to the study; 1,356 to the control and 1,354 to the experimental
arms (Fig 1). A total of 15 patients (1.1%) and 17 patients (1.3%) in the
control and experimental arms, respectively, had no clinical follow-up
and were excluded from the OS analysis. Thus, there were 2,678 (1,341
in the control group and 1,337 in the experimental group) patients
evaluated for OS. There were an additional three patients in the con-
trol arm and two in the bevacizumab arm found to have unclear
margins or metastatic disease at entry so that they were not at risk for
recurrence, leaving 2,673 patients (1,338 in the control arm and 1,335
in the bevacizumab arm) evaluable for DFS. Patient characteristics are
well balanced by treatment arm (Table 1). The median follow-up was
4.9 years. Slightly more than half the patients were younger than 60
years and approximately 15% were older than 70 years. There was an
equal gender distribution. Stage 2 patients constituted approximately
25% of the total.
Toxicity
Toxicity information related to patients enrolled onto NSABP
C-08 has been published,
7
and no additional toxicity signals have been
noted. The addition of bevacizumab to mFOLFOX6 was not associ-
ated with an increase in mortality. Grade ⱖ3 toxicities that occurred
significantly more frequently included hypertension, wound compli-
cations, pain, and proteinuria. To evaluate whether toxicities associ-
ated with bevacizumab changed during the course of the 1-year
Randomly assigned
(N = 2,710)
Assigned to mFF6
(n = 1,356)
Assigned to mFF6 + Bev
(n = 1,354)
Analyzed for OS
(n = 1,341)
Excluded (no follow-up; n = 15)
Analyzed for OS
(n = 1,337)
Excluded (no follow-up; n = 17)
Analyzed for DFS
(n = 1,338)
Excluded (not at risk
for recurrence; n = 3)
Analyzed for DFS
(n = 1,335)
Excluded (not at risk
for recurrence; n = 2)
Fig 1. CONSORT diagram. DFS, disease-free survival; mFF6, modified fluorou-
racil, leucovorin, and oxaliplatin for 6 months; mFF6 ⫹Bev, mFF6 for 6 months
plus bevacizumab for 12 months; OS, overall survival.
Allegra et al
360 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
bevacizumab exposure, we compared toxicities that occurred during
the first 6 months with those occurring during the last 6 months of
bevacizumab, excluding patients who had the same toxicity during the
first 6 months. Grade 3-4 bevacizumab-associated toxicities with an
incidence of at least 1% occurred less frequently during the last 6
months of exposure (hypertension, 7% v5.5%; pain, 6.6% v4.1%;
arterial thrombotic episodes, 1% v0.6%). To examine toxicities asso-
ciated with having been previously exposed to bevacizumab within the
context of our study, we compared toxicities generally associated with
the use of bevicizumab between the two arms during the 9-month
therapy-free interval beginning 3 months after completion of all ther-
apy. Toxicity data were not collected beyond 1 year after therapy
completion. As listed in Table 2, toxicities were few and equally dis-
tributed between the two arms of the study. None of the noted differ-
ences was found to be statistically significant.
DFS
As shown in Figure 2, the addition of bevacizumab to
mFOLFOX6 did not result in an overall significant increase in DFS
(HR, 0.93; 95% CI, 0.81 to 1.08; P⫽.35). The point estimates for
3-year DFS were 77.9% and 75.1% for the experimental and control
arms, respectively. The effect of bevacizumab treatment did not vary
by stage (interaction P⫽.60). For patients with stage 2 disease, 3-year
DFS was 87.3% and 85.4% for the experimental and control arms,
respectively (HR, 0.86; 95% CI, 0.59 to 1.25; P⫽.43) and for patients
with stage 3 disease, 73.5% and 71.7% for the experimental and con-
trol arms, respectively (HR, 0.95; 95% CI, 0.82 to 1.11; P⫽.55).
Outcomes were similar for the end point of time to recurrence (ignor-
ing second primary cancer and death unrelated to recurrence).
We previously published the time-varying treatment effect.
8
Now, with 5 years median follow-up, this effect remains highly statis-
tically significant (time-treatment interaction P⬍.0001), supporting
a different effect of bevacizumab during and immediately following its
discontinuation compared with its later effects. The HR before the
15-month landmark strongly favored bevacizumab (HR, 0.61; 95%
CI, 0.48 to 0.78; P⬍.0001), whereas this benefit was entirely lost
subsequently (HR, 1.19; 95% CI, 0.99 to 1.42; P⫽.059).
OS
As shown in Figure 3, the addition of bevacizumab to
mFOLFOX6 resulted in no significant difference in OS (HR, 0.95;
95% CI, 0.79 to 1.13; P⫽.56). The point estimates for 5-year OS were
82.5% and 80.7% for the experimental and control arms, respectively.
The effect of bevacizumab on OS did not vary significantly with time
as it did for DFS (time-treatment interaction P⫽.08).
For patients with stage 2 disease, the 5-year OS estimates were
94.3% and 90.3% for the experimental and control arms, respectively
(HR, 0.62; 95% CI, 0.36 to 1.08; P⫽.093). Stage 3 patients had 5-year
OS estimates of 78.7% and 77.6% for the experimental and control
Table 1. Patient Characteristics (analyzed patients) of NSABP C-08
Characteristic
mFF6
(n ⫽1,338)
mFF6⫹Bev
(n ⫽1,335)
Total
(N ⫽2,673)
No. of
Patients %
No. of
Patients %
No. of
Patients %
Age, years
⬍50 332 24.8 342 25.6 674 25.2
50-59 447 33.4 435 32.6 882 33.0
60-69 347 25.9 366 27.4 713 26.7
ⱖ70 212 15.8 192 14.4 404 15.1
Sex
Female 673 50.3 669 50.1 1,342 50.2
Male 665 49.7 666 49.9 1,331 49.8
Race
White 1,172 87.6 1,161 87 2,333 87.3
Black 101 7.5 114 8.5 215 8
Other 50 3.7 43 3.2 93 3.5
Multiracial 2 0.1 1 0.1 3 0.1
Unknown 13 1.0 16 1.2 29 1.1
ECOG performance status
0 (fully active) 1,089 81.4 1,075 80.6 2,164 81.0
1 (no strenuous activity) 249 18.6 259 19.4 508 19.0
Nodal stage
N0 (node negative) 332 24.8 334 25.0 666 24.9
N1 (1-3 positive nodes) 611 45.7 607 45.5 1,218 45.6
N2 (ⱖ4 positive nodes) 395 29.5 394 29.5 789 29.5
Abbreviations: ECOG, Eastern Cooperative Oncology Group; mFF6, modified
fluorouracil, leucovorin, and oxaliplatin for 6 months; mFF6 ⫹Bev, mFF6 for 6
months plus bevacizumab for 12 months; NSABP, National Surgical Adjuvant
Breast and Bowel Project.
Table 2. Grade ⱖ3 Toxicities Generally Associated With Bevacizumab
During the 9-Month Period Beginning 3 Months After Completion of
All Therapy
Toxicity mFF6 mFF6⫹Bev
Hypertension 0.6 0.7
Pain 1.1 1.1
Proteinuria 0.1 0
ATE 0.1 0.5
VTE 0.4 0.2
Hemorrhage 0.3 0.3
Abbreviations: ATE, arterial thrombotic event; mFF6, modified fluorouracil,
leucovorin, and oxaliplatin for 6 months; mFF6 ⫹Bev, mFF6 for 6 months plus
bevacizumab for 12 months; VTE, venous thrombotic event.
0
Disease-Free Survival (%)
Time Since Random Assignment (years)
100
80
60
40
20
1 2 3 4 5
mFF6 (n = 1,338; events, 387)
mFF6 + Bev (n = 1,335; events, 381)
HR, 0.93; 95% CI, 0.81 to 1.08
P = .35
No. at risk
mFF6
mFF6 + Bev
1,338
1,335
1,181
1,240
1,036
1,086
954
990
894
922
894
427
Fig 2. Disease-free survival (DFS). Overall DFS for patients treated with
modified fluorouracil, leucovorin, and oxaliplatin (mFF6) alone for 6 months or
mFF6 for 6 months plus bevacizumab for 12 months (mFF6 ⫹Bev). HR,
hazard ratio.
5-Year OS and DFS Results of NSABP Trial C-08
www.jco.org © 2012 by American Society of Clinical Oncology 361
arms, respectively (HR, 1.00; 95% CI, 0.83 to 1.21; P⫽.99). A test for
a stage-treatment interaction on OS was not significant (P⫽.11).
Survival After Recurrence
Cancer recurred in 286 and 283 patients in the control and
bevacizumab-containing arms, respectively. Of these patients, 191
and 190 have died in each arm, respectively. Although not statistically
significant (P⫽.1), patients in the bevacizumab arm appeared to have
a more rapid rate of death relative to those whose disease recurred in
the control arm (HR, 1.15; 95% CI, 0.94 to 1.41). To explore whether
the decrement in survival after relapse may be related to ongoing or
recently completed bevacizumab exposure, we investigated survival
after relapse within 18 months of study entry when the exposure to
bevicizumab would be expected to be greatest (Fig 4A) and beyond 18
months after study entry when the exposure to bevacizumab would be
expected to be negligible (Fig 4B). As shown in Figure 4, the effect of
bevacizumab on survival after relapse did not seem to vary by the
timing of the relapse (before or after 18 months from study entry; HR,
1.21 v1.28, respectively).
DISCUSSION
The NSABP C-08 study was designed to investigate the use of anti-
VEGF therapy for the adjuvant treatment of stage 2 and 3 colon
cancer. The addition of 1 year of bevacizumab to 6 months of modi-
fied FOLFOX6 chemotherapy in this setting did not improve either
DFS or OS. Although there was a hint of a possible effect on OS in stage
2(P⫽.093), the HR confidence limits were wide and the stage-
treatment interaction was not significant (P⫽.11), suggesting that
this may be a result of chance variation. However, with 5 years’ median
follow-up, there continues to be a highly significant time-by-
treatment interaction with DFS such that the effect of bevacizumab
was favorable before a 15-month landmark but detrimental subse-
quently, resulting in no positive effect overall. However, it should be
noted that because there was a 6-month difference in the duration of
therapy between the study arms and because the scanning intervals
were not mandated by the protocol, the timing of post-therapy scans
was different between the arms such that patients on the control arm
were scanned earlier than patients in the experimental arm (mean,
1.09 months). The biased timing of imaging is confounded with the
estimated DFS times such that definitive conclusions concerning the
DFS differences across the arms at the early time points cannot be
justified. However, bias-adjusted analyses presented in our previous
publication suggest these differences cannot be entirely explained by
the imaging bias. The presence of time-dependent differences in DFS
in the AVANT
16
study support the noted time-dependent differences
in DFS as nonartifactual. Given the suggestion from the recently
disclosed data from the AVANT study
16
that bevacizumab exposure
may result in a harmful effect on outcomes, it is important to note that
there was no evidence of a detrimental effect of bevicizumab on any
of the end points investigated in NSABP C-08, including DFS and OS.
These data support the conclusion that although bevacizumab may
delay recurrence, its use does not prevent recurrence.
We observed that patients in the bevacizumab-containing arm
who relapsed after adjuvant treatment seemed to have a higher rate of
death than did those patients treated with chemotherapy alone. Al-
though this difference did not reach statistical significance, a similar
observation was reported in the AVANT trial.
16
Hypotheses to explain
this phenomenon include the possibility that bevacizumab changes
Overall Survival (%)
No. at risk
mFF6
mFF6 + Bev
1,341
1,337
1,269
1,289
1,206
1,233
1,139
1,164
1,051
1,077
466
502
0
Time Since Random Assignment (years)
100
80
60
40
20
1 2 3 4 5
mFF6 (n = 1,341; deaths, 245)
mFF6 + Bev (n = 1,337; deaths, 237)
HR, 0.95; 95% CI, 0.79 to 1.13
P = .56
Fig 3. Overall survival for all patients treated with modified fluorouracil,
leucovorin, and oxaliplatin (mFF6) alone for 6 months or mFF6 for 6 months plus
bevacizumab for 12 months, (mFF6 ⫹Bev). HR, hazard ratio.
0
Survival After
Recurrence (%)
Time Since Recurrence (years)
100
80
60
40
20
0.5 1.0 1.5 2.0 2.5 3.53.0
mFF6 (recurrences, 159; deaths, 131)
mFF6 + Bev (recurrences, 121; deaths, 101)
HR, 1.21; 95% CI, 0.93 to 1.57
P = .15
mFF6 (recurrences, 127; deaths, 60)
mFF6 + Bev (recurrences, 162; deaths, 89)
HR, 1.28; 95% CI, 0.92 to 1.78
P = .14
A
0
Survival After
Recurrence (%)
Time Since Recurrence (years)
100
80
60
40
20
0.5 1.0 1.5 2.0 2.5 3.53.0
B
Fig 4. Survival after recurrence for patients relapsing (A) within the first 18
months after study entry and (B) relapsing 18 months after study entry. HR,
hazard ratio; mFF6, modified fluorouracil, leucovorin, and oxaliplatin for 6 months;
mFF6 ⫹Bev, mFF6 for 6 months plus bevacizumab for 12 months.
Allegra et al
362 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
the biology of the disease to a more aggressive phenotype. Several
publications using preclinical murine models have suggested that ex-
posure to anti-VEGF therapy may result in the development of a more
aggressive tumor phenotype with a greater propensity for growth and
metastatic spread.
17-21
However, in this case, we would have expected
to see a detrimental effect on OS in the bevacizumab-treated patient
group, which was not observed. An alternative explanation is that
bevacizumab is less effective and/or less frequently used in relapsed
patients previously exposed to bevacizumab in the adjuvant setting.
22
A decrement in OS would also be expected if this hypothesis were true.
Finally, it is plausible that bevacizumab may interfere with the sensi-
tivity of computed tomography scanning owing to its effects on tumor
vascularity and permeability and thereby potentially delay the detec-
tion of a small recurrence. However, we found no evidence for a
change in survival after relapse in patients who relapsed early, in
whom bevacizumab would be expected to have its greatest effect on
scanning sensitivity compared with those who relapse beyond 18
months from study entry, for whom any effects of bevacizumab would
be expected to be minimal (Fig 4).
The failure of bevacizumab to enhance the outcomes associated
with FOLFOX chemotherapy calls into question our traditional para-
digm of adjuvant colon drug development, namely, to consider agents
for testing in the adjuvant setting only after they are found to be
beneficial in the treatment of patients with advanced disease. The
addition of bevacizumab to oxaliplatin-based chemotherapy has been
shown to be beneficial for patients with advanced colorectal cancer
both as initial and subsequent therapy.
3,4
Similarly, cetuximab and
irinotecan have been shown to have beneficial effects in patients with
advanced disease, yet have not been shown to be associated with
benefit in the adjuvant colon setting.
22-25
These experiences along with
the present bevacizumab observations suggest that we should not
assume that therapy associated with benefit in the metastatic setting
will necessarily translate into benefit in the adjuvant setting.
On the basis of our results, which showed a lack of benefit asso-
ciated with the use of bevacizumab for 1 year along with 6 months of
FOLFOX chemotherapy, bevacizumab should not be used for the
management of patients with stage 2 or 3 colon cancer in the adju-
vant setting.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Carmen J. Allegra, Genentech (C); Greg Yothers, Genentech (C);
Norman Wolmark, Genentech (U) Stock Ownership: None Honoraria:
None Research Funding: None Expert Testimony: None Other
Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Carmen J. Allegra, Greg Yothers, Michael J.
O’Connell, Saima Sharif
Administrative support: Greg Yothers, Saima Sharif
Collection and assembly of data: Carmen J. Allegra, Greg Yothers,
Saima Sharif
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
REFERENCES
1. Andre´ T, Boni C, Mounedji-Boudiaf L, et al:
Oxaliplatin, fluorouracil, and leucovorin as adjuvant
treatment for colon cancer. N Engl J Med 350:2343-
2351, 2004
2. Kuebler JP, Wieand HS, O’Connell MJ, et al:
Oxaliplatin combined with weekly bolus fluorouracil
and leucovorin as surgical adjuvant chemotherapy
for stage II and III colon cancer: Results from
NSABP C-07. J Clin Oncol 25:2198-2204, 2007
3. Giantonio BJ, Catalano PJ, Meropol NJ, et al:
Bevacizumab in combination with oxaliplatin, fluo-
rouracil, and leucovorin (FOLFOX4) for previously
treated metastatic colorectal cancer: Results from
the Eastern Cooperative Oncology Group Study
E3200. J Clin Oncol 25:1539-1544, 2007
4. Saltz LB, Clarke S, Díaz-Rubio E, et al: Bevaci-
zumab in combination with oxaliplatin-based chem-
otherapy as first-line therapy in metastatic colorectal
cancer: A randomized phase III study. J Clin Oncol
26:2013-2019, 2008. [Errata: J Clin Oncol 26:3110,
2008 and J Clin Oncol 27:653, 2009]
5. Kozloff M, Yood MU, Berlin J, et al: Clinical
outcomes associated with bevacizumab-containing
treatment of metastatic colorectal cancer: The
BRiTE observational cohort study. Oncologist 14:
862-870, 2009
6. Van Cutsem E, Rivera F, Berry S, et al: Safety
and efficacy of first-line bevacizumab with FOLFOX,
XELOX, FOLFIRI and fluoropyrimidines in metastatic
colorectal cancer: The BEAT study Ann Oncol 20:
1842-1847, 2009
7. Allegra CJ, Yothers G, O’Connell MJ, et al:
Initial safety report of NSABP C-08: A randomized
phase III study of modified FOLFOX6 with or with-
out bevacizumab for the adjuvant treatment of pa-
tients with stage II or III colon cancer. J Clin Oncol
27:3385-3390, 2009
8. Allegra CJ, Yothers G, O’Connell MJ, et al:
Phase III trial assessing the efficacy of bevacizumab
in stages II and III carcinoma of the colon: Results of
NSABP protocol C-08. J Clin Oncol 29:11-16, 2011
9. White SJ, Freedman LS: Allocation of patients
to treatment groups in a controlled clinical study.
Br J Cancer 37:849-857, 1978
10. Kaplan EL, Meier P: Nonparametric estima-
tion from incomplete observations. J Am Stat Assoc
53:457-481, 1958
11. Cox DR: Regression models and life tables.
J Royal Stat Soc Series B 34:187-220, 1972
12. Mantel N: Evaluation of survival data and two
new rank order statistics arising in its consideration.
Cancer Chemother Rep 50:163-170, 1966
13. Fisher RA: On the interpretation of
2 from
contingency tables, and the calculation of P. J Royal
Stat Soc 85:87-94, 1922
14. Lachin JM: Statistical considerations in the
intent-to-treat principle. Control Clin Trials 21:167-
189, 2000
15. Klein JP, Moeschberger ML: Survival Analy-
sis: Techniques for Censored and Truncated Data.
New York, NY, Springer, 2003
16. De Gramont A, Van Custem E, Tabernero J, et
al: AVANT: Results from a randomized, three-arm multi-
national phase III study to investigate bevacizumab with
either XELOX or FOLFOX4 versus FOLFOX4 alone as
adjuvant treatment for colon cancer. J Clin Oncol 29:
2011 (suppl 4; abstr 362)
17. Ebos JM, Lee CR, Cruz-Munoz W, et al:
Accelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesis. Can-
cer Cell 15:232-239, 2009
18. Pa`ez-Ribes M, Allen E, Hudock J, et al: Anti-
angiogenic therapy elicits malignant progression of
tumors to increased local invasion and distant me-
tastasis. Cancer Cell 15:220-231, 2009
19. Loges S, Mazzone M, Hohensinner P, et al:
Silencing or fueling metastasis with VEGF inhibitors:
Antiangiogenesis revisited. Cancer Cell 15:167-170,
2009
20. Reynolds AR, Hart IR, Watson AR, et al:
Stimulation of tumor growth and angiogenesis by
low concentrations of RGD-mimetic integrin inhibi-
tors. Nat Med 15:392-400, 2009
21. Ellis LM, Reardon DA: Cancer: The nuances of
therapy. Nature 458:290-292, 2009
5-Year OS and DFS Results of NSABP Trial C-08
www.jco.org © 2012 by American Society of Clinical Oncology 363
22. Saltz LB, Niedzwiecki D, Hollis D, et al: Irino-
tecan fluorouracil plus leucovorin is not superior to
fluorouracil plus leucovorin alone as adjuvant treat-
ment for stage III coloncancer: Results of CALGB
89803. J Clin Oncol 25:3456-3461, 2007
23. Ychou M, Raoul JL, Douillard JY, et al: A
phase III randomised trial of LV5FU2 ⫹irinotecan
versus LV5FU2 alone in adjuvant high-risk colon
cancer (FNCLCC Accord02/FFCD9802). Ann Oncol
20:674-680, 2009
24. Van Cutsem E, Labianca R, Bodoky G, et al:
Randomized phase III trial comparing biweekly infu-
sional fluorouracil/leucovorin alone or with irinotecan
in the adjuvant treatment of stage III colon cancer:
PETACC-3. J Clin Oncol 27:3117-3125, 2009
25. Alberts SR, Sargent DJ, Smyrk TC, et al:
Adjuvant mFOLFOX6 with or without cetuxiumab
(Cmab) in KRAS wild-type (WT) patients (pts) with
resected stage III colon cancer (CC): Results from
NCCTG Intergroup Phase III Trial N0147. J Clin
Oncol 28:262s, 2010 (suppl; abstr CRA3507)
■■■
2013 Genitourinary Cancers Symposium
Each year, ASCO organizes a wide array of high-quality meetings that provide educational and scientific programs to
advance our understanding of cancer. At each of ASCO’s meetings, you can expect an engaging and interactive agenda
featuring high-level scientific or clinical abstracts and educational sessions led by world-class faculty. Join us to earn CME
credit, network with colleagues, and interact with cancer experts.
Join us February 14-16, in Orlando, Florida, for the 2013 Genitourinary Cancers Symposium. Collaborate with top experts
in the field on the latest clinical and scientific strategies in management of genitourinary cancers in a small forum.
Cosponsored by ASCO, ASTRO, and SUO.
For more information, visit gucasym.org.
Allegra et al
364 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
