Originally published as JCO Early Release 10.1200/JCO.2008.16.3212 on October 14 2008

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grothey, A. Articles by Kozloff, M. Search for Related Content PubMed PubMed Citation Articles by Grothey, A. Articles by Kozloff, M. Related Articles Related Article Related Editorials Social Bookmarking                            What's this?

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, 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

Corresponding author: Axel Grothey, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: grothey.axel{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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-than-expected overall survival (OS) of 25.1 months was reported. The association between various pre- and 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 bevacizumab-related 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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-naïve patients who have mCRC when it is added to first- and second-line chemotherapy regimens.^2-5 In preclinical experiments, sustained VEGF inhibition has 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, community-based 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 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).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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.

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, patient's decision, investigator's decision, or sponsor's 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.

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   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.

Statistical Analyses
OS and SBP were analyzed using the Kaplan-Meier method, which included medians, 95% CIs, 1-year landmark estimates, and survival curves. 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 based on local practice standards, rather than on individual patient characteristics. A site's 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.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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 no-BBP groups, except for some subtle differences—most 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).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   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.

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 first-line 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 post-PD treatment had shorter median OS and SBP despite a similar first-line TTP.

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 post-treatment variables (Fig 3).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   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.

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 site-specific 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 median OS (27.7 months v 22.0 months) and median SBP (18.4 months v 12.3 months). The high–and low–BBP 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 post-treatment 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 high–BBP 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 low–BBP 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.

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

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 regimens, 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 pre- and post-treatment prognostic factors and from other post-treatment variables of unknown significance (eg, use of epidermal growth factor receptor–inhibiting 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 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.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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 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: 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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Frequency distribution of time from first progression to the restart of bevacizumab post–first progression (BBP) for patients in the BBP group. PD, progressive disease.

	ACKNOWLEDGMENTS

 
We thank the many patients, investigators, and site personnel who participated in BRiTE; Jordan Berlin, MD, PJ Flynn, MD, and Fairooz Kabbinavar, MD, for their input and support throughout the study; Padmaja Chiruvolu, Scott Osowski, and Meredith Kleiner for biostatistical analysis support; Robert Mass, MD, Amy Sing, MD, Michael Ostland, PhD, Laura Chu, MPH, Somnath Sarkar, PhD, and Ken Rothman, DrPH, for critical evaluation of the manuscript; and Genentech Inc.

	NOTES

 
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 trial information can be found for the following: NCT00097578 [ClinicalTrials.gov]

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Presta LG, Chen H, O'Connor SJ, et al: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593-4599, 1997[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

5. Hochster HS, Hart LL, Ramanathan RK, et al: Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line 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[Medline]

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[Abstract/Free Full Text]

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 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 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[Abstract/Free Full Text]

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

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[Abstract/Free Full Text]

17. D'Agostino 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[CrossRef][Medline]

18. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004[Abstract/Free Full Text]

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[Free Full Text]

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)

Submitted January 20, 2008; accepted April 18, 2008.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Cetuximab Plus Irinotecan in Heavily Pretreated Metastatic Colorectal Cancer Progressing on Irinotecan: MABEL Study
  Hansjochen Wilke, Robert Glynne-Jones, Josef Thaler, Antoine Adenis, Peter Preusser, Enrique Aranda Aguilar, Matti S. Aapro, Regina Esser, Anja H. Loos, and Salvatore Siena
  JCO 2008 26: 5335-5343 [Abstract] [Full Text]

Related Editorials

• Bevacizumab Beyond Progression: Does This Make Sense?
  Lee M. Ellis and Daniel G. Haller
  JCO 2008 26: 5313-5315 [Full Text]
• Registries That Show Efficacy: Good, but Not Good Enough
  Mark N. Levine and Jim A. Julian
  JCO 2008 26: 5316-5319 [Full Text]

This article has been cited by other articles:

				M. I. Koukourakis, A. Giatromanolaki, H. Sheldon, F. M. Buffa, G. Kouklakis, I. Ragoussis, E. Sivridis, A. L. Harris, and for the Tumour and Angiogenesis Research Group Phase I/II Trial of Bevacizumab and Radiotherapy for Locally Advanced Inoperable Colorectal Cancer: Vasculature-Independent Radiosensitizing Effect of Bevacizumab Clin. Cancer Res., November 15, 2009; 15(22): 7069 - 7076. [Abstract] [Full Text] [PDF]

				M. Zangari, L. M. Fink, F. Elice, F. Zhan, D. M. Adcock, and G. J. Tricot Thrombotic Events in Patients With Cancer Receiving Antiangiogenesis Agents J. Clin. Oncol., October 10, 2009; 27(29): 4865 - 4873. [Abstract] [Full Text] [PDF]

				R. MARUYAMA, H. WATAYA, T. SETO, and Y. ICHINOSE Treatment after the Failure of Gefitinib in Patients with Advanced or Recurrent Non-small Cell Lung Cancer Anticancer Res, October 1, 2009; 29(10): 4217 - 4221. [Abstract] [Full Text] [PDF]

				N. Damjanov, J. Weiss, and D. G. Haller Resection of the Primary Colorectal Cancer Is Not Necessary in Nonobstructed Patients with Metastatic Disease Oncologist, October 1, 2009; 14(10): 963 - 969. [Abstract] [Full Text] [PDF]

				A. Grothey Review: Medical treatment of advanced colorectal cancer in 2009 Therapeutic Advances in Medical Oncology, September 1, 2009; 1(2): 55 - 68. [Abstract] [PDF]

				M. Kozloff, M. U. Yood, J. Berlin, P. J. Flynn, F. F. Kabbinavar, D. M. Purdie, M. A. Ashby, W. Dong, M. M. Sugrue, A. Grothey, et al. Clinical Outcomes Associated with Bevacizumab-Containing Treatment of Metastatic Colorectal Cancer: The BRiTE Observational Cohort Study Oncologist, September 1, 2009; 14(9): 862 - 870. [Abstract] [Full Text] [PDF]

				S. Kopetz and J. L. Abbruzzese Hidden Biases in an Observational Study of Bevacizumab Beyond Progression J. Clin. Oncol., April 1, 2009; 27(10): 1732 - 1733. [Full Text] [PDF]

				A. Grothey, D. J. Sargent, and M. Kozloff In Reply J. Clin. Oncol., April 1, 2009; 27(10): 1733 - 1733. [Full Text] [PDF]

				A. Grothey Optimized Treatment of Metastatic Colorectal Cancer ASCO Educational Book, January 1, 2009; 2009(1): 209 - 211. [Abstract] [Full Text] [PDF]

				L. M. Ellis and D. G. Haller Bevacizumab Beyond Progression: Does This Make Sense? J. Clin. Oncol., November 20, 2008; 26(33): 5313 - 5315. [Full Text] [PDF]

				M. N. Levine and J. A. Julian Registries That Show Efficacy: Good, but Not Good Enough J. Clin. Oncol., November 20, 2008; 26(33): 5316 - 5319. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grothey, A. Articles by Kozloff, M. Search for Related Content PubMed PubMed Citation Articles by Grothey, A. Articles by Kozloff, M. Related Articles Related Article Related Editorials Social Bookmarking                            What's this?