VOLUME 26 NUMBER 33 NOVEMBER 20 2008

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Bevacizumab Beyond First Progression Is Associated With

Prolonged Overall Survival in Metastatic Colorectal Cancer:
Results From a Large Observational Cohort Study (BRiTE)
Axel Grothey, Mary M. Sugrue, David M. Purdie, Wei Dong, Daniel Sargent, Eric Hedrick, and Mark Kozloff
From the Mayo Clinic Rochester, Rochester, MN; Genentech Inc, South San
Francisco, CA; Ingalls Hospital, Harvey;
and the University of Chicago,
Chicago, IL.
Submitted January 20, 2008; accepted
April 18, 2008; published online ahead
of print at www.jco.org on October 13,
2008.
Supported by Genentech Inc.
Presented in part at the 43rd Annual
American Society of Clinical Oncology,
June 1-5, 2007, Chicago, IL; the 9th
World Congress on Gastrointestinal
Cancer, June 27-30, 2007, Barcelona,
Spain; and the 14th European Cancer
Conference, September 23-27, 2007,
Barcelona, Spain.
Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical Trials registry information for
this article available at www.jco.org.
Corresponding author: Axel Grothey,
MD, Division of Medical Oncology,
Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: grothey.axel@
mayo.edu.
2008 by American Society of Clinical
Oncology
0732-183X/08/2633-5326/$20.00

Purpose
Bevacizumab provides a survival benefit in first- and second-line metastatic colorectal cancer
(mCRC). In a large, observational, bevacizumab treatment study (Bevacizumab Regimens:
Investigation of Treatment Effects and Safety [BRiTE]) in patients who had mCRC, a longer-thanexpected overall survival (OS) of 25.1 months was reported. The association between various preand post-treatment factors (including the use of bevacizumab beyond first progression [BBP]) and
survival was examined.
Patients and Methods
The 1,445 of 1,953 previously untreated patients with mCRC who were enrolled in BRiTE and who
experienced disease progression (PD) were classified into three groups: no post-PD treatment
(n 253), post-PD treatment without bevacizumab (no BBP; n 531), and BBP (n 642).
Relevant baseline and on-study variables, including BBP, were analyzed with a Cox model with
respect to their independent effect on survival beyond first PD.
Results
Median OS was 25.1 months (95% CI, 23.4 to 27.5 months), and median progression-free survival
was 10.0 months in the overall BRiTE population. Baseline and postbaseline factors were well
balanced between the BBP and no-BBP groups. Median OS rates were 12.6, 19.9, and 31.8
months in the no post-PD treatment, no-BBP, and BBP groups, respectively. In multivariate
analyses, compared with no BBP, BBP was strongly and independently associated with improved
survival (HR, 0.48; P .001). Hypertension that required medication was the only bevacizumabrelated safety event that occurred more frequently in the BBP group (24.6% v 19.2%).
Conclusion
These results from a large, prospective, observational study suggest that continued vascular
endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important
role improving the overall success of therapy for patients who have mCRC.
J Clin Oncol 26:5326-5334. 2008 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2008.16.3212

INTRODUCTION

In the last decade, the development of novel therapies that target critical biologic pathways has
greatly expanded treatment options for patients
with metastatic colorectal cancer (mCRC) and has
shown substantial improvement in survival and
progression-free survival (PFS). Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a
recombinant, humanized monoclonal antibody
that binds to and neutralizes vascular endothelial
growth factor (VEGF),1 has improved overall survival (OS) and PFS in bevacizumab-nave patients
who have mCRC when it is added to first- and
second-line chemotherapy regimens.2-5 In preclinical experiments, sustained VEGF inhibition has
5326

been shown to achieve and maintain tumor regression.6,7 However, the clinical benefit and risks associated with continued bevacizumab use after initial
progressive disease are currently unknown.
After the US Food and Drug Administration
approval of bevacizumab in 2004, the Bevacizumab Regimens: Investigation of Treatment Effects and Safety (BRiTE) prospective observational
cohort study (OCS)8-11 was initiated to evaluate the
safety and effectiveness of bevacizumab in combination with chemotherapy in a large, communitybased patient population with previously untreated
mCRC. Earlier reports from BRiTE showed a median PFS of 10.0 months (95% CI, 9.7 to 10.4
months) and a median OS of 25.1 months (95%
CI, 23.4 to 27.5 months).8,9 This PFS estimate is

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Bevacizumab Beyond First Progression in BRiTE Observational Study

generally consistent with results from recent randomized clinical trials

(RCTs) of bevacizumab. Given that the BRiTE study included a less
selective patient population than RCTs (eg, a higher proportion of
patients who were elderly and a higher proportion of patients with
poor prognostic factors), the OS estimate was longer than
expected.2,3,5,8,12-14 The apparent dissociation of PFS and OS
prompted an analysis of various pre- and post-treatment factors in
BRiTE, which included the use of bevacizumab beyond first progression (BBP).

Overall Survival
Time to
progression

Begin
bevacizumab
treatment

Patients
In BRiTE, disease progression (PD) was determined by the investigator
via clinical and/or radiographic assessment. For this analysis, patients with an
investigator-assessed PD (n 1,445) were classified on the basis of the reported post-PD therapy they received: no post-PD treatment; post-PD treatment without bevacizumab (no BBP); and BBP. Post-PD treatment was
defined as any systemic anticancer therapy, including cytotoxic and/or biologic agents. Patients who received bevacizumab alone post-PD were excluded
from the analysis (n 19), because this group was too small to consider
separately. Patients who discontinued bevacizumab within 28 days after first
PD were considered not exposed to BBP (n 75); the effect of this classification was explored in a sensitivity analysis. Gaps in bevacizumab or chemotherapy administration of less than 28 days were considered continuous treatment.
Data were collected at baseline and every 3 months via a Web-based
electronic data collection system, as previously described.8-11
Clinical Outcomes
Measures of clinical outcomes were based on physician determination
and included time to progression from the date of initiation of first-line
treatment to first PD; OS from the date of initiation of first-line treatment to
death; and survival beyond first progression (SBP), which was measured only
for patients who had reported first PD from the date of first PD to death (Fig
1A). Patients who were not dead were censored at study termination (because
of loss to follow-up, patients decision, investigators decision, or sponsors
decision) or at the data cutoff date (January 21, 2007). The primary end point
for the BBP analysis was SBP, because classification into post-PD therapy
groups only became relevant after first PD and because the purpose of the
analysis was to explore reasons for the longer OS observed in BRiTE despite the
equivalent time to first PD.
Safety outcomes focused on previously described bevacizumab-related
adverse events (AEs)2 and were classified according to the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),
version 3.0.
Statistical Analyses
OS and SBP were analyzed using the Kaplan-Meier method, which
included medians, 95% CIs, 1-year landmark estimates, and survival curves.
www.jco.org

Death

First progression

Assessable patients
(N = 1,953)
First progression*
(n = 1,445)

PATIENTS AND METHODS

Study Design
BRiTE is a large, US-based, prospective OCS that was conducted at 248
study sites in 49 states.8-11 Patients were able to participate if they met the
following criteria: previously untreated mCRC; treatment with bevacizumab
in first-line therapy; and signed informed consent. There were no specific
exclusion criteria. Patients were considered on study until death, withdrawal of
consent, or loss to follow-up. There were no protocol-specified treatments or
assessments. All aspects of patients treatments over time, including specific
chemotherapy agents and/or combinations, and the dose, schedule, and duration of bevacizumab treatment, including BBP, were determined by a physician. Bevacizumab was not supplied by the sponsor (Genentech Inc). Sites
were reimbursed only for data submission; no compensation was provided for
laboratory tests, patient assessments, or patient participation. The protocol
was reviewed by a central institutional review board or committee.

Survival beyond first progression

Physician decision; no random assignment

No postprogression
treatment
(n = 253)

Postprogression
treatment without
bevacizumab
(No BBP)
(n = 531)

Postprogression
treatment with
bevacizumab
(BBP)
(n = 642)

Fig 1. Schematic of patient observation periods and patient disposition. (A)

Diagram of disease progression (PD). Time to PD is measured from the start of
first-line bevacizumab treatment to first PD; survival beyond first PD is measured
from first PD to death; overall survival is measured from the start of first-line
treatment to death. (B) Disposition of patients enrolled on the BRiTE study: 508
patients either had no physician-assessed first PD or had died; 19 patients
received post-PD treatment with bevacizumab (BBP) only and were excluded
from the analysis.

The Cox proportional hazards model was used to assess the independent
effects of pre- and post-treatment patient-related factors on SBP. Prespecified
measured variables, including prognostic variables previously shown to be
associated with survival in mCRC, were included in the multivariate analyses.3,13,14 In the primary analysis, these included age at first PD, ethnicity,
baseline Eastern Cooperative Oncology Group performance status (ECOG
PS), baseline serum albumin, baseline serum alkaline phosphatase, site of
primary tumor, first-line chemotherapy regimen, first-line time to progression
(TTP), best first-line response, exposure to three active chemotherapy agents
(ie, FU or capecitabine, irinotecan, oxaliplatin), exposure to epidermal growth
factor receptor inhibitors, and BBP. To assess the extent of possible immortal
time bias15 introduced by the fact that patients who had a delayed initiation
of post-PD therapy must have lived long enough to receive additional
therapy distant from first PD, an alternative definition of BBP was used,
wherein all patients who initiated post-PD therapy (with or without bevacizumab) more than 2 months after first PD were excluded (n 249). The
end point for this analysis was survival from 2 months after first PD
until death.
Sensitivity Analyses
Multiple sensitivity analyses were performed to compare the BBP and
no-BBP groups. These included the use of BBP as a time-dependent
covariate, conduction of a stratified Cox regression model by treatment
site, and conduction of a frailty Cox model that included treatment site as
a random effect.16 An analysis was also performed, whereby BBP patients
were matched in a 1:1 ratio with patients in the no-BBP group on their
propensity score (a patient-level summary measure of the difference between the groups),17 to create groups that were more alike with respect to
prognostic factors.
An additional analysis was performed to assess the site propensity for
BBP use on the basis of the supposition that variations in BBP use by study site
could affect OS and that such variations in treatment would conceivably be
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5327

Grothey et al

Table 1. Baseline Characteristics of Patient Groups Based on Treatment Beyond First PD

Treatment Group
Characteristic
Median age at baseline, years
Median age at first progression, years
Ethnicity, %
White
Black
Other
Baseline ECOG PS, %
0
1
2
Unknown
Mean baseline albumin, g/dL (range)
Mean
Range
Mean baseline alkaline phosphatase, U/L (range)
Mean
Range
Site of primary tumor, %
Colon
Rectum
Missing information
First-line chemotherapy, %
FOLFOX
FOLFIRI
IFL
FU bolus
XELOX
Other
Best first-line response, %
CR
PR
SD
PD
NA
Exposure to three active chemotherapy agents, %
Exposure to EGFR inhibitors postfirst PD, %
Median duration of first-line bevacizumab, months
Median
Range
Median duration of total bevacizumab use, months
Median
Range
Dosage of bevacizumab, %
5 mg/kg Q2W
7.5 mg/kg Q3W
10 mg/kg Q2W
Other
Median time to first progression, months
Median
Range
Median duration of first-line chemotherapy use, months
Median
Range
Median duration of total chemotherapy use (including EGFR inhibitors), months
Median
Range

All Patients
(N 1,953)

No Post-PD Treatment
(n 253)

No BBP
(n 531)

BBP
(n 642)

63.6
63.8

65.6
66.6

63.5
64.3

61.0
61.8

81.4
11.6
7.0

80.6
13.0
6.4

81.4
11.5
7.1

80.7
12.5
6.9

42.9
42.2
7.0
7.9

38.7
44.3
10.3
6.7

39.9
46.9
4.7
8.5

50.2
36.9
5.6
7.3

3.7
1.0-5.8

3.6
1.1-5.8

3.7
1.1-5.0

3.7
1.0-5.0

147.41
7.4-1,547.0

161.3
7.4-962.0

141.7
10.7-1,247.0

148.5
14.0-1,212.0

79.4
20.4
0.2

81.0
19.0

78.2
21.8

79.6
20.1
0.3

55.9
14.3
9.7
6.8
4.8
8.5

50.6
12.3
13.8
9.9
4.3
9.1

57.1
14.7
8.3
7.5
4.0
8.4

55.0
16.8
9.5
4.8
5.9
8.0

14.4
30.3
33.1
16.3
5.9
38.4
27.8

8.3
24.1
37.5
30.0
0.0
7.1
0.0

10.5
33.3
37.1
19.0
0.0
61.2
50.9

12.3
35.8
30.5
21.3
0.0
62.6
41.0

5.4
0.03-32.9

4.4
0.03-24.4

5.3
0.03-26.5

6.2
0.03-30.5

6.9
0.03-34.7

4.4
0.03-24.4

5.3
0.03-28.1

12.8
1.05-34.7

95.7
1.7
0.7
1.9

90.7
3.6
2.3
3.4

9.4
0.7-34.3

8.0
0.5-30.1

8.7
0.3-30.3

8.9
0.8-30.5

5.7
0.03-33.6

4.8
0.4-23.7

6.0
0.3-27.1

6.3
0.5-30.5

10.4
0.03-35.2

4.8
0.4-23.7

12.2
1.1-34.2

15.6
1.5-35.2

Abbreviations: PD, disease progression; BBP, bevacizumab use beyond progression; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX,
oxaliplatin infusional fluorouracil/leucovorin; FOLFIRI, irinotecan infusional fluorouracil/leucovorin; IFL, inirotecan bolus fluorouracil/leucovorin; XELOX,
capecitabine/oxaliplatin; CR, complete response; PR, partial response; SD, stable disease; NA, not assessable; EGFR, epidermal growth factor receptor; Q2W, every
2 weeks; Q3W, every 3 weeks.

Active chemotherapy agents included FU (or capecitabine), irinotecan, and oxaliplatin.

Dosage of bevacizumab for all patients (N 1,953) at baseline and for the BBP group (n 642) post disease progression.

5328

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Bevacizumab Beyond First Progression in BRiTE Observational Study

Pattern of Bevacizumab Use

The median duration of first-line bevacizumab therapy was similar in the BBP and no-BBP groups; however, as expected, the median
duration of total bevacizumab exposure was substantially longer in the
BBP group (Table 1). Of the 642 patients in the BBP group, 444
(69.2%) either received bevacizumab continuously from first-line to
beyond first PD (n 312) or discontinued bevacizumab before first
PD and restarted within 1 month of first PD (n 132; Appendix Fig
A1, online only). The remaining 198 patients (30.8%) discontinued
bevacizumab before (n 159) or at (n 43) first PD and restarted
more than 1 month after first PD. Only 71 patients in the BBP group
restarted bevacizumab more than 4 months after first PD. An alternative definition of BBP was examined that excluded patients who had
an interval from first PD to restart of bevacizumab longer than
2 months.

Survival Outcomes
The median OS for the overall BRiTE group was 25.1 months
(95% CI, 23.4 to 27.5 months). Univariate analyses showed that OS
was longer in patients with better ECOG PS at baseline, higher albumin levels, lower alkaline phosphatase levels, primary tumor of the
rectum, exposure to three active chemotherapy agents, longer firstline TTP, complete or partial response to first-line therapy, and exposure to any post-PD therapy (Table 2). The median OS was longer for
the BBP group compared with the no-BBP group (Table 2). Similarly,
SBP was longer for the BBP group (Fig 2B). Patients who received no
www.jco.org

Progression-Free Survival (%)

Patient Characteristics
Between February 2004 and June 2005, 1,953 patients were enrolled on BRiTE. The median follow-up time was 19.6 months. As of
January 21, 2007, 97 patients (5.0%) were lost to follow-up, and 74
patients (3.8%) had withdrawn from the study; 850 (44%) remained
alive. Of the 1,953 patients, 1,445 (74.0%) had experienced first PD,
and the remaining 508 (26.0%) were either alive without documented
PD (n 320) or had died without having a PD assessment (n 188;
Fig 1B). Of patients with documented PD, 253 (17.5%) received no
post-PD treatment, 531 (36.7%) received no BBP, and 642 (44.4%)
received BBP (Fig 1B). Baseline characteristics for the post-PD groups
are listed in Table 1 and appeared similar between the BBP and noBBP groups, except for some subtle differencesmost notably a
higher proportion patients with baseline ECOG PS 1 in the no-BBP
group. Multivariate analyses adjusted for these differences between
groups. The Kaplan-Meier curves for first-line TTP for the three
post-PD treatment groups are presented in Figure 2A, which shows
that the median first-line TTP for the no-BBP and BBP groups were
similar (8.7 months v 8.9 months, respectively).

100

80

60

40

20

Postprogression therapy
No treatment
No BBP
BBP

10

15

20

25

Time to First Progression (months)

B
100

Overall Survival (%)

RESULTS

80

60

40

20

Postprogression therapy
No treatment
No BBP
BBP

10

15

20

25

Survival Beyond First Progression (months)

Number of deaths
Percent
1-year survival rate, %
95% CI
Median survival beyond first
progression, months
95% CI

All patients
(N = 1,953)

No postprogression
treatment
(n = 253)

No BBP
(n = 531)

BBP
(n = 642)

932
47.7

168
66.4

305
57.8

260
40.5

74.7
72.7 to 76.7

52.5
46.2 to 58.8

77.3
73.7 to 80.9

87.7
85.2 to 90.3

12.0

3.6

9.5

19.2

11.1 to 13.3

2.7 to 4.3

8.4 to 11.2

16.8 to 20.7

15

20

25

C
100

Overall Survival (%)

based on local practice standards, rather than on individual patient characteristics. A sites propensity to use BBP was calculated as the number of patients at
a site who were treated with BBP divided by the number of patients at the site
who had first PD. Sites then were grouped into quartiles, and patients outcomes at sites in the highest BBP-use quartile were compared with those at sites
in the lowest BBP-use quartile.

80

60

40

20

Postprogression therapy
No treatment
No BBP
BBP

10

Survival Beyond First Progression (months)

Fig 2. Survival outcomes by groups on the basis of post disease progression
(post-PD) therapy. Kaplan-Meier estimates of (A) time to first progression for
patients who received no post-PD treatment (yellow), post-PD treatment without
bevacizumab (no BBP; blue), or post-PD treatment with bevacizumab (BBP; gray);
(B) survival beyond first progression; and (C) survival starting from 2 months after
first PD to death for patients who initiated post-PD therapy (with or without
bevacizumab) within 2 months from first PD.

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Grothey et al

Table 2. Median OS of Pre- and Post-Treatment Variables and Multivariate Analysis of the Variables on SBP
Evaluation Time Point
OS
Variable
Age at first progression (per 10 years)
Ethnicity
White (n 1,152)
Black (n 178)
Other (n 96)
Baseline ECOG PS
0 (n 632)
1 (n 598)
2 (n 87)
Baseline albumin, per g/dL
Baseline alkaline phosphatase, per 100 U/L
Site of primary tumor, %
Colon (n 1,131)
Rectum (n 293)
Exposure to EGFR inhibitors
No (n 884)
Yes (n 542)
Exposure to all three active chemotherapy
agents
No (n 681)
Yes (n 745)
Time to first progression, per month
Best first-line response
CR (n 156)
PR (n 468)
SD (n 488)
PD (n 314)
Postfirst progression therapy
No BBP (n 531)
BBP (n 642)
No postprogression treatment (n 253)

Median

Multivariate Analysis
SBP

95% CI

Median

95% CI

HR

95% CI

1.04

0.97 to 1.10

.284

0.88
0.77

1.0 (reference)
0.70 to 1.11
0.57 to 1.05

.268
.103

1.30
1.60
0.73
1.18

1.0 (reference)
1.10 to 1.53
1.21 to 2.12
0.64 to 0.82
1.13 to 1.23

.002
.001
.001
.001

22.9
24.2
27.5

21.4 to 25.1
20.7 to 31.3
20.3 to NA

11.6
13.7
13.2

10.4 to 13.0
12.0 to 15.8
10.0 to NA

29.5
19.9
12.8

27.2 to NA
17.8 to 21.6
10.9 to 16.3

16.5
9.6
6.2

15.0 to 19.2
8.4 to 11.1
3.9 to 8.5

21.9
29.2

20.4 to 24.1
26.2 to NA

11.3
17.5

10.2 to 12.6
12.8 to 22.1

0.79

1.0 (reference)
0.65 to 0.97

.020

22.4
24.8

19.9 to 26.6
22.2 to 27.0

11.0
13.4

9.0 to 13.0
12.1 to 15.7

0.97

1.0 (reference)
0.81 to 1.16

.738

20.2
26.6

17.5 to 22.6
24.7 to 28.4

8.7
14.4

7.5 to 11.1
12.7 to 15.9

0.94
0.91

1.0 (reference)
0.78 to 1.14
0.89 to 0.93

.539
.001

NA
27.2
22.9
11.6

29.2 to NA
24.7 to 33.2
20.2 to 25.2
10.3 to 13.0

NA
14.0
12.0
7.5

17.8 to NA
11.6 to 15.9
10.0 to 13.4
6.3 to 9.0

1.64
1.64
1.33

1.0 (reference)
1.15 to 2.35
1.15 to 2.35
0.89 to 1.99

.007
.007
.158

19.9
31.8
12.6

18.0 to 22.0
27.9 to NA
10.6 to 15.7

9.5
19.2
3.6

8.4 to 11.2
16.8 to 20.7
2.7 to 4.3

0.49
2.05

1.0 (reference)
0.41 to 0.58
1.64 to 2.56

.001
.001

NOTE. First-line chemotherapy regimen was also included in the model.

Abbreviations: OS, overall survival; SBP, survival beyond first progression; HR, hazard ratio; ECOG PS, Eastern Cooperative Oncology Group performance
status; EGFR, epidermal growth factor receptor; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; BBP, bevacizumab
use beyond progression.

Sample sizes (n) relate to patients who had an investigator-assessed disease response and were included in the multivariate model.
Unadjusted median overall survival and survival beyond first progression for patients who had investigator-assessed disease progression.
Multivariate result for survival beyond first progression performed only on patients who had an investigator-assessed disease response.
Unknown performance status score (n 109) was included in the model as a separate level.
Includes cetuximab and/or other epidermal growth factor receptor monoclonal antibodies.
Active chemotherapy agents include FU (or capecitabine), irinotecan, and oxaliplatin.

post-PD treatment had shorter median OS and SBP despite a similar

first-line TTP.
An analysis to address potential immortal time bias excluded
patients who initiated post-PD therapy (with or without bevacizumab) more than 2 months postfirst PD (n 249), which left 447
patients in the no-BBP group and 477 in the BBP group. In analysis of
survival from 2 months postfirst PD to death as the measured outcome, there was a similar improved survival associated with use of
post-PD therapy started within 2 months of PD (Fig 2C). Furthermore, there was a greater improvement in survival in the BBP group
compared with the no-BBP group when therapy was initiated for both
within 2 months of PD (Fig 2C). The median SBP associated with BBP
started within 2 months of PD was 16.8 months (95% CI, 14.7 to 19.6
months) compared with 9.2 months (95% CI, 8.3 to 11.2 months) for
patients who started chemotherapy without bevacizumab within 2
months of PD (Fig 2C).
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Multivariate Analyses
In multivariate analyses, baseline ECOG PS, baseline albumin
levels, baseline alkaline phosphatase levels, site of primary tumor
(measured at baseline), first-line TTP, best first-line response, and
post-PD therapy were all significantly and independently related to
SBP (Table 2). After analysis was adjusted for other important prognostic factors, BBP maintained a statistically significant effect on SBP
compared with no BBP (HR, 0.49; 95% CI, 0.41 to 0.58; P .001). The
multivariate (ie, adjusted) hazard ratios for BBP versus no BBP were
consistent across groups of patients stratified by pre- and posttreatment variables (Fig 3).
Sensitivity Analyses
A series of sensitivity analyses were performed to address the
contribution of observed variability in the treatment patterns of bevacizumab and chemotherapy to the effect of BBP on survival. Different
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Bevacizumab Beyond First Progression in BRiTE Observational Study

Subgroup

Hazard Ratio

Age at disease progression

< 65 years
65 years
Race
White
Black
Other
Baseline ECOG PS
0
1
2
Site of primary tumor
Colon
Rectum
First-line chemotherapy regimen
FOLFOX
FOLFIRI
Other
Exposed to EGFR inhibitors
No
Yes
Exposed to all 3 active chemotherapy agents
No
Yes
Time to first progression
< 6 months
6 months
Best first-line response
CR/PR
SD/PD
All Patients

95% CI

0.47
0.51

0.37 to 0.60
0.40 to 0.65

0.51
0.32
0.48

0.42 to 0.62
0.18 to 0.57
0.21 to 1.08

0.53
0.45
0.37

0.40 to 0.71
0.35 to 0.59
0.18 to 0.76

0.49
0.49

0.40 to 0.59
0.32 to 0.75

0.47
0.38
0.62

0.37 to 0.59
0.24 to 0.59
0.46 to 0.85

0.52
0.42

0.41 to 0.66
0.32 to 0.54

0.51
0.42

0.39 to 0.68
0.33 to 0.52

0.48
0.52

0.37 to 0.62
0.41 to 0.65

0.44
0.50

0.33 to 0.59
0.41 to 0.63

0.49

0.41 to 0.58

Fig 3. Forest Plot that illustrates multivariate (ie, adjusted) hazard ratios for survival beyond progression (SBP) for the
comparison of bevacizumab use beyond
progression (BBP) v no BBP, according to
subgroups of pre- and post-treatment factors. The relative size of each square represents the number of patients, and larger
squares indicate a greater number. Solid
bar represents 95% confidence interval.
Hazard ratios less than 1 (dotted line)
represent a longer median SBP of patients
in the BBP than of those in the no-BBP
group. PD, progressive disease; ECOG,
Eastern Cooperative Oncology Group;
FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, fluorouracil,
leucovorin, and irinotecan; EGFR, epidermal growth factor receptor; CT, chemotherapy; CR, complete response; PR,
partial response; SD, stable disease.

classifications of BBP were created on the basis of the patterns of

bevacizumab treatment observed across lines of therapy. Compared
with patients in the no-BBP group (n 531), patients in the BBP
group (n 642) who received bevacizumab continuously from firstline into post-PD (n 312) demonstrated significantly improved SBP
(adjusted HR, 0.51; 95% CI, 0.42 to 0.62). After patients who initiated
post-PD therapy more than 2 months after first-PD were excluded, the
HR associated with BBP compared with no BBP was 0.51 (95% CI,
0.42 to 0.63). In an analysis that reclassified BBP as post-PD therapy
with any use of bevacizumab (ie, including patients who discontinued bevacizumab within 28 days of first PD), the HR associated
with BBP compared with no BBP was consistent at 0.53 (95%
CI, 0.45 to 0.63).
In all the sensitivity analyses performed, the HRs for the survival
comparison between the BBP and no-BBP groups resulted in HRs that
ranged from 0.46 to 0.53 (data not shown).
Site Propensity to Use BBP
To test the robustness of the prolongation of OS in the BBP group
and to assess the potential impact of unmeasured patient- and sitespecific variables, an analysis was conducted on the BBP group on the
basis of the site propensity to use BBP. Patients treated at sites with a
high propensity to use BBP (highest quartile; n 49 sites; 210 patients) compared with patients treated at sites with a low propensity to
use BBP (lowest quartile; n 59 sites; 240 patients) had a longer
www.jco.org

0.5

median OS (27.7 months v 22.0 months) and median SBP (18.4

months v 12.3 months). The high and lowBBP use sites had similar
patient characteristics at baseline (data not shown), with the exception
of a higher proportion of patients with ECOG PS 0 at the high-BBP use
sites (43% v 34%). After analysis was adjusted for the pre- and posttreatment variables listed in Table 2 in a multivariate analysis, patients
who were treated at sites with a high propensity to use BBP (highest
quartile) had a significantly improved SBP (HR, 0.63; 95% CI, 0.48 to
0.83; P .001) compared with patients who were treated at sites with
a low propensity to use BBP (lowest quartile).
To assess whether the prolonged survival observed in highBBP
use sites was due to actual patient use of BBP or to an unmeasured
effect of being treated at those sites, a multivariate analysis that included site propensity to use BBP and actual patient treatment with
BBP was conducted. After analysis was adjusted for actual patient use
of BBP, the site propensity to use BBP was no longer significantly
associated with improved survival (HR, 1.25 for high v lowBBP use
sites; 95% CI, 0.92 to 1.67), which suggests that individual use of BBP,
as opposed to other site-related factors, was responsible for the superior outcomes at high-propensity BBP sites. Furthermore, after analysis that accounted for site propensity to use BBP, the adjusted HR
associated with individual patient treatment with BBP was 0.46
(95% CI, 0.38 to 0.55), which suggested that patients who received
BBP have improved prognosis, regardless of the site at which they
were treated.
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5331

Grothey et al

Safety
The incidence of most bevacizumab-associated AEs described in
the BRiTE study, including arterial thromboembolic events, grades 3
to 4 bleeding events, and GI perforation, were similar in the no
post-PD treatment, no-BBP, and BBP groups (Table 3). There was a
higher incidence of new or worsening hypertension in the BBP group
compared with the no-BBP group or with the overall BRiTE population (19.2% v 24.6%), which is expected, given the longer exposure to
bevacizumab in the BBP group.

DISCUSSION

During the past 10 years, incremental improvements in the survival of

patients with mCRC have been observed, primarily from the addition
of novel active therapeutic agents. Although previous reports have
emphasized that OS in mCRC is associated with exposure to all
available active cytotoxic agents, and that the addition of bevacizumab to either first- or second-line chemotherapy prolongs survival,
questions remain regarding the optimal use and sequencing of these
agents.13,18,19 To date, no RCT has evaluated the effect of the continuation of bevacizumab beyond tumor progression in patients with
mCRC to examine the clinical benefit of sustained VEGF suppression.
PD generally implies resistance to the therapy and leads to a
change in therapy regimen. The mechanisms of primary or secondary
cytotoxic drug resistance are typically the result of genetic instability
inherent in cancer that renders mutant cells insensitive to chemotherapeutic agents. In contrast, the mechanisms of resistance are not well
understood for biologic agents, like bevacizumab, that are directed
toward a genetically stable target (ie, the effect of VEGF on vascular
endothelial cells). The emergence of tumor cells that are resistant to a
cytotoxic regimen does not necessarily imply that the disease is no
longer partially or significantly dependent on VEGF-mediated endothelial cell mitogenesis and survival. One hypothesis is that persistent
VEGF suppression, along with secondary and tertiary cytotoxic regi-

mens, may result in continuing clinical benefit. The results of the BBP
survival analyses from BRiTE provide support for this hypothesis.
The multivariate analysis was prompted by the observation of a
median OS of 25 months, which was longer than expected, given that
the patient population was less selective compared with RCTs (ie, it
included a higher proportion of patients who were elderly and a higher
proportion of patients who had poor prognostic characteristics), in a
setting in which the first-line PFS was similar to the previous reports
from multiple RCTs. As expected, historically recognized baseline
prognostic variables and post-treatment variables, such as first-line
TTP and response to first-line therapy, were each significantly associated with survival beyond PD.13 The novel finding from this analysis
was the significant and independent association between BBP and
survival. Although it is not possible to estimate the absolute length of
survival improvement afforded by BBP in this type of analysis, the HR
for SBP between the BBP and no-BBP groups (HR, 0.49 after adjustment for other variables) suggests an appreciable survival benefit.
Inherent with all OCSs are limitations that are based largely on
the fact that patients are not randomly assigned to the treatment
groups being compared. To the extent possible, multivariate analyses
were used to adjust for possible confounding factors, and the effect of
BBP on survival was independent from historically recognized preand post-treatment prognostic factors and from other post-treatment
variables of unknown significance (eg, use of epidermal growth factor
receptorinhibiting agents). Although ECOG PS, serum albumin, and
serum alkaline phosphatase were collected only at baseline and were
not updated at the time of PD, these variables were significantly
related to SBP in these analyses. Some residual confounding as a
result of the timing of, or errors in, measurement of prognostic
variables is possible. Multiple sensitivity analyses also were performed,
the results of which uniformly supported the association between BBP
and survival in this study. In addition, the analysis of site propensity to
address unmeasured site-related variables that may have influenced
the decision to use BBP confirmed a strong and significant association
between BBP use at the patient level and survival. Another potential

Table 3. Incidence of Bevacizumab-Targeted Adverse Events in BRiTE Patient Groups Based on Treatment Beyond First Progression
Treatment Group
Adverse Event
New or worsened HTN (which required medication), %
ATE, %
Total
Prefirst PD
Postfirst PD
Bleeding event (grades 3 to 4), %
Total
Prefirst PD
Postfirst PD
GI perforation, %
Total
Prefirst PD
Postfirst PD

All Patients
(N 1,953)

No Post-PD Treatment
(n 253)

No BBP
(n 531)

BBP
(n 642)

19.4

19.0

19.2

24.6

1.8
1.4
0.4

2.0
2.0
0.0

1.3
1.1
0.2

1.2
0.3
0.9

2.4
1.8
0.5

2.4
1.6
0.8

2.1
1.9
0.2

1.9
0.6
0.9

1.8
1.4
0.5

2.4
2.0
0.8

1.5
1.1
0.4

1.6
0.8
0.6

Abbreviations: PD, disease progression; BBP, bevacizumab use beyond progression; HTN, hypertension; ATE, arterial thromboembolic event.

Date of onset was not collected and, therefore, could not be classified as pre- or post-PD.
Percentages of pre- and post-PD adverse events may not sum to the total because of missing onset dates or because a patient was counted in both the pre- and
post-progression periods if 1 adverse event was experienced; however, patients were counted only once in the total percentage.

5332

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Bevacizumab Beyond First Progression in BRiTE Observational Study

limitation is that actual administration dates for bevacizumab and

chemotherapy were not collected, and consequently, misclassification
of BBP may have occurred. However, such misclassification likely
would have produced more similar groups and would have biased the
effect toward the no-BBP group. Finally, because patients who survived longer had a greater potential to be treated with BBP, the small
group of patients who received bevacizumab late in their post-PD
therapy could bias the observed association. Analyses that examined
all of these potential biases were performed, and minimal effect was
noted on the observed association.
The effect of long-term exposure to bevacizumab in patients who
received BBP is a concern. The safety outcomes in BRiTE showed no
apparent increase in serious AEs reported in the BBP group compared
with the no-BBP group. The reporting of the safety outcomes of
BBP use may be affected by lack of random assignment, which
suggests that the BBP and no-BBP groups were not at comparable
risk for bevacizumab-associated events, and by the collection of only
certain types of events (ie, any serious AEs assumed related to bevacizumab, including GI perforation, arterial thromboembolic events,
bleeding, and hypertension). The higher cumulative incidence of hypertension in the BBP group was not unexpected, given that the risk of
developing bevacizumab-associated hypertension appears constant
over time20 and that the BBP group had substantially longer bevacizumab exposure.
These data are the first report of a survival benefit associated with
continuation of bevacizumab beyond PD in patients who received
bevacizumab-containing first-line therapy. In BRiTE, the use of BBP,
which was observed in 44% of patients who experienced PD, is one
possible explanation for the longer-than-expected median OS observed in the study population, and it suggests that traditionally defined tumor progression may not indicate a loss of clinical benefit
from bevacizumab. These results support the hypothesis that continued suppression of the VEGF pathway may be important to maximize
the clinical benefit from bevacizumab in mCRC. Ongoing phase III
clinical trials, such as SWOG S0600, will help to additionally delineate
the optimal duration of bevacizumab therapy in this setting.
REFERENCES
1. Presta LG, Chen H, OConnor SJ, et al: Humanization of an anti-vascular endothelial growth
factor monoclonal antibody for the therapy of solid
tumors and other disorders. Cancer Res 57:45934599, 1997
2. Hurwitz H, Fehrenbacher L, Novotny W, et al:
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med
350:2335-2342, 2004
3. Kabbinavar FF, Hambleton J, Mass RD, et al:
Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer.
J Clin Oncol 23:3706-3712, 2005
4. Giantonio BJ, Catalano PJ, Meropol NJ, et al:
Bevacizumab in combination with oxaliplatin, fluorouracil, 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
5. Hochster HS, Hart LL, Ramanathan RK, et al:
Safety and efficacy of oxaliplatin/fluoropyrimidine
regimens with or without bevacizumab as first-line
www.jco.org

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS

OF INTEREST
Although all authors completed the disclosure declaration, the following
author(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
ASCOs 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: Mary M. Sugrue, Genentech (C);
David M. Purdie, Genentech (C); Wei Dong, Genentech (C); Eric
Hedrick, Genentech (C) Consultant or Advisory Role: Axel Grothey,
Genentech (C), Sanofi-aventis (C), Bristol-Myers Squibb Co (C); Daniel
Sargent, Genentech (C), Roche (C), Sanofi-aventis (C); Mark Kozloff,
Genentech (U), Pfizer Inc (U) Stock Ownership: Mary M. Sugrue,
Genentech; David M. Purdie, Genentech; Wei Dong, Genentech; Eric
Hedrick, Genentech Honoraria: Axel Grothey, Genentech,
Sanofi-aventis, Bristol-Myers Squibb Co; Daniel Sargent, Genentech,
Roche, Sanofi-aventis; Mark Kozloff, Genentech, Pfizer, Sanofi-aventis
Research Funding: Axel Grothey, Genentech, Sanofi-aventis,
Bristol-Myers Squibb Co Expert Testimony: None Other
Remuneration: None

AUTHOR CONTRIBUTIONS
Conception and design: Axel Grothey, Mary M. Sugrue, Wei Dong, Eric
Hedrick, Mark Kozloff
Provision of study materials or patients: Mary M. Sugrue, Mark Kozloff
Collection and assembly of data: Axel Grothey, Mary M. Sugrue, David
M. Purdie
Data analysis and interpretation: Axel Grothey, Mary M. Sugrue, David
M. Purdie, Wei Dong, Daniel Sargent, Eric Hedrick, Mark Kozloff
Manuscript writing: Axel Grothey, Mary M. Sugrue, David M. Purdie,
Wei Dong, Daniel Sargent, Eric Hedrick, Mark Kozloff
Final approval of manuscript: Axel Grothey, Mary M. Sugrue, David M.
Purdie, Wei Dong, Daniel Sargent, Eric Hedrick, Mark Kozloff

treatment of metastatic colorectal cancer (mCRC):

Final analysis of the TREE Study. J Clin Oncol
24:148S, 2006 (suppl; abstr 3510)
6. Klement G, Baruchel S, Rak J, et al: Continuous
low-dose therapy with vinblastine and VEGF receptor-2
antibody induces sustained tumor regression without
overt toxicity. J Clin Invest 105:R15-R24, 2000
7. Klement G, Huang P, Mayer B, et al: Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody
in multidrug-resistant human breast cancer xenografts. Clin Cancer Res 8:221-232, 2002
8. Grothey A, Sugrue M, Hedrick E, et al: Association between exposure to bevacizumab (BV) beyond
first progression (BBP) and overall survival (OS) in
patients (pts) with metastatic colorectal cancer
(mCRC): Results from a large observational study
(BRiTE). J Clin Oncol 25:172s, 2007 (suupl; abstr 4036)
9. Kozloff M, Hainsworth J, Badarinath S, et al:
Efficacy of bevacizumab plus chemotherapy as firstline treatment of patients with metastatic colorectal
cancer: Updated results from a large observational
registry in the US (BRiTE). J Clin Oncol 24:155s,
2006 (suppl; abstr 3537)
10. Hedrick E, Kozloff M, Hainsworth J, et al:
Safety of bevacizumab plus chemotherapy as first-

line treatment of patients with metastatic colorectal

cancer: Updated results from a large observational
registry in the US (BRiTE). J Clin Oncol 24:155s,
2006 (suppl; abstr 3536)
11. Sugrue M, Kozloff M, Hainsworth J, et al: Risk
factors for gastrointestinal perforations in patients
with metastatic colorectal cancer receiving bevacizumab plus chemotherapy. J Clin Oncol 24:154s,
2006 (suppl; abstr 3535)
12. Kabbinavar FF, Schulz J, McCleod M, et al:
Addition of bevacizumab to bolus fluorouracil and
leucovorin in first-line metastatic colorectal cancer:
Results of a randomized phase II trial. J Clin Oncol
23:3697-3705, 2005
13. Hurwitz H, Kabbinavar F: Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer.
Oncology 69:17-24, 2005 (suppl 3)
14. De Gramont A, Cervantes A, Andre T, et al:
OPTIMOX study: FOLFOX 7/LV5FU2 compared to
FOLFOX 4 in patients with advanced colorectal
cancer. J Clin Oncol 22:251s,2004 (suppl; abstr
3525)
15. Rothman KJ, Greenland SG: Modern Epidemiology (ed 2). Philadelphia, PA, Lippincott, Williams,
& Wilkins, 1998

2008 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org by Alina Muntean on December 4, 2013 from 194.102.61.170

Copyright 2008 American Society of Clinical Oncology. All rights reserved.

5333

Grothey et al

16. Localio AR, Berlin JA, Ten Have TR, et

al: Adjustments for center in multicenter studies:
An overview. Ann Intern Med 135:112-123,
2001
17. DAgostino RB Jr: Propensity score methods
for bias reduction in the comparison of a treatment
to a non-randomized control group. Stat Med 17:
2265-2281, 1998

18. Grothey A, Sargent D, Goldberg RM, et al:

Survival of patients with advanced colorectal cancer improves with the availability of fluorouracilleucovorin, irinotecan, and oxaliplatin in the
course of treatment. J Clin Oncol 22:1209-1214,
2004
19. Grothey A, Sargent D: Overall survival of
patients with advanced colorectal cancer correlates

with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent
therapy is used first line. J Clin Oncol 23:9441-9442,
2005
20. Lowery M, Power D, Behbehani A, et al:
Hypertension is a significant adverse effect of bevacizumab treatment. J Clin Oncol 25:622s, 2007
(suppl; abstr 14134)

Acknowledgment
The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF
version (via Adobe Reader).
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 version
(via Adobe Reader).

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