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 Chen, H. X. Articles by Kaplan, R. S. Search for Related Content PubMed PubMed Citation Articles by Chen, H. X. Articles by Kaplan, R. S. Related Articles Related Editorial Social Bookmarking                            What's this?

Phase II Multicenter Trial of Bevacizumab Plus Fluorouracil and Leucovorin in Patients With Advanced Refractory Colorectal Cancer: An NCI Treatment Referral Center Trial TRC-0301

Helen X. Chen, Margaret Mooney, Matthew Boron, Don Vena, Kimberly Mosby, Louise Grochow, Carl Jaffe, Lawrence Rubinstein, James Zwiebel, Richard S. Kaplan

From the Cancer Treatment Evaluation Program, National Cancer Institute, Bethesda; and The EMMES Corporation, Rockville, MD

Address reprint requests to Helen X. Chen, MD, Cancer Treatment Evaluation Program, National Cancer Institute, 6130 Executive Blvd, EPN 7131, Bethesda, MD 20892; e-mail: Helen_Chen{at}nih.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To provide bevacizumab (BV) -based therapy to patients with advanced colorectal cancers (CRC) who had exhausted standard chemotherapy options, and to evaluate the response to BV combined with fluorouracil (FU) and leucovorin (LV) in this patient population.

PATIENTS AND METHODS: This was a multicenter, single-arm treatment trial conducted under the National Cancer Institute Treatment Referral Center network nationwide. Patients were treated with BV 5 mg/kg every 2 weeks combined with FU/LV; FU was administered by bolus or continuous infusion. Eligibility criteria included advanced CRC that had progressed after irinotecan- and oxaliplatin-based chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 2, and absence of thromboembolism. The primary end point was objective response rate (RR) in the first 100 assessable patients. All patients received follow-up for toxicity and survival.

RESULTS: Due to rapid accrual, a total of 350 patients were enrolled at 32 participating sites nationwide by October 2003. In the initially planned cohort of 100 assessable patients, the objective RR was 4% (95% CI, 1.1% to 9.9%) by investigators' assessment and 1% (95% CI, 0% to 5.5%) based on independent review; median progression-free survival was 3.5 months and median overall survival was 9.0 months. The safety profile was similar to prior BV trials in CRC. Grade 3 to 4 hemorrhage occurred in 5% of patients, including 3.8% with bleeding in the GI tract. Other adverse events such as hypertension, thrombosis, and bowel perforation were also observed at rates consistent with other studies.

CONCLUSION: For patients with advanced CRC that had progressed after both irinotecan-based and oxaliplatin-based chemotherapy regimens, the combination of BV and FU/LV was associated with rare objective responses.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Until recently, treatment for patients with advanced colorectal cancer (CRC) was limited to three approved chemotherapeutic agents: fluorouracil (FU), irinotecan, and oxaliplatin. Specifically, combination of FU/leucovorin (LV) with either irinotecan or oxaliplatin have demonstrated survival benefit and were regarded as standard first-line or second-line chemotherapy regimens for patients with advanced CRC.^1,2-4

Bevacizumab (BV; Avastin; Genentech Inc, South San Francisco, CA), a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF),⁵ has been evaluated in various solid tumors. A randomized phase II trial of BV plus FU/LV in untreated patients with advanced CRC suggested favorable response rate (RR) and progression-free survival (PFS) of the combination with acceptable toxicity.⁶ In May 2003, Hurwitz et al^7,8 presented results of the pivotal phase III trial sponsored by Genentech Inc, which demonstrated that the addition of BV to irinotecan/FU/LV in the first-line setting of metastatic CRC was associated with a significant prolongation in survival (15.6 months v 20.3 months), as well as improvement in RR (34.8% v 44.8%) and PFS (6.2 months v 10.6 months). Recent results of the interim analysis of the Eastern Cooperative Oncology Group's phase III trial E3200 in the second-line setting has also shown that BV improved RR, PFS, and overall survival (OS) when combined with oxaliplatin plus FU/LV (FOLFOX).⁹ However, the BV alone arm in that trial was closed by the data monitoring committee after an early analysis suggested inferior survival for patients on the BV-only arm compared with patients on the control arm (FOLFOX4).

In May 2003, when the pivotal trial results were first reported,^7,8 BV was not yet commercially available, although a biologic license application by Genentech Inc for the agent was under review by the US Food and Drug Administration. In response to inquiries from patients and physicians for access to BV, the Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute (NCI; Bethesda, MD) developed the current treatment referral center (TRC) protocol (TRC-0301) for patients with advanced CRC in the third-line setting, for whom no standard treatment options were available at the time. Because no data were available about the effect of BV in this patient population, this TRC protocol had two goals: to evaluate the safety and activity of BV plus FU/LV in patients with advanced CRC that had progressed after treatment with both irinotecan-based and oxaliplatin-based chemotherapy regimens and; to provide broad geographic access to BV in the setting of a clinical trial for patients without standard therapeutic options.

The TRC mechanism was established in 1991 at CTEP/NCI¹⁰ to handle inquiries for investigational agents from physicians seeking treatment options for their patients, and to provide NCI-designated cancer centers access to promising investigational agents through a clinical trials mechanism. The first TRC clinical trial studied paclitaxel in patients with platinum-refractory ovarian cancer not eligible for other trials.¹⁰ For the current TRC protocol, in addition to NCI-designated cancer centers, other institutions were also included to provide access over a broader geographic area in the United States.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Study Design
This was an open-label, multicenter, single-arm clinical trial conducted between July 14, 2003 and October 31, 2003 through NCI's TRC mechanism. Participating sites were located across 25 states and included 18 NCI-designated cancer centers, 12 Community Clinical Oncology Program centers, and two other cancer institutes (Online Only Appendix). Patients and physicians who contacted CTEP were referred to the nearest participating sites for screening and treatment. All participating sites received local institutional review board approval before patient enrollment and all patients provided informed, written consent.

The study was designed with two stages. In stage I, the primary objective was to obtain RR in 100 response-assessable patients. If the target activity end point was met, indicating potential efficacy in this patient population (see Statistical Considerations), the second stage would open as a compassionate access protocol for the same patient population until BV became commercially available.

BV was supplied to NCI, free of charge, for this study under the Clinical Research and Development Agreement (CRADA) established between Genentech Inc and CTEP/NCI.

Patients
Eligible patients were 18 years of age or older and had locally advanced or metastatic CRC that had progressed after both irinotecan-based and oxaliplatin-based chemotherapy regimens; if either irinotecan- or oxaliplatin-based regimen was only used as adjuvant therapy, the last course should have been within 6 months of relapse. There was no limitation on the number of prior therapies. Eligibility criteria also included Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; adequate organ function (absolute neutrophil count, 1500/µL; platelet count, 100,000/µL; urine protein, < 1+ by dipstick or < 500 mg/24 hours; total bilirubin, < 1.5 mg/dL; AST and alkaline phosphatase < 5 x upper limit of normal, PT INR 1.5 and PTT 1.5 upper limit of normal). Exclusion criteria included thromboembolism requiring therapeutic anticoagulation, CNS metastasis, major surgery within 6 weeks, nonhealing wound, bleeding diathesis, active or recent cardiovascular disease or cerebrovascular accident, or prior BV therapy.

Treatment
Treatment was delivered in 8-week cycles until tumor progression or unacceptable toxicity. BV was administered by intravenous infusion at 5 mg/kg every 2 weeks in combination with one of the two FU/LV regimens listed in Table 1 based on physician's choice for individual patients at study entry.

Assessments
Clinical and laboratory assessments (CBC with differential, liver function tests, and urine protein) were performed every 2 weeks. Toxicities were graded using the NCI Common Terminology Criteria for Adverse Events version 3.0. Radiographic assessments were performed at baseline (within 4 weeks of study entry) and every 8 weeks. All patients were observed until death.

Grade 4 to 5 hematologic and grade 3 to 5 nonhematologic adverse events were reported through off-study forms after a patient was removed from protocol therapy (adverse events of lower grades were not collected). Serious adverse events were also reported in an expedited fashion to CTEP. Study reports were submitted through a web-based system.

Response Criteria
Response evaluation was based on the Response Evaluation Criteria in Solid Tumors (RECIST).¹¹ Stable disease had to be maintained through the first evaluation, at 8 weeks on completion of cycle 1. To be assigned a status of partial response (PR) or complete response (CR), the changes in tumor measurements had to be confirmed by repeat assessment by at least 4 weeks after PR or CR criteria were first met.

Patients were considered assessable for response if they were eligible, had measurable disease, and had received at least one dose of study therapy. Independent review of radiographic evidence for response was conducted for all investigator-reported PR/complete responses in the first 100 response-assessable patients.

Statistical Analysis
The primary end point of this study was RR. One hundred response-assessable patients were required to distinguish a RR of 2% or less versus 10% or higher with the probability of type I and type II error both at 0.05. If five or more PRs/CRs were observed in the 100 patients, the alternate hypothesis would be accepted.

All patients who received at least one dose of study therapy were included in the PFS and OS analyses as secondary end points. OS was measured from the start of study therapy. PFS was defined as time from initiation of study therapy to date of (progressive disease) PD or removal from study. Patients who died without PD documented were considered to have had PD at the time of death. Patients removed from therapy for toxicity without clinical or radiographic evidence of PD were censored. Patients lost to follow-up were censored at the last contact date. Kaplan-Meier methodology was used to obtain median survival time and 95% CIs.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
A total of 32 sites in 25 states participated in this trial, and accrual was rapid. Within 15 weeks from the first institutional review board approval on July 14, 2003, the study had reached the accrual target of 100 response-assessable patients (stage I), and the study design called for a temporary accrual suspension for RR assessment. However, due to significant interest in this study, many patients were being evaluated and awaiting study entry at multiple sites at the time. After discussion with patient advocacy groups, and with the support of Genentech Inc and the US Food and Drug Administration, enrollment was extended for 2 weeks to accommodate patients already being screened. Consequently, an additional 250 patents entered the study for a total of 350 registered.

Among the 350 patients enrolled on TRC-0301, 11 patients never received protocol therapy. The results reported herein are based on the 339 patients who received at least one dose of the study regimen. Median follow-up for the 339 treated patients is 14.2 months (range, 12.7 months to 17.3 months). The median number of cycles (1 cycle was 8 weeks) received was two (range, 1 to 8).

Patient Characteristics
The first 100 consecutive patients assessable for response (stage I) are identified as the Response Assessment cohort. Baseline patient characteristics are presented in Table 2 for both the Response Assessment cohort and all treated patients.

Patient characteristics and choice of FU schedules were similar in the extended cohort of 239 patients. However, three patients were found to be ineligible due to prior therapy with BV (1 patient), presence of CNS metastasis (1 patient), and nonCRC diagnosis (1 patient).

Objective Response and Survival
Table 3 lists best response to treatment for the 100 patient Response Assessment cohort. Radiographic scans from all reported responses were reviewed by an independent panel at NCI. A total of four PRs were reported by investigators (4%; 95% CI, 1.1% to 9.9%). Independent review confirmed one PR (1%; 95% CI, 0% to 5.5%); the duration of response in this patient was 8.5 months. Best responses in the other three patients with investigator reported PRs were assessed to be stable disease (SD).

View larger version (18K): [in this window] [in a new window]   Fig 1. The Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS) for the Response Assessment cohort.

Toxicity
All patients who received at least one dose of BV and chemotherapy were assessable for adverse event assessment. Dose modifications or interruptions were required in 34% of patients. Adverse event data were pooled for all treated patients, as there were no statistical differences in the adverse event rates between the two FU regimens or between the initial Response Assessment cohort and subsequent patients enrolled.

Adverse events grade 3 or worse, regardless of attribution, were reported in 47% of all treated patients. Forty-five patients (14%) were taken off the study due to adverse events. Selected adverse events based on the case report forms are listed in Table 4. Selected adverse events possibly related to BV were compiled based on both routine and expedited reports (Table 5). Grade 3 to 4 hemorrhage was reported in 17 patients (5%), with 13 events (4%) occurring in the GI tract. Three of the GI bleeds were from esophageal/gastric varices. The rate of venous thrombosis was 5.9%. Grade 4 arterial thromboembolic events occurred in three patients (< 1%), including a cerebrovascular accident, a myocardial infarction, and bowel ischemia. Other cardiovascular events included hypertension (4%) and supraventricular arrhythmia.

There have been 181 reported deaths, of which 173 were due to PD, three were due to pneumonia/aspiration, and two were of unknown etiology; causes of the other three deaths were not reported. Twenty two of the deaths occurred within 30 days of the last protocol treatment, and four deaths were due to non-PD related causes including pneumonia (3) and unknown etiology (1).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
TRC-0301 was initiated to provide access to BV when the agent was still investigational but had demonstrated a significant survival advantage when added to first-line FU-based chemotherapy in patients with advanced CRC. The study served the dual purpose of providing access to BV to patients with CRC who had exhausted existing standard treatment options and assessing the activity of BV combined with FU/LV in this patient population.

The study demonstrated that for patients with advanced CRC that had progressed after treatment with both oxaliplatin- and irinotecan-based chemotherapy regimens, the combination of BV and 5-FU/LV was associated with a low response rate: 4% based on investigator assessment and 1% based on independent review. Median PFS and OS were 3.7 months and 9.1 months, respectively. The safety profile was similar to that observed in the first-line setting with similar regimens, with a 5% rate of grade 3 or 4 hemorrhage.

Response data reported in TRC-0301 stand in contrast to several other studies with BV in CRC. Specifically, the addition of BV to FU- based chemotherapy in both first- and second-line settings was not only associated with improved PFS and OS, but also an increase in RR by approximately 10% above that seen with chemotherapy alone.^8,9 Compared with previous studies, patients in TRC-0301 were more heavily pretreated, with tumors progressing after both first- and second-line chemotherapy. Another important variable among these studies is the activity of the chemotherapy backbone, FU/LV, in the respective clinical settings. In TRC-0301, almost all patients would have been exposed to FU/LV, either as a doublet or as a component of prior regimens. Therefore, the chemotherapy component of this trial would be expected to have limited activity on its own. Indeed, in a controlled phase III trial in patients with CRC refractory to bolus FU, combination of FU/LV, even with continuous infusion, was associated with a RR of 0% (2.6% by investigators' assessment) and median time to progression of 2.7 months.⁴ While the TRC-0301 investigators were aware of the limitation of FU/LV in this setting, it was also recognized that no alternatives with proven activity were available at the time that might have served as a more effective backbone. Treatment with BV alone was not considered appropriate, given lack of data to support BV monotherapy in CRC.⁹ Furthermore, it was hypothesized that BV, by potentially normalizing tumor vasculature, might enhance tumor uptake of the cytotoxic agents and thus improve their efficacy. Data from TRC-0301, however, failed to demonstrate significant activity as measured by objective RR for the combination of BV with a presumably inactive chemotherapy backbone.

This single-arm trial was not designed to evaluate the impact of the study regimen on tumor progression and patient survival. Any comparison with historical data should be interpreted with caution considering differences in patient selection, availability of subsequent therapies, and other unrecognized factors. There have been few clinical trials in the third-line setting that could provide historical estimates of PFS and OS. In studies with cetuximab after failure of irinotecan-based or both irinotecan- and oxaliplatin-based regimens, median OS was 6.4 months to 6.9 months.^12,13 Similar median OS was reported in other trials for patients receiving best supportive care after failure of first-line FU/LV.² In this study, the median PFS and OS (3.5 months and 9.0 months, respectively) compare favorably with these historical data. However, several differences across trials should be noted. First, a unique eligibility criterion for this trial was absence of venous thromboembolism at baseline, which was not required in other CRC clinical trials. In addition, unlike studies with cetuximab that selected patients with epidermal growth factor receptor–overexpressing tumors, patients in TRC-0301 were entered regardless of their tumor's molecular features. TRC-0301 was also different from typical cooperative group studies, as most of the TRC sites were tertiary care cancer centers, and patients often had to travel a significant distance for protocol therapy. Indeed, 95% of the patients on this trial had ECOG PS of 0 to 1. Standard options of salvage therapy were also evolving during the course of this trial. Although the impact on survival is still unknown, cetuximab was given accelerated approval by the US Food and Drug Administration in February 2004. However, formal collection of data regarding subsequent therapies was not part of TRC-0301.

In the absence of placebo-controlled, randomized trials, one cannot completely exclude the possibility that the study regimen may have some effect on tumor progression. However, given the low RR demonstrated in TRC-0301, it is reasonable to conclude that BV, alone or in combination with an ineffective chemotherapy in the third-line setting, is likely to be of minimal, if any, clinical benefit. In contrast, in another NCI-sponsored study in the similar clinical setting,¹⁴ the combination of BV with an active agent, cetuximab, has demonstrated promising efficacy results. Implication of this result in the current practice in second- or third-line CRC is, however, unclear now that BV is part of the standard first-line therapy for CRC. A more relevant clinical question now is whether, after failure of first-line therapy, BV should be continued with subsequent cytotoxic regimens. This important question will be addressed in upcoming clinical trials.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Helen X. Chen, Margaret Mooney, Louise Grochow, Richard S. Kaplan, Lawrence Rubinstein, James Zwiebel Administrative support: Matthew Boron, Don Vena, Kimberly Mosby Collection and assembly of data: Helen X. Chen, Don Vena, Kimberly Mosby Data analysis and interpretation: Helen X. Chen, Margaret Mooney, Don Vena, Louise Grochow, Richard S. Kaplan, Carl Jaffe, Lawrence Rubinstein, James Zwiebel Manuscript writing: Helen X. Chen, Margaret Mooney, Louise Grochow, Richard S. Kaplan, James Zwiebel Final approval of manuscript: Helen X. Chen, Margaret Mooney, James Zwiebel

 

	ACKNOWLEDGMENTS

 
We thank the participating investigators and staff (see online only appendix) for their contribution to TRC-0301; the patient advocacy groups, the US Food and Drug Administration, and Genentech Inc for their shared involvement in this trial. We also thank David Shide, PhD, for assistance in manuscript preparation.

	NOTES

 
H.X.C. and M.M. contributed equally to this trial.

Supported by Cancer Therapy Evaluation Program of National Cancer Institute (NCI), under the Collaborative Research and Development Agreement between NCI and Genentech Inc.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. 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]

2. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline]

3. 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]

4. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003[Abstract/Free Full Text]

5. 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]

6. 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]

7. Hurwitz H, Fehrenbacher L, Carwright T, et al: Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-flurouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 21, 2003 (abstr 3646)

8. 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]

9. Giantonio BJ, Catalano P, Meropol NJ, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005

10. Trimble EL, Adams JD, Vena D, et al: Paclitaxel for platinum-refractory ovarian cancer: Results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11:2405-2410, 1993[Abstract/Free Full Text]

11. 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]

12. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004[Abstract/Free Full Text]

13. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004[Abstract/Free Full Text]

14. Saltz LB, Lenz H, Kindler H, et al: Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005

Submitted December 13, 2005; accepted February 21, 2006.

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

Related Editorial

• Progress With Biological Agents in Metastatic Colorectal Cancer Leads to Many Challenges
  Eric Van Cutsem
  JCO 2006 24: 3325-3327 [Full Text]

This article has been cited by other articles:

				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]

				H. Yasui, T. Yoshino, N. Boku, Y. Onozawa, S. Hironaka, A. Fukutomi, K. Yamazaki, K. Taku, T. Kojima, and N. Machida Retrospective Analysis of S-1 Monotherapy in Patients with Metastatic Colorectal Cancer After Failure to Fluoropyrimidine and Irinotecan or to Fluoropyrimidine, Irinotecan and Oxaliplatin Jpn. J. Clin. Oncol., May 1, 2009; 39(5): 315 - 320. [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]

				R. Brake, C. Starnes, J. Lu, D. Chen, S. Yang, R. Radinsky, and L. Borges Effects of Palifermin on Antitumor Activity of Chemotherapeutic and Biological Agents in Human Head and Neck and Colorectal Carcinoma Xenograft Models Mol. Cancer Res., August 1, 2008; 6(8): 1337 - 1346. [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. Kanter, S. Y. Khan, M. Kelher, L. Gore, and C. C. Silliman Oncogenic and Angiogenic Growth Factors Accumulate during Routine Storage of Apheresis Platelet Concentrates Clin. Cancer Res., June 15, 2008; 14(12): 3942 - 3947. [Abstract] [Full Text] [PDF]

				A. F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y. A. Abubakr, M. P. Lutz, M. E. Vega-Villegas, C. Eng, E. U. Steinhauer, J. Prausova, et al. EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer J. Clin. Oncol., May 10, 2008; 26(14): 2311 - 2319. [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]

				W. Chen, S. Delaloye, D. H.S. Silverman, C. Geist, J. Czernin, J. Sayre, N. Satyamurthy, W. Pope, A. Lai, M. E. Phelps, et al. Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study J. Clin. Oncol., October 20, 2007; 25(30): 4714 - 4721. [Abstract] [Full Text] [PDF]

				T. Liu, Y. Ding, W. Xie, Z. Li, X. Bai, X. Li, W. Fang, C. Ren, S. Wang, R. M. Hoffman, et al. An Imageable Metastatic Treatment Model of Nasopharyngeal Carcinoma Clin. Cancer Res., July 1, 2007; 13(13): 3960 - 3967. [Abstract] [Full Text] [PDF]

				M. Yang, P. Jiang, and R. M. Hoffman Whole-Body Subcellular Multicolor Imaging of Tumor-Host Interaction and Drug Response in Real Time Cancer Res., June 1, 2007; 67(11): 5195 - 5200. [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]

				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]

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 Chen, H. X. Articles by Kaplan, R. S. Search for Related Content PubMed PubMed Citation Articles by Chen, H. X. Articles by Kaplan, R. S. Related Articles Related Editorial Social Bookmarking                            What's this?