Originally published as JCO Early Release 10.1200/JCO.2005.05.112 on February 28 2005

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 Kabbinavar, F. F. Articles by Novotny, W. F. Search for Related Content PubMed PubMed Citation Articles by Kabbinavar, F. F. Articles by Novotny, W. F. Related Articles Related Editorial Social Bookmarking                            What's this?

Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial

From the University of California, Los Angeles (UCLA) School of Medicine, Los Angeles; Genentech Inc, South San Francisco, CA; Virginia Oncology Associates, Newport News, VA; Florida Cancer Specialists, Ft Myers, FL; Mid Ohio Oncology Hematology Inc, Westerville, OH; Louisville Oncology, Louisville, KY

Address reprint requests to Fairooz F. Kabbinavar, MD, Division of Hematology/Oncology, UCLA School of Medicine, 10945 LeConte Ave, Suite 2338J, Los Angeles, CA 90095-7187; e-mail: fkabbina{at}mednet.ucla.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan.

PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed.

RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation.

CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The concept of targeting tumor vasculature as a therapeutic strategy in human cancer was initially based on the observation that rapid growth of transplanted tumors was often preceded by a local increase in vascular density.¹ This process, termed angiogenesis, was subsequently shown to be mediated by diffusible factors released by tumor cells.² One of the most potent of these endothelial cell-specific mitogens is vascular endothelial growth factor (VEGF), a highly conserved, homodimeric, heparin-binding glycoprotein that exists in several isoforms.³ VEGF mediates its effects by interacting with the membrane-bound tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR, flk-1), activating specific downstream survival and proliferation pathways.⁴ VEGF is considered essential for normal developmental vasculogenesis, and there is substantial evidence implicating VEGF as a critical factor in tumor angiogenesis.^5,6 Transformed cell lines commonly express increased levels of both VEGF mRNA and protein.⁷ Transfection of Chinese hamster ovary cells with expression vectors encoding VEGF allows these cells to form tumors in nude mice.⁸ Increased VEGF expression has been described in most human tumors³ and in many instances is correlated with an adverse prognosis (increased risk of tumor recurrence and metastasis and decreased survival).^9-13 Finally, an antibody against human VEGF, used either alone or in combination with chemotherapy, inhibits the growth of human tumors implanted in immunodeficient mice.¹⁴

Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) is the recombinant humanized version of a murine antihuman VEGF monoclonal antibody A4.6.1.¹⁵ In phase I trials, bevacizumab was generally well tolerated, was not associated with a dose-limiting toxicity, and, when combined with classical cytotoxic chemotherapy agents, did not exacerbate their expected toxicities.^16,17 Based on the observed prognostic role of VEGF in colorectal cancer (CRC), a randomized phase II clinical trial comparing chemotherapy alone (fluorouracil and leucovorin [FU/LV]) or in combination with bevacizumab in patients with previously untreated metastatic CRC was conducted. The results of this trial suggested that the addition of bevacizumab to chemotherapy provided a higher response rate, longer median time to disease progression, and longer median survival.¹⁸ A post hoc exploratory analysis of this trial suggested that the effect of bevacizumab was particularly significant in a subset of patients with poor prognostic features (Eastern Cooperative Oncology Group [ECOG] performance status [PS] > 0, age 65 years, and albumin 3.5 g/dL).

The study described here was reported around the same time of publication of two randomized phase III clinical trials^19,20 demonstrating that the addition of irinotecan (CPT-11) to FU/LV resulted in statistically significant increases in response rate, time to disease progression, and survival, and established irinotecan-containing regimens as a new standard of care for metastatic CRC. However, retrospective analyses of these results suggested that the benefit derived from irinotecan might be limited to patients with a performance status of 0.^21,22 Also, certain subgroups, including those with advanced age, impaired PS, low serum albumin, and prior pelvic radiotherapy, may experience significant toxicities when adding irinotecan to FU/LV regimens.^23-27

Cognizant of these results, two subsequent randomized trials of bevacizumab were conducted in patients with previously untreated metastatic CRC. A pivotal trial utilized a regimen of irinotecan, bolus FU, and leucovorin (bolus IFL) with or without bevacizumab in a fully powered, phase III, placebo-controlled design in patients with a good ECOG PS (PS 0 or 1).²⁸ This trial demonstrated statistically significant and clinically relevant improvements in response rate, time to disease progression, and survival. Median survival was increased by 4.7 months (15.6 v 20.3 months; P < .001). A second, supportive, placebo-controlled, randomized, phase II trial was conducted concurrently with the pivotal trial in patients deemed nonoptimal candidates for first-line irinotecan-containing regimens. This trial was designed to evaluate the safety and efficacy of bevacizumab in combination with FU/LV delivered on a weekly, high-dose schedule. The final results of this trial are reported here.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patient Eligibility
Patients with histologically confirmed, previously untreated, measurable metastatic CRC were eligible if, in the judgment of the investigator, they were not optimal candidates for first-line irinotecan-containing therapy. In addition, they were required to have at least one of the following characteristics: age 65 years, ECOG PS of 1 or 2, serum albumin 3.5 g/dL, or prior radiotherapy to abdomen or pelvis. Patients were excluded if they had undergone major surgical procedures or open biopsy, or had experienced significant traumatic injury, within 28 days before study entry; had an anticipated need for major surgery during the course of the study; were currently using or had recently used therapeutic anticoagulants (except as required for catheter patency), thrombolytic therapy, or chronic, daily treatment with aspirin (> 325 mg/d) or nonsteroidal anti-inflammatory medications; had a serious, nonhealing wound, ulcer, or bone fracture; had a history or evidence of CNS metastases; were pregnant or lactating; or had proteinuria or clinically significant impairment of renal function at baseline. All patients provided written informed consent for their participation. The study was approved by the institutional review boards of all participating centers and conducted in accordance with the US Food and Drug Administration Good Clinical Practice (GCP), and local ethical and legal requirements.

Study Design and Treatments
An interactive voice response system was used to randomly assign eligible patients to one of two treatment groups: FU/LV plus placebo, or FU/LV plus bevacizumab. A dynamic randomization algorithm was utilized to achieve balance overall and within each of the following categories: study center, baseline ECOG PS (0 v 1), site of primary disease (colon v rectum), and number of metastatic sites (1 v > 1). The FU/LV treatment, comprising LV 500 mg/m² over 2 hours and FU 500 mg/m² as a bolus midway through the LV infusion (Roswell Park regimen²⁹), was administered weekly for the first 6 weeks of each 8-week cycle. Chemotherapy was continued until study completion (96 weeks) or disease progression. Bevacizumab 5 mg/kg or placebo was administered every 2 weeks. Patients in the bevacizumab arm who had a confirmed complete response or experienced unacceptable toxicity as a result of chemotherapy treatment were allowed to discontinue FU/LV and continue receiving bevacizumab alone as first-line treatment. At the time of disease progression, patients were unblinded to their treatment assignment and could receive any second-line treatment at the discretion of the investigator. Only patients who had been randomly assigned to the bevacizumab group could receive bevacizumab as a component of second-line treatment. After completing the study, patients were followed up for any subsequent treatment and survival every 4 months until death, loss to follow-up, or termination of the study.

Study Assessments
Patients underwent an assessment of tumor status at baseline and at completion of every 8-week cycle using appropriate radiographic techniques, typically spiral computed tomography scanning. Tumor response or progression was determined by both the investigator and an independent radiology facility (IRF) utilizing the Response Evaluation Criteria in Solid Tumors.³⁰ The IRF assessment was performed without knowledge of the treatment assignment or investigator assessment. In addition, patients completed the Functional Assessment of Cancer Therapy—Colorectal (FACT-C), Version 4, a validated instrument for assessing quality of life (QOL) in CRC patients,³¹ at baseline and before each treatment cycle until disease progression.

Safety was assessed from reports of adverse events, laboratory test results, and vital sign measurements. Adverse events and abnormal laboratory results were categorized using the National Cancer Institute Common Toxicity Criteria version 2. Prespecified safety measures included four adverse events of special interest (hypertension, proteinuria, thrombosis, and bleeding) based on findings of previous clinical trials of bevacizumab.

Statistical Analysis
The primary outcome measure was duration of overall survival. Secondary outcome measures included progression-free survival, objective response rate (complete and partial), response duration, and change in the FACT-C QOL score. Survival duration was defined as the time from random assignment to death. For patients alive at the time of analysis, duration of survival was censored at the date of last contact. Progression-free survival was defined as the time from random assignment to the earlier of disease progression or death on study, defined as death from any cause within 30 days of the last dose of study drug or chemotherapy. For patients alive without disease progression at the time of analysis, progression-free survival was censored at their last tumor assessment or at the day of random assignment (the first day of study treatment) if no postbaseline assessment was performed. In the analysis of objective response, patients without tumor assessments were categorized as nonresponders. Disease progression and response analyses were based on the IRF assessments. Change in QOL was analyzed as time to deterioration in QOL (TDQ), defined as the length of time from random assignment to the earliest of a 3-point decrease from baseline in colon-cancer specific FACT-C subscale score (CCS), disease progression, or death on study. TDQ was also determined for the TOI-C (sum of CCS, physical and functional well-being) and total FACT-C for changes from baseline of 7 and 9 points, respectively.

To detect a hazard ratio of 0.61 for death in the FU/LV/bevacizumab group relative to the FU/LV/placebo group, approximately 133 deaths were required. A two-tailed log-rank test at the .05 level of significance with 80% power and two interim analyses were assumed in the calculations. Interim analyses were conducted by an unblinded, independent data monitoring committee. A safety interim analysis was conducted after 44 deaths, and a second safety and efficacy interim analysis was conducted after 89 deaths. The interim efficacy analysis was governed by a formal group sequential stopping rule based on an O’Brien-Fleming spending function. Kaplan-Meier methodology was applied to estimate the median survival, progression-free survival, and duration of response time for each treatment group. Hazard ratios for the bevacizumab group relative to the placebo group were determined using the stratified Cox proportional hazards model. A two-sided stratified log-rank test was used to compare the two groups. Stratified analyses included baseline ECOG PS, site of primary disease, and the number of metastatic sites. Objective response rates were compared by the ² test. As exploratory analyses, the Cox proportional hazards model was used to estimate the effect of risk factors on modifications of treatment effect for duration of survival and progression-free survival. Efficacy analyses were performed on the intent-to-treat population, defined as all randomly assigned patients. Safety analyses included all patients who received at least one dose of study drug.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patient Characteristics
Between August 2000 and July 2002, 209 patients were randomly assigned at 60 sites in the United States and Australia/New Zealand. For the intent-to-treat analysis of the primary end point (overall survival), there were 105 patients in the FU/LV/placebo group and 104 in the FU/LV/bevacizumab group. Table 1 presents selected demographic and baseline characteristics, which were reasonably balanced between treatment groups. Low serum albumin ( 3.5 g/dL) at baseline was less common in the bevacizumab group than in the placebo group.

Efficacy
Overall survival, the primary end point, was longer in the FU/LV/bevacizumab group (median, 16.6 months) than in the FU/LV/placebo group (median, 12.9 months). The hazard ratio of death was estimated to be 0.79 (95% CI, 0.56 to 1.10; P = .16; Table 2 and Fig 1). The addition of bevacizumab to FU/LV was associated with increases in median progression-free survival (9.2 v 5.5 months; hazard ratio, 0.50; 95% CI, 0.34 to 0.73; P = .0002; Table 2 and Fig 2), response rate (26.0% v 15.2%; P = .055), and median duration of response (9.2 v 6.8 months; hazard ratio, 0.42; 95% CI, 0.15 to 1.17; P = .088). An analysis of treatment effect on overall survival and progression-free survival, by baseline characteristics, is presented in Figures 3 and 4. Patients with low serum albumin ( 3.5 g/dL) at baseline seemed to derive a significant survival benefit (hazard ratio, 0.46; 95% CI, 0.29 to 0.74; P = .001).

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates for duration of survival. FU, fluorouracil; LV, leucovorin; BV, bevacizumab.

View larger version (16K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates for progression-free survival. FU, fluorouracil; LV, leucovorin; BV, bevacizumab.

View larger version (38K): [in this window] [in a new window]   Fig 3. Duration of survival by baseline risk factor, including (in this order) all subjects, sex, age, location of primary tumor, prior adjuvant chemotherapy, prior radiotherapy, performance status, number of metastatic sites, and baseline albumin.

Safety
A total of 204 patients (104 FU/LV/placebo and 100 FU/LV/bevacizumab) who received at least one dose of study drug comprised the safety population. Table 3 presents the incidence of selected adverse events during the assigned treatment. A 16% increase (71% v 87%) in total grade 3 and 4 toxicities was observed for patients receiving bevacizumab. Adverse events leading to death or study discontinuation were similar in the two groups, as were adverse events known to be associated with FU/LV (specifically, diarrhea and leukopenia). Two patients, both in the FU/LV/bevacizumab group, experienced a bowel perforation event. These events occurred at day 110 and day 338 of treatment, respectively, and both were determined to be associated with a colonic diverticulum at surgical exploration. One patient died as a result of this complication. Previous clinical trials had suggested hemorrhage, thromboembolism, proteinuria, and hypertension as possible bevacizumab-associated toxicities; however, in this study, no increases were seen in venous thrombosis, grade 3 bleeding, or clinically significant ( grade 3) proteinuria. Arterial thrombotic events (myocardial infarction, stroke, or peripheral arterial thrombotic event) occurred in 10 patients in the FU/LV/bevacizumab group, compared with five patients in the FU/LV/placebo group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The results of this clinical trial add to a growing body of data demonstrating that bevacizumab, a humanized monoclonal antibody against VEGF, provides important clinical benefit when added to first-line chemotherapy for the treatment of metastatic CRC. When compared with FU/LV alone, the addition of bevacizumab prolonged median survival by 3.7 months, progression-free survival by 3.7 months, and response duration by 2.4 months, and increased the response rate by 11%.

These results should be viewed in the context of the study population. We specifically selected patients who were deemed by their treating physician to be suboptimal candidates for first-line irinotecan-containing therapy, either because of a low likelihood of benefit or a high likelihood of treatment-associated toxicities. Retrospective analyses of the pivotal irinotecan trials suggested that clinical benefit from this agent was largely confined to patients with a normal ECOG PS (PS 0).^21,22 Advanced age, prior pelvic radiation therapy, impaired PS, and low serum albumin have all been reported to increase irinotecan-associated toxicities.^23-27 Patients with these characteristics may benefit from less toxic alternative therapeutic options. We previously conducted a retrospective subset analysis from a smaller randomized phase II trial evaluating bevacizumab and FU/LV in CRC and noted that bevacizumab provided a substantial treatment effect in the subset of patients with baseline PS 1 or 2 (median survival, 6.3 v 15.2 months), in the subset aged 65 years (11.2 v 17.7 months), and in the subset with serum albumin less than 3.5 g/dL (8.1 v 14.1 months). These results encouraged us to design the current trial, specifically including a poor-prognosis study population and powering the trial to detect a large treatment effect on survival. We were largely successful in enrolling a population different from that in the concurrently conducted pivotal trial of IFL/placebo versus IFL/bevacizumab. Compared with the pivotal trial, patients in the present trial had a higher median age (72 v 61 years) and substantially more patients had a PS more than 0 (72% v 43%) and albumin 3.5 mg/dL (46% v 33%).

Despite this higher-risk study population, the regimen of FU/LV/bevacizumab seemed to be well tolerated. The well-described bevacizumab-associated adverse event of grade 3 hypertension was seen in 16% of the FU/LV/bevacizumab group versus 3% in the FU/LV/placebo group. No cases of grade 4 hypertension occurred. Proteinuria of any grade was seen in 38% of the FU/LV/bevacizumab group versus 19% of the FU/LV/placebo group; however, only a single patient in the bevacizumab group developed grade 3 proteinuria, and there were no cases of grade 4 proteinuria. No increases in grade 3 or 4 bleeding or venous thrombotic events were seen in bevacizumab-treated patients. There was an imbalance in the incidence of arterial thrombotic events: 10% in the FU/LV/bevacizumab group compared with 4.8% in the FU-/LV/placebo group. A similar imbalance was noted in the pivotal bevacizumab trial (1.0% in the IFL/placebo group and 3.3% in the IFL/bevacizumab group). The more advanced age of the population included in the present study may have contributed to a higher overall incidence of this adverse event; however, the imbalance in both studies is noteworthy. Large, observational safety trials may be required to further define the incidence and potential risk factors for these and other uncommon adverse events associated with bevacizumab therapy.

Two patients (2%) in the FU/LV/bevacizumab group developed gastrointestinal (bowel) perforation. This unusual adverse event was seen in 1.5% of bevacizumab-treated patients in the pivotal trial and has also been reported in approximately 1% of patients treated with bevacizumab in an ongoing randomized trial in second-line treatment of CRC.³² The two cases in this trial were associated with a perforated colonic diverticulum. In the previous CRC trial reports, perforation seemed to be associated with an inflammatory process involving the gastrointestinal tract, including peptic ulcer disease, peritoneal carcinomatosis, and inflammation due to recent colonic instrumentation (colonoscopy). Given the role that VEGF plays in neovascularization and wound healing, these events might not be unexpected in patients undergoing anti-VEGF treatment, and clinicians should be alert to this potential toxicity when using bevacizumab.

Two prior clinical trials have explored the use of bevacizumab in combination with FU/LV. In a small, randomized phase II trial, bevacizumab improved median survival by 4.2 months (13.8 v 18.0 months; P = .55) and progression-free survival by 2.2 months (5.2 v 7.4 months; P = .013). The pivotal bevacizumab trial that compared IFL/placebo with IFL/bevacizumab initially contained a third arm of FU/LV/bevacizumab until the safety of IFL/bevacizumab was established by an independent data monitoring committee. These patients had a median progression-free survival of 8.8 months and a median survival of 18.3 months, which compared favorably to the IFL/placebo control arm (6.8 and 15.1 months, respectively). The progression-free survival and overall survival observed in these two prior trials are remarkably consistent with the current results.

It should be noted that this trial failed to achieve the prespecified primary end point, a substantial 39% reduction in the hazard of death (hazard ratio, 0.61). There may be several possible explanations. The small sample size may have resulted in unmeasured imbalances in important baseline prognostic characteristics between the two groups. For instance, the treatment effect of bevacizumab on overall survival was particularly striking within the subgroup of patients with low serum albumin at baseline (hazard ratio, 0.46; P = .001). These patients were underrepresented in the FU/LV/bevacizumab group (42% v 49%). Another potentially important confounding factor is postprogression therapy. During the conduct of the first randomized trial evaluating FU/LV/bevacizumab¹⁸ (which provided the treatment estimates for powering the current trial), few patients received active postprogression therapy (specifically, irinotecan or oxaliplatin). However, in the current trial, 46% of the FU/LV/placebo group and 39% of the FU/LV/bevacizumab group received irinotecan, oxaliplatin, or both following initial disease progression (Table 4). Such differences in postprogression therapy have confounded the interpretation of overall survival in other randomized clinical trials in first-line metastatic CRC, most notably Intergroup trial N9741.³³ The substantial difference in time to disease progression that we observed (9.2 v 5.5 months; hazard ratio, 0.50; P = .0002) is unaffected by postprogression therapy and may be a more representative assessment of the clinical benefit provided by the addition of bevacizumab to FU/LV (Fig 4).

View larger version (37K): [in this window] [in a new window]   Fig 4. Duration of progression-free survival during first-line therapy by baseline risk factor, including (in this order) all subjects, sex, age, location of primary tumor, prior adjuvant chemotherapy, prior radiotherapy, performance status, number of metastatic sites, and baseline albumin.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Genentech; William F. Novotny, Genentech. Consultant/Advisory Role: Taral Patel, Amgen, Barlex, Genentech. Stock Ownership: Robert Mass, Genentech; Brent Perrou, Genentech; Betty Nelson, Benentech; William F. Novotny, Genentech. Honoraria: Fairooz F. Kabbinavar, Genentech; Taral Patel, Amgen, Genentech; John T. Hamm, Genentech. Research Funding: John T. Hamm, Genentech. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

	NOTES

 
Supported by Genentech Inc.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
1. Algire GH, Chalkley HW, Legallais FY, et al: Vascular reactions of normal and malignant tissue in vivo, I: Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6:73-85, 1945

2. Greenblatt M, Shubi P: Tumor angiogenesis: Transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst 41:111-124, 1968

3. Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18:4-25, 1997[Abstract/Free Full Text]

4. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 9:669-676, 2003[CrossRef][Medline]

5. Ferrara N: Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Semin Oncol 29:10-14, 2002 (suppl 16)

6. Folkman J: Antiangiogenic therapy, in DeVita VTJ, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 3075-3085

7. Ferrara N, Houck K, Jakeman L, et al: Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13:18-32, 1992[Abstract/Free Full Text]

8. Ferrara N, Winer J, Burton T, et al: Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. J Clin Invest 91:160-170, 1993

9. Takahashi Y, Kitadai Y, Bucana CD, et al: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55:3964-3968, 1995[Abstract/Free Full Text]

10. Takahashi Y, Tucker SL, Kitadai Y, et al: Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:541-546, 1997[Abstract/Free Full Text]

11. Warren RS, Yuan H, Matli MR, et al: Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95:1789-1797, 1995

12. Radinsky R, Ellis LM: Molecular determinants in the biology of liver metastasis. Surg Oncol Clin N Am 5:215-229, 1996[Medline]

13. Tokunaga T, Oshika Y, Abe Y, et al: Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77:998-1002, 1998[Medline]

14. Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841-844, 1993[CrossRef][Medline]

15. 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]

16. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001[Abstract/Free Full Text]

17. Margolin K, Gordon MS, Holmgren E, et al: Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: Pharmacologic and long-term safety data. J Clin Oncol 19:851-856, 2001[Abstract/Free Full Text]

18. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003[Abstract/Free Full Text]

19. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000[Abstract/Free Full Text]

20. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline]

21. Knight RD, Miller LL, Pirotta N, et al: First-line irinotecan (C), fluorouracil (F), leucovorin (L) especially improves survival (OS) in metastatic colorectal cancer (MCRC) patients (PT) with favorable prognostic indicators. Proc Am Soc Clin Oncol 19:255a, 2000 (abstr 991)

22. Camptosar (irinotecan, CPT-11): First-line therapy of metastatic colorectal cancer. Presented at: Oncologic Drug Advisory Committee Meeting; Bethesda, MD, March 16, 2000

23. Bleiberg H, Cvitkovic E: Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: The European perspective. Eur J Cancer 32A:S18-23, 1996 (suppl 3)

24. CPT-11 for the treatment of patients with metastatic colorectal cancer that has progressed following initial 5-FU based chemotherapy. Presented at: Oncologic Drug Advisory Committee Meeting; Bethesda, MD, June 13, 1996

25. Rougier P, Bugat R: CPT-11 in the treatment of colorectal cancer: Clinical efficacy and safety profile. Semin Oncol 23:34-41, 1996 (suppl 3)[Medline]

26. Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997[Abstract/Free Full Text]

27. Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999[CrossRef][Medline]

28. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab (rhuMAb VEGF) to bolus IFL in the first-line treatment of patients with metastatic colorectal cancer: Results of a randomized phase III trial. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

29. Petrelli N, Douglass HO Jr, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial—Gastrointestinal Tumor Study Group. J Clin Oncol 7:1419-1426, 1989[Abstract]

30. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

31. Ward WL, Hahn EA, Mo F, et al: Reliability and validity of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) quality of life instrument. Qual Life Res 8:181-195, 1999[CrossRef][Medline]

32. Giantonio BJ, Catalano PJ, Meropol NJ, et al: The addition of bevacizumab (anti-VEGF) to FOLFOX4 in previously treated advanced colorectal cancer (advCRC): An updated interim toxicity analysis of the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at: Gastrointestinal Cancers Symposium: Colon and Rectal Cancers; Hollywood, FL, Jan 27-29, 2005 (abstr 169a)

33. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004[Abstract/Free Full Text]

Submitted May 20, 2004; accepted September 23, 2004.

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

Related Editorial

• Bevacizumab Plus Fluorouracil: The Value of Being Part of a Developing Story
  Alberto Sobrero and Paolo Bruzzi
  JCO 2005 23: 3660-3662 [Full Text]

This article has been cited by other articles:

				S. Welch, K. Spithoff, R. B. Rumble, J. Maroun, and the Gastrointestinal Cancer Disease Site Group Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review Ann. Onc., November 25, 2009; (2009) mdp533v1. [Abstract] [Full Text] [PDF]

				J. Tabernero and T. Macarulla Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development J. Clin. Oncol., November 20, 2009; 27(33): 5487 - 5491. [Full Text] [PDF]

				E. Van Cutsem, F. Rivera, S. Berry, A. Kretzschmar, M. Michael, M. DiBartolomeo, M.-A. Mazier, J.-L. Canon, V. Georgoulias, M. Peeters, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study Ann. Onc., November 1, 2009; 20(11): 1842 - 1847. [Abstract] [Full Text] [PDF]

				F. Montagnani, C. Migali, and G. Fiorentini Progression-Free Survival in Bevacizumab-Based First-Line Treatment for Patients With Metastatic Colorectal Cancer: Is It a Really Good End Point? J. Clin. Oncol., October 1, 2009; 27(28): e132 - e133. [Full Text] [PDF]

				N. T. Okita, Y. Yamada, D. Takahari, Y. Hirashima, J. Matsubara, K. Kato, T. Hamaguchi, K. Shirao, Y. Shimada, H. Taniguchi, et al. Vascular Endothelial Growth Factor Receptor Expression as a Prognostic Marker for Survival in Colorectal Cancer Jpn. J. Clin. Oncol., September 1, 2009; 39(9): 595 - 600. [Abstract] [Full Text] [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]

				K E Schmid-Kubista, I Krebs, B Gruenberger, F Zeiler, J Schueller, and S Binder Systemic bevacizumab (Avastin) therapy for exudative neovascular age-related macular degeneration. The BEAT-AMD-Study Br J Ophthalmol, July 1, 2009; 93(7): 914 - 919. [Abstract] [Full Text] [PDF]

				E. T.H. Yeh and C. L. Bickford Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2231 - 2247. [Abstract] [Full Text] [PDF]

				S. S. Shord, L. R. Bressler, L. A. Tierney, S. Cuellar, and A. George Understanding and managing the possible adverse effects associated with bevacizumab Am. J. Health Syst. Pharm., June 1, 2009; 66(11): 999 - 1013. [Abstract] [Full Text] [PDF]

				C.-H. Kohne and H.-J. Lenz Chemotherapy with Targeted Agents for the Treatment of Metastatic Colorectal Cancer Oncologist, May 1, 2009; 14(5): 478 - 488. [Abstract] [Full Text] [PDF]

				D. J. Sargent, C. H. Kohne, H. K. Sanoff, B. M. Bot, M. T. Seymour, A. de Gramont, R. Porschen, L. B. Saltz, P. Rougier, C. Tournigand, et al. Pooled Safety and Efficacy Analysis Examining the Effect of Performance Status on Outcomes in Nine First-Line Treatment Trials Using Individual Data From Patients With Metastatic Colorectal Cancer J. Clin. Oncol., April 20, 2009; 27(12): 1948 - 1955. [Abstract] [Full Text] [PDF]

				S. M Gressett and S. R Shah Intricacies of Bevacizumab-Induced Toxicities and Their Management Ann. Pharmacother., March 1, 2009; 43(3): 490 - 501. [Abstract] [Full Text] [PDF]

				J. R. Hecht, E. Mitchell, T. Chidiac, C. Scroggin, C. Hagenstad, D. Spigel, J. Marshall, A. Cohn, D. McCollum, P. Stella, et al. A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer J. Clin. Oncol., February 10, 2009; 27(5): 672 - 680. [Abstract] [Full Text] [PDF]

				F. F. Kabbinavar, H. I. Hurwitz, J. Yi, S. Sarkar, and O. Rosen Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients From Two Randomized Clinical Trials J. Clin. Oncol., January 10, 2009; 27(2): 199 - 205. [Abstract] [Full Text] [PDF]

				A. Grothey, M. M. Sugrue, D. M. Purdie, W. Dong, D. Sargent, E. Hedrick, and M. Kozloff Bevacizumab Beyond First Progression Is Associated With Prolonged Overall Survival in Metastatic Colorectal Cancer: Results From a Large Observational Cohort Study (BRiTE) J. Clin. Oncol., November 20, 2008; 26(33): 5326 - 5334. [Abstract] [Full Text] [PDF]

				S. R. Nalluri, D. Chu, R. Keresztes, X. Zhu, and S. Wu Risk of Venous Thromboembolism With the Angiogenesis Inhibitor Bevacizumab in Cancer Patients: A Meta-analysis JAMA, November 19, 2008; 300(19): 2277 - 2285. [Abstract] [Full Text] [PDF]

				H. J. Meulenbeld, L. N. van Steenbergen, M. L. G. Janssen-Heijnen, V. E. P. P. Lemmens, and G. J. Creemers Significant improvement in survival of patients presenting with metastatic colon cancer in the south of The Netherlands from 1990 to 2004 Ann. Onc., September 1, 2008; 19(9): 1600 - 1604. [Abstract] [Full Text] [PDF]

				F. F. Kabbinavar, J. F. Wallace, E. Holmgren, J. Yi, D. Cella, K. J. Yost, and H. I. Hurwitz Health-Related Quality of Life Impact of Bevacizumab When Combined with Irinotecan, 5-Fluorouracil, and Leucovorin or 5-Fluorouracil and Leucovorin for Metastatic Colorectal Cancer Oncologist, September 1, 2008; 13(9): 1021 - 1029. [Abstract] [Full Text] [PDF]

				C. P. Carden, J. M.G. Larkin, and M. A. Rosenthal What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro-oncol, August 1, 2008; 10(4): 624 - 630. [Abstract] [Full Text] [PDF]

				K. Shitara, M. Munakata, O. Muto, and Y. Sakata Metastatic Rectal Cancer Responding to Third-line Therapy Employing Bevacizumab After Failure of Oxaliplatin and Irinotecan: Case Report Jpn. J. Clin. Oncol., July 1, 2008; 38(7): 493 - 496. [Abstract] [Full Text] [PDF]

				J. R. Hecht Current and emerging therapies for metastatic colorectal cancer: Applying research findings to clinical practice Am. J. Health Syst. Pharm., June 1, 2008; 65(11_Supplement_4): S15 - S21. [Abstract] [Full Text] [PDF]

				L. B. Saltz, S. Clarke, E. Diaz-Rubio, W. Scheithauer, A. Figer, R. Wong, S. Koski, M. Lichinitser, T.-S. Yang, F. Rivera, et al. Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study J. Clin. Oncol., April 20, 2008; 26(12): 2013 - 2019. [Abstract] [Full Text] [PDF]

				B. Gruenberger, D. Tamandl, J. Schueller, W. Scheithauer, C. Zielinski, F. Herbst, and T. Gruenberger Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer J. Clin. Oncol., April 10, 2008; 26(11): 1830 - 1835. [Abstract] [Full Text] [PDF]

				C. Brostjan, K. Gebhardt, B. Gruenberger, V. Steinrueck, H. Zommer, H. Freudenthaler, S. Roka, and T. Gruenberger Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels Clin. Cancer Res., April 1, 2008; 14(7): 2065 - 2074. [Abstract] [Full Text] [PDF]

				C.-H. Kohne, G. Folprecht, R. M. Goldberg, E. Mitry, and P. Rougier Chemotherapy in Elderly Patients with Colorectal Cancer Oncologist, April 1, 2008; 13(4): 390 - 402. [Abstract] [Full Text] [PDF]

				B. D. Badgwell, E. R. Camp, B. Feig, R. A. Wolff, C. Eng, L. M. Ellis, and J. N. Cormier Management of bevacizumab-associated bowel perforation: a case series and review of the literature Ann. Onc., March 1, 2008; 19(3): 577 - 582. [Abstract] [Full Text] [PDF]

				C.R. Dass, T.M.N. Tran, and P.F.M. Choong Angiogenesis Inhibitors and the Need for Anti-angiogenic Therapeutics Journal of Dental Research, October 1, 2007; 86(10): 927 - 936. [Abstract] [Full Text] [PDF]

				P. Mathew, P. F. Thall, C. D. Bucana, W. K. Oh, M. J. Morris, D. M. Jones, M. M. Johnson, S. Wen, L. C. Pagliaro, N. M. Tannir, et al. Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases Clin. Cancer Res., October 1, 2007; 13(19): 5816 - 5824. [Abstract] [Full Text] [PDF]

				F. A. Scappaticci, J. R. Skillings, S. N. Holden, H.-P. Gerber, K. Miller, F. Kabbinavar, E. Bergsland, J. Ngai, E. Holmgren, J. Wang, et al. Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab J Natl Cancer Inst, August 15, 2007; 99(16): 1232 - 1239. [Abstract] [Full Text] [PDF]

				A. Sandler Bevacizumab in Non Small Cell Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4613s - 4616s. [Abstract] [Full Text] [PDF]

				L. Martin and R. Schilder Novel Approaches in Advancing the Treatment of Epithelial Ovarian Cancer: The Role of Angiogenesis Inhibition J. Clin. Oncol., July 10, 2007; 25(20): 2894 - 2901. [Abstract] [Full Text] [PDF]

				D. L. Reidy, K. Y. Chung, J. P. Timoney, V. J. Park, E. Hollywood, N. T. Sklarin, R. J. Muller, and L. B. Saltz Bevacizumab 5 mg/kg Can Be Infused Safely Over 10 Minutes J. Clin. Oncol., July 1, 2007; 25(19): 2691 - 2695. [Abstract] [Full Text] [PDF]

				J. Meyerhardt, K Stuart, C. Fuchs, A. Zhu, C. Earle, P Bhargava, L Blaszkowsky, P Enzinger, R. Mayer, S Battu, et al. Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastastic colorectal cancer Ann. Onc., July 1, 2007; 18(7): 1185 - 1189. [Abstract] [Full Text] [PDF]

				P. Heiduschka, H. Fietz, S. Hofmeister, S. Schultheiss, A. F. Mack, S. Peters, F. Ziemssen, B. Niggemann, S. Julien, K. U. Bartz-Schmidt, et al. Penetration of Bevacizumab through the Retina after Intravitreal Injection in the Monkey Invest. Ophthalmol. Vis. Sci., June 1, 2007; 48(6): 2814 - 2823. [Abstract] [Full Text] [PDF]

				E. Van Cutsem, M. Peeters, S. Siena, Y. Humblet, A. Hendlisz, B. Neyns, J.-L. Canon, J.-L. Van Laethem, J. Maurel, G. Richardson, et al. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer J. Clin. Oncol., May 1, 2007; 25(13): 1658 - 1664. [Abstract] [Full Text] [PDF]

				B. M. Wolpin, J. A. Meyerhardt, H. J. Mamon, and R. J. Mayer Adjuvant Treatment of Colorectal Cancer CA Cancer J Clin, May 1, 2007; 57(3): 168 - 185. [Abstract] [Full Text] [PDF]

				B. J. Giantonio, P. J. Catalano, N. J. Meropol, P. J. O'Dwyer, E. P. Mitchell, S. R. Alberts, M. A. Schwartz, and A. B. Benson III 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., April 20, 2007; 25(12): 1539 - 1544. [Abstract] [Full Text] [PDF]

				M. Los, J. M. L. Roodhart, and E. E. Voest Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer Oncologist, April 1, 2007; 12(4): 443 - 450. [Abstract] [Full Text] [PDF]

				K. S. Panageas, L. Ben-Porat, M. N. Dickler, P. B. Chapman, and D. Schrag When You Look Matters: The Effect of Assessment Schedule on Progression-Free Survival J Natl Cancer Inst, March 21, 2007; 99(6): 428 - 432. [Abstract] [Full Text] [PDF]

				J. Tabernero The Role of VEGF and EGFR Inhibition: Implications for Combining Anti-VEGF and Anti-EGFR Agents Mol. Cancer Res., March 1, 2007; 5(3): 203 - 220. [Abstract] [Full Text] [PDF]

				B. I. Rini Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions Clin. Cancer Res., February 15, 2007; 13(4): 1098 - 1106. [Abstract] [Full Text] [PDF]

				S. Gill, A. W. Blackstock, and R. M. Goldberg Colorectal Cancer Mayo Clin. Proc., January 1, 2007; 82(1): 114 - 129. [Abstract] [Full Text] [PDF]

				R. M. Goldberg, M. L. Rothenberg, E. Van Cutsem, A. B. Benson III, C. D. Blanke, R. B. Diasio, A. Grothey, H.-J. Lenz, N. J. Meropol, R. K. Ramanathan, et al. The Continuum of Care: A Paradigm for the Management of Metastatic Colorectal Cancer Oncologist, January 1, 2007; 12(1): 38 - 50. [Abstract] [Full Text] [PDF]

				J. S. Heier, D. S. Boyer, T. A. Ciulla, P. J. Ferrone, J. M. Jumper, R. C. Gentile, D. Kotlovker, C. Y. Chung, R. Y. Kim, and for the FOCUS Study Group Ranibizumab Combined With Verteporfin Photodynamic Therapy in Neovascular Age-Related Macular Degeneration: Year 1 Results of the FOCUS Study. Arch Ophthalmol, November 1, 2006; 124(11): 1532 - 1542. [Abstract] [Full Text] [PDF]

				J Heidemann, D G Binion, W Domschke, and T Kucharzik Antiangiogenic therapy in human gastrointestinal malignancies. Gut, October 1, 2006; 55(10): 1497 - 1511. [Full Text] [PDF]

				B. D. Zeitlin, E. Joo, Z. Dong, K. Warner, G. Wang, Z. Nikolovska-Coleska, S. Wang, and J. E. Nor Antiangiogenic Effect of TW37, a Small-Molecule Inhibitor of Bcl-2. Cancer Res., September 1, 2006; 66(17): 8698 - 8706. [Abstract] [Full Text] [PDF]

				B. Giantonio, D. Levy, P. O'Dwyer, N. Meropol, P. Catalano, and A. Benson III A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the eastern cooperative oncology group study E2200 Ann. Onc., September 1, 2006; 17(9): 1399 - 1403. [Abstract] [Full Text] [PDF]

				T. D. Yan, D. Black, R. Savady, and P. H. Sugarbaker Systematic Review on the Efficacy of Cytoreductive Surgery Combined With Perioperative Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis From Colorectal Carcinoma J. Clin. Oncol., August 20, 2006; 24(24): 4011 - 4019. [Abstract] [Full Text] [PDF]

				E. Van Cutsem Progress With Biological Agents in Metastatic Colorectal Cancer Leads to Many Challenges J. Clin. Oncol., July 20, 2006; 24(21): 3325 - 3327. [Full Text] [PDF]

				A. Morabito, E. De Maio, M. Di Maio, N. Normanno, and F. Perrone Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions Oncologist, July 1, 2006; 11(7): 753 - 764. [Abstract] [Full Text] [PDF]

				{blacktriangledown}Bevacizumab and {blacktriangledown}cetuximab for colorectal cancer DTB, May 1, 2006; 44(5): 37 - 40. [Abstract] [Full Text] [PDF]

				D. Vallbohmer, J. H. Peters, H. Kuramochi, D. Oh, D. Yang, D. Shimizu, S. R. DeMeester, J. A. Hagen, P. T. Chandrasoma, K. D. Danenberg, et al. Molecular Determinants in Targeted Therapy for Esophageal Adenocarcinoma Arch Surg, May 1, 2006; 141(5): 476 - 482. [Abstract] [Full Text] [PDF]

				V. R. Adams Evolving role of antineoplastic agents in colorectal cancer Am. J. Health Syst. Pharm., May 1, 2006; 63(9_Supplement_2): S4 - S11. [Abstract] [Full Text] [PDF]

				C. A. Townsley, G. R. Pond, A. M. Oza, H. W. Hirte, E. Winquist, G. Goss, P. Degendorfer, M. J. Moore, and L. L. Siu Evaluation of adverse events experienced by older patients participating in studies of molecularly targeted agents alone or in combination. Clin. Cancer Res., April 1, 2006; 12(7): 2141 - 2149. [Abstract] [Full Text] [PDF]

				P. Glusker, L. Recht, B. Lane, C. Ozcan, S. J. Wong, P. Hari, and H. Barron Reversible posterior leukoencephalopathy syndrome and bevacizumab. N. Engl. J. Med., March 2, 2006; 354(9): 980 - 982. [Full Text] [PDF]

				J. R. Goffin and J. R. Talavera Overstated Conclusions of a Pooled Analysis of Bevacizumab in Colon Cancer J. Clin. Oncol., January 20, 2006; 24(3): 528 - 529. [Full Text] [PDF]

				F. F. Kabbinavar, J. Hambleton, R. D. Mass, and S. Sarkar In Reply: J. Clin. Oncol., January 20, 2006; 24(3): 529 - 530. [Full Text] [PDF]

				A. J. Bilchik, G. Poston, S. A. Curley, S. Strasberg, L. Saltz, R. Adam, B. Nordlinger, P. Rougier, and L. S. Rosen Neoadjuvant Chemotherapy for Metastatic Colon Cancer: A Cautionary Note J. Clin. Oncol., December 20, 2005; 23(36): 9073 - 9078. [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 Kabbinavar, F. F. Articles by Novotny, W. F. Search for Related Content PubMed PubMed Citation Articles by Kabbinavar, F. F. Articles by Novotny, W. F. Related Articles Related Editorial Social Bookmarking                            What's this?