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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1145-1151
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.03.6780
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Phase I Trial Evaluating the Safety of Bevacizumab With Concurrent Radiotherapy and Capecitabine in Locally Advanced Pancreatic Cancer

Christopher H. Crane, Lee M. Ellis, James L. Abbruzzese, Christina Amos, Henry Q. Xiong, Linus Ho, Douglas B. Evans, Eric P. Tamm, Chaan Ng, Peter W.T. Pisters, Chusilp Charnsangavej, Marc E. Delclos, Michael O'Reilly, Jeffrey E. Lee, Robert A. Wolff

From the Departments of Radiation Oncology, Cancer Biology, Gastrointestinal Medical Oncology, Diagnostic Imaging, and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Pancreatic Tumor Study Group

Address reprint requests to Christopher H. Crane, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ccrane{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: To study the safety of bevacizumab with capecitabine-based chemoradiotherapy.

PATIENTS AND METHODS: Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients).

RESULTS: Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy.

CONCLUSION: Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Vascular endothelial growth factor (VEGF) is a highly conserved glycoprotein that functions as the predominant regulator of developmental, physiologic, and neoplastic angiogenesis (reviewed in Ferrara N and Dvorak HF1,2). VEGF-A (hereafter referred to as VEGF) is the dominant member of the VEGF family which is composed of six related proteins. VEGF produces a number of biologic effects, including endothelial cell mitogenesis and migration, induction of proteinases leading to remodeling of the extracellular matrix, increased vascular permeability, and maintenance of survival of newly formed blood vessels (reviewed in Ferrara N1). VEGF-mediated tumor cell migration and invasion have also recently been described.3,4 Increased levels of VEGF expression have been found in most human tumors,1 and increased VEGF expression in tumors has been correlated with invasiveness, vascular density, metastasis, and recurrence.1,2,5-7

Bevacizumab is a humanized monoclonal antibody to VEGF that effectively prevents it from binding to its receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1 and KDR). It is the first antiangiogenic agent to be approved by the United States Food and Drug Administration in February, 2004; its approval was based on the results of a randomized trial demonstrating that the combination of bevacizumab with standard chemotherapy improved efficacy without adding significantly increasing toxicity in patients with metastatic colorectal cancer.8 In vivo studies have shown that a radioresistant phenotype can be overcome using agents that neutralize VEGF activity or prevent its signaling.9-11

Capecitabine has been shown to be well tolerated when given continuously during radiation at doses similar to the recommended phase II continuous dosing schedule in colon cancer.12-14 When the present trial was conceived in February 2002, the safety of combining anti-VEGF therapy with radiotherapy was not known. However, because locally advanced, unresectable pancreatic cancer is essentially incurable with standard therapies, experimental therapy is appropriate as a first-line strategy. This phase I trial was designed to study the safety of bevacizumab with concurrent capecitabine-based chemoradiotherapy and to look for preliminary evidence of efficacy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Eligibility Criteria
Patient eligibility criteria are depicted in Table 1; exclusion criteria are depicted in Table 2.


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  		Table 1. Eligibility Criteria

 

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  		Table 2. Exclusion Criteria

 
All patients had to sign a study specific consent form. This study was reviewed, approved, and monitored by the University of Texas M.D. Anderson Cancer Center institutional review board.

Study Design and Treatment Plan
The primary end point of this study was the safety of the combination of bevacizumab, radiotherapy, and capecitabine. Secondary end points were radiographic evidence of local tumor response and median survival duration. The dose escalation schema for this study is depicted in Table 3. All patients were treated, monitored during therapy, and followed up by the principal investigator (C.H.C.).


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  		Table 3. Dose Escalation Schema

 
Bevacizumab Dose Escalation Schema and Protocol Modifications
Dose limiting toxicity (DLT) was defined as any treatment-related grade 3 or 4 toxicity (National Cancer Institute common toxicity criteria, version 3) other than lymphopenia, hyperglycemia, hypoglycemia, deep venous thrombosis, or hyperbilirubinemia secondary to biliary stent occlusion. Initially, three patients were treated in each cohort. The original plan was that if no more than one of the six patients assigned to a given dose level of bevacizumab experienced DLT, patients were accrued to the next dose level. If two of six patients experienced DLT at a dose level, the dose level was considered the maximum-tolerated dose. After the institutional review board reviewed the safety data from the first 15 patients, the cohorts three through five were expanded to 12 patients in an attempt to clarify the risk, incidence, and clinical characteristics of infrequent bleeding events that were initially seen. The protocol was further revised for patients 19 through 30 (six of whom received 5 mg/kg/2 weeks and six of whom received 7.5 mg/kg/2 weeks of bevacizumab during chemoradiotherapy) to include bevacizumab (5 mg/kg/2 weeks) administration between the end of chemoradiotherapy and the first restaging evaluation 6 weeks later. For the final 18 patients (patients 31 through 48), the final dose of bevacizumab during chemoradiotherapy was dropped in an effort to prevent impaired healing of acute radiation-associated mucosal reactions. Thus, the final 18 patients received bevacizumab 2 weeks before the start of chemoradiotherapy, on the first day of chemoradiotherapy, and on the 15th day of chemoradiotherapy.

Further Therapy
At the completion of protocol-based chemoradiotherapy, all patients with responding or stable disease were given the option of receiving any other available treatment or continuing single-agent bevacizumab (5 mg/kg intravenously every 2 weeks until disease progression). Surgery was considered in patients whose tumors were considered technically resectable at any time during follow-up.

Conformal Radiation Technique
Treatment was delivered to the gross tumor only. Elective nodal irradiation was not used. All patients underwent treatment simulation in the supine arms up position using a computed tomography (CT) -simulator. After simulation, the gross primary tumor and any lymph nodes > 5 mm seen in the typical pancreatic drainage basin were identified and contoured. Then, customized blocking using a multileaf collimator was created. A radial block margin of 2 cm and a cranial and caudal block margin of 3 cm were used. The dose of 50.4 Gy/28 fractions/5.5 weeks was prescribed to the 95% isodose line using 15- or 18-MV photons and a four-field technique with equal weighting in all patients. There was no field reduction.

Treatment Interruption and Dose Adjustment
Capecitabine was withheld in cases of grade 2 or greater neutropenia, hand-foot syndrome, mucositis, or gastrointestinal toxicities (eg, anorexia, nausea, vomiting, diarrhea, dehydration) unresponsive to medical management and was restarted after recovery to grade 1. The dose was adjusted according to the number of occurrences of grade 2 or greater gastrointestinal toxicity or hand-foot syndrome: first occurrence = 75% of starting dose and second occurrence = 50% of starting dose. Capecitabine was discontinued for the third occurrence. Missed doses of capecitabine were not made up. Bevacizumab and radiotherapy were interrupted for grade 3 or greater toxicity believed to be related to the drug until the toxicity resolved to grade 1; then, continued without adjustment. Bevacizumab was discontinued permanently if toxicity recurred.

Patient Monitoring
Monitoring during chemoradiotherapy. The radiation oncologist (C.H.C.) and a medical oncologist independently recorded the history and performed a physical examination of each patient weekly. Serum hemoglobin, hematocrit, WBC, platelet levels, and serum chemistries were evaluated every week during chemoradiotherapy. Capecitabine pill diaries were monitored weekly to verify compliance.

Follow-Up After Chemoradiotherapy
Chest radiography, Ca 19 to 9 level measurement, and multidetector CT of the abdomen performed according to the M.D. Anderson Cancer Center Pancreas Protocol15 were obtained 6 weeks after therapy and every two months following the completion of all therapy until disease progression.

Response Criteria and Statistics
Local tumor response was assessed using standard response criteria.16 Survival duration was estimated using Kaplan-Meier actuarial methodology and binary end points were evaluated using the {chi}2 test software package (version 11.5, Statistical Package for the Social Sciences Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patient Characteristics
Between November 8, 2002 and January 11, 2005, 48 patients were enrolled. Median follow-up was 9.6 months (range, 5.0-32.0) for living patients and 10.0 months (range, 3.9-32.0) for all patients from the initiation of protocol treatment. Patient characteristics are reported in Table 4. Thirty-one of the 48 patients enrolled had received prior gemcitabine or a gemcitabine-based chemotherapy combination for a median of 3.2 months (range, 1.4-13.1) before protocol entry.


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  		Table 4. Patient and Tumor Characteristics

 
Chemoradiotherapy-Related Toxicity
Gastrointestinal toxicity. In Table 5 we report the worst gastrointestinal toxicity that individual patients experienced. When multiple treatment-related grade 2 gastrointestinal adverse events of the same grade occurred in the same patient, dehydration requiring intravenous rehydration for less than 24 hours was considered worse than nausea, vomiting, or anorexia, which in turn were considered worse than diarrhea or constipation. Twenty (43%) of 47 patients had grade 2 acute gastrointestinal toxicity, but only two (4%) experienced grade 3 toxicity and required admission to the hospital for supportive care. One of the patients had early onset grade 3 gastrointestinal toxicity (gastritis, nausea, vomiting, and diarrhea) and low-grade pancytopenia requiring hospitalization. For this reason, all treatment was interrupted on day 13 and radiotherapy and bevacizumab, but not capecitabine, were restarted after a 9-day treatment break. The patient then received the full radiation dose and subsequently continued bevacizumab for 8 more months until progressing with metastatic disease without further gastrointestinal toxicity. The other patient with grade 3 gastrointestinal toxicity was hospitalized briefly for rehydration.


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  		Table 5. Worst Gastrointestinal Toxicity

 
There was no correlation between prior gemcitabine-based chemotherapy and incidence of grade 2 or 3 gastrointestinal toxicity (40% of patients who had received prior chemotherapy experienced grade 2 or 3 toxicity compared with 59% with no prior chemotherapy, P = .219).

Hematologic and Miscellaneous Toxicity
There was minimal hematologic toxicity. Three patients developed transient uncomplicated grade 4 neutropenia and two patients developed grade 3 thrombocytopenia. One patient developed grade 3 hypomagnesemia. Eleven patients (23%) developed grade 2 hand-foot syndrome.

Adverse Events Possibly Attributable to Bevacizumab
Four patients had grade 3 or greater ulceration with bleeding or perforation in the radiation field that could have been related to bevacizumab or the combination of bevacizumab and chemoradiotherapy (Table 6). Three of these patients had bleeding arising from ulcerated mucosa adjacent to the tumor within the radiation field 3, 10, and 20 weeks after the completion of chemoradiotherapy. CT evidence of a small fistulous connection was retrospectively identified in two of the three patients. In two patients, the bleeding was stabilized with transfusion, endoscopic laser coagulation, and discontinuation of maintenance bevacizumab. In the third, bleeding from gross tumor invading the duodenum could not be controlled despite intra-arterial tumor embolization. The patient decided to forego further supportive care and transfusion, and died 2 weeks later at home. The fourth patient had a grade 3 contained perforation of the duodenum immediately adjacent to the primary tumor, 10 weeks after the completion of chemoradiotherapy. In addition to the three patients with bleeding described above, two patients had grade 3 bleeding outside of the radiation field (bladder and small bowel), and one had acute appendicitis complicated by perforation. After these events occurred, the protocol was amended in the interests of patient safety. Thus for the final 18 patients, the fourth and final dose of bevacizumab was omitted and patients with tumors invading the duodenum seen on CT scan or endoscopy were excluded.


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  		Table 6. Toxicity Possibly Related to Bevacizumab

 
In addition, four of 174 planned doses of bevacizumab were omitted during chemoradiotherapy. Maintenance bevacizumab was discontinued for the bleeding and perforation events discussed above, in anticipation of pancreaticoduodenectomy in four patients, and was interrupted in one patient for urgent biliary and gastric bypass surgery (7 days after the last dose of maintenance bevacizumab), then restarted. Bevacizumab was discontinued for tumor progression in the remaining patients.

Dose Interruptions and Reductions of Capecitabine and Radiotherapy
Overall, there were capecitabine dose reductions in 19 patients (40%) for grade 2 or greater toxicity; before reduction, capecitabine was withheld for a median of 12 doses (6 days; range, 3-36 doses). Eight patients required either a second dose reduction or discontinuation of capecitabine due to recurrent grade 2 toxicity. In an effort to reduce grade 2 toxicity, the protocol was modified to eliminate the weekend doses of capecitabine in patients 37 through 48. Three patients (25%) in that final cohort had grade 2 gastrointestinal toxicity, and two patients had grade 2 hand and foot syndrome. All patients received the full dose of radiotherapy; four patients had radiotherapy interrupted (for 9, 2, 2, and 1 days, respectively) owing to toxicity.

Chemoradiotherapy Compliance
Other than the held doses, all radiation and bevacizumab doses were delivered as directed. Forty-six (96%) of 48 patients completed capecitabine pill diaries. Twenty-nine (63%) of 46 patients completed all capecitabine doses exactly as prescribed. Of the 17 patients who missed doses, eight missed only one dose (compliant with 98.7% of doses), seven missed only two doses (compliant with 97.5% of doses), one missed three doses (96.1% compliance), and one missed six doses (92.1% compliance).

Radiographic Response
Two patients were excluded from the response analysis. One patient was taken off of the study before the start of chemoradiotherapy because of a perforated appendix, and the other patient did not have a CT-defined mass. Overall, nine (20%) of 46 assessable patients' tumors had an objective partial response to initial therapy. This included six of 12 patients' tumors treated at a dose of 5 mg/kg of bevacizumab (Table 7). Ten patients' tumors (21%) had minor responses and all of the remaining patients had radiographically stable local disease except for one who had local disease progression after chemoradiotherapy.


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  		Table 7. Best Radiographic Response of the Primary Tumor

 
Surgical Resection
Four patients underwent a margin-negative pancreaticoduodenectomy after successful completion of the protocol treatment. Two of these four patients' tumors were found to be unresectable at the time of surgical exploration before referral to our institution on the basis of biopsy-proven regional lymph node metastases and venous involvement (the primary tumor was otherwise resectable). The other two patients had not undergone prior surgery and had CT evidence of minimal arterial involvement consisting of arterial abutment of less than 1 cm in length and less than 90° in circumference. One of the four patients had a radiographic partial response, and the other three had minor responses; all four patients had Ca 19-9 levels declined from baseline during treatment. The intervals between the last dose of bevacizumab and surgery were 4.0, 10.7, 13.0, and 18.4 weeks. There were no significant perioperative complications. Light microscopic examination of the tumors of all four patients demonstrated histologic evidence of significant treatment effect (20% to 50% viable tumor cells remaining).17 At last follow-up, three of the four patients were disease-free at 32.0, 20.3, and 14.2 months after initiation of study treatment.

Overall Survival
The earliest death occurred 3.9 months after the start of protocol therapy. Median, 1-year, and 18-month actuarial survival estimates were 14.4 months (95% CI, 11.3 to 17.4), 65.0%, and 24.4.0% from the start of any therapy, and 11.6 months (95% CI, 9.6 to 13.6), 45.8%, and 19.1% from the start of protocol therapy.

Pattern of Progression
Eight patients (17%) had local tumor growth as a component of progressive disease at any time during follow-up. Six of these patients had isolated local progression and two were in combination with distant metastases. The remaining patients (including all patients who had a partial response) have had no evidence for locally progressive disease.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Agents that target aberrant overexpression of growth-regulatory molecules such as growth factors and their receptors (for example bevacizumab, cetuximab, erlotinib, and gefitinib) are now being used in clinical practice and evaluated in clinical trials in combination with chemotherapy in various tumor types. These agents have enhanced the treatment effects of radiotherapy in preclinical studies,11,18,19 and may selectively improve local disease control. This study demonstrates that bevacizumab is generally safe when combined with chemoradiotherapy in patients with locally advanced pancreatic cancer. The acute gastrointestinal toxicity was much lower than what has been reported as acceptable in comparable chemoradiotherapy studies.20-23 Acute toxicity was minimal and easily managed with dose adjustments of capecitabine, without interruption or attenuation of either the bevacizumab or radiation dose. Limiting radiotherapy fields to the gross tumor volume alone was probably also a factor that contributed to minimizing the grade 3 acute toxicity. Despite the overall tolerability of this regimen, the four subacute adverse events (ulceration, bleeding, perforation) in the radiation field are concerning. These events occurred between 3 and 20 weeks after the completion of chemoradiotherapy, but did not occur after patients with duodenal involvement were excluded (the remaining 18 patients).

The only other published study evaluating bevacizumab in combination with chemoradiotherapy also suggests that bevacizumab enhances response to chemoradiotherapy.24 In that study, patients with locally advanced rectal cancer were treated with standard preoperative chemoradiotherapy with bevacizumab. Five (83%) of six patients had only microscopic residual disease on thorough histologic evaluation. By comparison 192 (45%) of 431 of patients treated at our institution with a similar chemoradiotherapy regimen (without bevacizumab) had only microscopic residual disease.25 Correlative studies supported the hypothesis that antiangiogenic therapy normalizes tumor vascular physiology by reducing permeability and eliminating immature and inefficient blood vessels.26 The relationship of the results of the correlative studies to response is not clear; one possibility is that a more efficient tumor vasculature could improve oxygenation, which is well known to improve radiation response.27,28

Other possible mechanisms for an increase in radiotherapy treatment effect are the direct enhancement of endothelial cell or tumor cell cytotoxicity. VEGF expression has been shown to be enhanced by radiation, and in vitro studies suggested the enhanced cytotoxicity of the combination of radiotherapy and antibody-mediated VEGF neutralization was due to the potentiation of endothelial cell death rather than to direct tumor cell cytotoxicity.9 These results seemed to suggest that VEGF is protective of endothelial cells exposed to the stress imposed by ionizing radiation,9 and that VEGF blockade could overcome this protective effect. However, recent investigation has also demonstrated expression of VEGF receptor-1 (VEGFR-1) protein, mRNA, and its ligands as well as protein kinase signaling in pancreatic and colon cancer cell lines as well as endothelial cells. VEGFR-1 mediated migration and invasion that is blocked by a VEGFR-1 neutralizing antibody have been also been demonstrated.3,4 Thus, VEGFR-1 is not only present on tumor cells, but also apparently can mediate their biologic behavior. It is therefore possible that the preliminary clinical evidence of enhancement of radiotherapy by bevacizumab is due to a direct effect on tumor cells.

In this study, the addition of concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen in this phase I study. Capecitabine and radiotherapy were generally well tolerated (4% grade 3 gastrointestinal toxicity), but aggressive dose reductions were needed to prevent grade 3 toxicity when capecitabine was given 7 days per week. When weekend doses were omitted in the remaining 12 patients, only 3 patients (25%) experienced grade 2 toxicity. A small number of patients experienced ulceration and bleeding in the radiation field that appeared to be related to tumor involvement of the duodenal mucosa. The risk of these events and the efficacy of this regimen should be further characterized in larger cohorts of patients. The recommended dose of capecitabine in this combination 825 mg/m2 on days of radiation only. The determination of the optimal dose of bevacizumab based on efficacy results will require a larger study.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. 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.
Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other
Christopher H. Crane Roche (A) Genetech, Inc (B)
Lee M. Ellis Genetech, Inc (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required


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

Conception and design: Christopher H. Crane, Lee M. Ellis, James L. Abbruzzese, Michael O'Reilly, Robert A. Wolff

Administrative support: Christina Amos

Provision of study materials or patients: Christopher H. Crane, James L. Abbruzzese, Henry Q. Xiong, Linus Ho, Douglas B. Evans, Jeffrey E. Lee, Robert A. Wolff

Collection and assembly of data: Christopher H. Crane, Christina Amos, Douglas B. Evans, Robert A. Wolff

Data analysis and interpretation: Christopher H. Crane, James L. Abbruzzese

Manuscript writing: Christopher H. Crane, Lee M. Ellis, James L. Abbruzzese, Henry Q. Xiong, Douglas B. Evans

Final approval of manuscript: Christopher H. Crane, Lee M. Ellis, James L. Abbruzzese, Henry Q. Xiong, Linus Ho, Douglas B. Evans, Eric P. Tamm, Chaan Ng, Peter W. T. Pisters, Chusilp Charnsangavej, Marc E. Delclos, Michael O'Reilly, Jeffrey E. Lee, Robert A. Wolff

 


   NOTES
 
Supported by Grant Nos. CA06294 and CA16672 from the National Cancer Institute, Department of Health and Human Services, and Genentech, Inc.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

This material has not been previously published in manuscript form.

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


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
1. Ferrara N: Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 25:581-611, 2004[Abstract/Free Full Text]

2. Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368-4380, 2002[Abstract/Free Full Text]

3. Fan F, Wey JS, McCarty MF, et al: Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24:2647-2653, 2005[CrossRef][Medline]

4. Wey J, Fan F, Gray M, et al: Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104:427-438, 2005[CrossRef][Medline]

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6. 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]

7. 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]

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. Gorski DH, Beckett MA, Jaskowiak NT, et al: Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59:3374-3378, 1999[Abstract/Free Full Text]

10. Geng L, Donnelly E, McMahon G, et al: Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 61:2413-2419, 2001[Abstract/Free Full Text]

11. Kozin SV, Boucher Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 61:39-44, 2001[Abstract/Free Full Text]

12. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983-3991, 2002[Abstract/Free Full Text]

13. Schneider BJ, Ben-Josef E, McGinn CJ, et al: Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 63:1325-1330, 2005[CrossRef][Medline]

14. Ben-Josef E, Shields AF, Vaishampayan U, et al: Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys 59:454-459, 2004[CrossRef][Medline]

15. Tamm EP, Silverman PM, Charnsangavej C, et al: Diagnosis, staging, and surveillance of pancreatic cancer. AJR Am J Roentgenol 180:1311-1323, 2003[Free Full Text]

16. Miller A, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

17. Evans DB, Rich TA, Byrd DR, et al: Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 127:1335-1339, 1992[Abstract/Free Full Text]

18. Bianco C, Tortora G, Bianco R, et al: Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8:3250-3258, 2002[Abstract/Free Full Text]

19. Milas L, Fan Z, Andratschke NH, et al: Epidermal growth factor receptor and tumor response to radiation: In vivo preclinical studies. Int J Radiat Oncol Biol Phys 58:966-971, 2004[CrossRef][Medline]

20. McGinn C, Talamonti M, Small W, et al: A phase II trial of full-dose gemcitabine with concurrent radiation therapy in patients with resectable or unresectable non-metastatic pancreatic cancer. Proc ASCO GI Symposium, San Francisco, CA, 89, 2004 (abstr 96)

21. McGinn CJ, Zalupski MM, Shureiqi I, et al: Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202-4208, 2001[Abstract/Free Full Text]

22. Crane CH, Janjan NA, Evans DB, et al: Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Pancreatol 29:9-18, 2001[Medline]

23. Mehta VK, Fisher G, Ford JA, et al: Preoperative chemoradiation for marginally resectable adenocarcinoma of the pancreas. J Gastrointest Surg 5:27-35, 2001[CrossRef][Medline]

24. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline]

25. Bonnen M, Crane C, Vauthey J-N, et al: Long-term results using local excision after preoperative chemoradiation among selected T3 rectal cancer patients. Int J Radiat Oncol Biol Phys 60:1098-1105, 2004[CrossRef][Medline]

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27. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563, 2004[Medline]

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Submitted August 2, 2005; accepted December 22, 2005.


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