This Article Full Text 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, K. D. Articles by Rugo, H. S. Search for Related Content PubMed PubMed Citation Articles by Miller, K. D. Articles by Rugo, H. S.

Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer

From the Indiana University, Indianapolis, IN; University of California Los Angeles, Los Angeles; Kaiser Northern California, Vallejo; Genentech Inc, South San Francisco; University of California San Francisco, San Francisco, CA; US Oncology, Houston, TX; Rush-Presbyterian-St Luke's Medical Center, Chicago, IL; Duke University, Durham, NC; Memorial Sloan Kettering Cancer Center, New York, NY; Case Western University, Cleveland, OH

Address reprint requests to Kathy D. Miller, MD, Indiana University Cancer Pavilion, 535 Barnhill Dr, RT-473, Indianapolis, IN 46202; e-mail: kathmill{at}iupui.edu

PURPOSE: This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PATIENTS AND METHODS: Patients were randomly assigned to receive capecitabine (2,500 mg/m²/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility.

RESULTS: From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment—Breast were comparable in both treatment groups.

CONCLUSION: Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

Supported by Genentech Inc. A full list of participating investigators and institutions can be found in the Appendix.

Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 11-14, 2002.

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

This article has been cited by other articles:

				L. B. Michaud Treatment-experienced breast cancer Am. J. Health Syst. Pharm., May 15, 2008; 65(10_Supplement_3): S4 - S9. [Abstract] [Full Text] [PDF]

				J.-J. Mourad, G. des Guetz, H. Debbabi, and B. I. Levy Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation Ann. Onc., May 1, 2008; 19(5): 927 - 934. [Abstract] [Full Text] [PDF]

				P. Schmid, D. Kuhnhardt, P. Kiewe, S. Lehenbauer-Dehm, W. Schippinger, R. Greil, W. Lange, J. Preiss, N. Niederle, P. Brossart, et al. A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines Ann. Onc., May 1, 2008; 19(5): 871 - 876. [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]

				M. Benesch, M. Windelberg, W. Sauseng, V. Witt, G. Fleischhack, H. Lackner, H. Gadner, U. Bode, and C. Urban Compassionate use of bevacizumab (Avastin(R)) in children and young adults with refractory or recurrent solid tumors Ann. Onc., April 1, 2008; 19(4): 807 - 813. [Abstract] [Full Text] [PDF]

				F. Petrelli, M. Cabiddu, M. E. Cazzaniga, M. Cremonesi, and S. Barni Targeted Therapies for the Treatment of Breast Cancer in the Post-trastuzumab Era Oncologist, April 1, 2008; 13(4): 373 - 381. [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]

				A. Ocana and A. Pandiella Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options Clin. Cancer Res., February 15, 2008; 14(4): 961 - 970. [Abstract] [Full Text] [PDF]

				M. Findlay, G. von Minckwitz, and A. Wardley Effective oral chemotherapy for breast cancer: pillars of strength Ann. Onc., February 1, 2008; 19(2): 212 - 222. [Abstract] [Full Text] [PDF]

				K. Miller, M. Wang, J. Gralow, M. Dickler, M. Cobleigh, E. A. Perez, T. Shenkier, D. Cella, and N. E. Davidson Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer N. Engl. J. Med., December 27, 2007; 357(26): 2666 - 2676. [Abstract] [Full Text] [PDF]

				G. H. Lyman, A. A. Khorana, A. Falanga, D. Clarke-Pearson, C. Flowers, M. Jahanzeb, A. Kakkar, N. M. Kuderer, M. N. Levine, H. Liebman, et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer J. Clin. Oncol., December 1, 2007; 25(34): 5490 - 5505. [Abstract] [Full Text] [PDF]

				E. S. Thomas, H. L. Gomez, R. K. Li, H.-C. Chung, L. E. Fein, V. F. Chan, J. Jassem, X. B. Pivot, J. V. Klimovsky, F. H. de Mendoza, et al. Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment J. Clin. Oncol., November 20, 2007; 25(33): 5210 - 5217. [Abstract] [Full Text] [PDF]

				A. Morabito, M. C. Piccirillo, K. Monaco, C. Pacilio, F. Nuzzo, P. Chiodini, C. Gallo, A. de Matteis, F. Perrone, and NCI Naples Breast Cancer Group First-Line Chemotherapy for HER-2 Negative Metastatic Breast Cancer Patients Who Received Anthracyclines as Adjuvant Treatment Oncologist, November 1, 2007; 12(11): 1288 - 1298. [Abstract] [Full Text] [PDF]

				E. T. Wong and S. Brem Taming Glioblastoma: Targeting Angiogenesis J. Clin. Oncol., October 20, 2007; 25(30): 4705 - 4706. [Full Text] [PDF]

				O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]

				D. G. Duda, R. K. Jain, and C. G. Willett Antiangiogenics: The Potential Role of Integrating This Novel Treatment Modality With Chemoradiation for Solid Cancers J. Clin. Oncol., September 10, 2007; 25(26): 4033 - 4042. [Abstract] [Full Text] [PDF]

				S. E. Strome, E. A. Sausville, and D. Mann A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects Oncologist, September 1, 2007; 12(9): 1084 - 1095. [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]

				E. A. Perez, G. Lerzo, X. Pivot, E. Thomas, L. Vahdat, L. Bosserman, P. Viens, C. Cai, B. Mullaney, R. Peck, et al. Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine J. Clin. Oncol., August 10, 2007; 25(23): 3407 - 3414. [Abstract] [Full Text] [PDF]

				K. A. Varker, J. E. Biber, C. Kefauver, R. Jensen, A. Lehman, D. Young, H. Wu, G. B. Lesinski, K. Kendra, H. X. Chen, et al. A Randomized Phase 2 Trial of Bevacizumab with or without Daily Low-Dose Interferon Alfa-2b in Metastatic Malignant Melanoma Ann. Surg. Oncol., August 1, 2007; 14(8): 2367 - 2376. [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]

				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]

				S. Verma and M. Clemons First-Line Treatment Options for Patients with HER-2 Negative Metastatic Breast Cancer: The Impact of Modern Adjuvant Chemotherapy Oncologist, July 1, 2007; 12(7): 785 - 797. [Abstract] [Full Text] [PDF]

				G. Agrawal, J. H. Chen, C. H. Baick, A. E. Chen, R. S. Mehta, O. Nalcioglu, and M.-Y. Su Pathological Complete Response in Triple Negative Poorly Differentiated Invasive Ductal Breast Carcinoma Detected During Pregnancy J. Clin. Oncol., June 20, 2007; 25(18): 2618 - 2620. [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]

				R. P.M. Dings, M. Loren, H. Heun, E. McNiel, A. W. Griffioen, K. H. Mayo, and R. J. Griffin Scheduling of Radiation with Angiogenesis Inhibitors Anginex and Avastin Improves Therapeutic Outcome via Vessel Normalization Clin. Cancer Res., June 1, 2007; 13(11): 3395 - 3402. [Abstract] [Full Text] [PDF]

				R. P A Manzano, G. A Peyman, P. Khan, P. E Carvounis, M. Kivilcim, M. Ren, J. C Lake, and P. Chevez-Barrios Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin) Br. J. Ophthalmol., June 1, 2007; 91(6): 804 - 807. [Abstract] [Full Text] [PDF]

				D. Tripathy Capecitabine in Combination with Novel Targeted Agents in the Management of Metastatic Breast Cancer: Underlying Rationale and Results of Clinical Trials Oncologist, April 1, 2007; 12(4): 375 - 389. [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]

				M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]

				S Beslija, J Bonneterre, H Burstein, V Cocquyt, M Gnant, P Goodwin, V Heinemann, J Jassem, W. Kostler, M Krainer, et al. Second consensus on medical treatment of metastatic breast cancer Ann. Onc., February 1, 2007; 18(2): 215 - 225. [Abstract] [Full Text] [PDF]

				H. B. Muss Targeted Therapy for Metastatic Breast Cancer N. Engl. J. Med., December 28, 2006; 355(26): 2783 - 2785. [Full Text] [PDF]

				R B Bhisitkul Vascular endothelial growth factor biology: clinical implications for ocular treatments. Br. J. Ophthalmol., December 1, 2006; 90(12): 1542 - 1547. [Abstract] [Full Text] [PDF]

				T. A. Traina, L. Norton, K. Drucker, and B. Singh Nasal Septum Perforation in a Bevacizumab-Treated Patient with Metastatic Breast Cancer Oncologist, November 1, 2006; 11(10): 1070 - 1071. [Full Text] [PDF]

				J. Ruan, E. Hyjek, P. Kermani, P. J. Christos, A. T. Hooper, M. Coleman, B. Hempstead, J. P. Leonard, A. Chadburn, and S. Rafii Magnitude of Stromal Hemangiogenesis Correlates with Histologic Subtype of Non-Hodgkin's Lymphoma. Clin. Cancer Res., October 1, 2006; 12(19): 5622 - 5631. [Abstract] [Full Text] [PDF]

				M. S. Gordon, D. Matei, C. Aghajanian, U. A. Matulonis, M. Brewer, G. F. Fleming, J. D. Hainsworth, A. A. Garcia, M. D. Pegram, R. J. Schilder, et al. Clinical Activity of Pertuzumab (rhuMAb 2C4), a HER Dimerization Inhibitor, in Advanced Ovarian Cancer: Potential Predictive Relationship With Tumor HER2 Activation Status J. Clin. Oncol., September 10, 2006; 24(26): 4324 - 4332. [Abstract] [Full Text] [PDF]

				S. M Gressett, B. L Stanford, and F. Hardwicke Management of hand-foot syndrome induced by capecitabine Journal of Oncology Pharmacy Practice, September 1, 2006; 12(3): 131 - 141. [Abstract] [PDF]

				R Leonard, J O'Shaughnessy, S Vukelja, V Gorbounova, C. Chan-Navarro, D Maraninchi, N Barak-Wigler, J. McKendrick, W. Harker, A. Bexon, et al. Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage? Ann. Onc., September 1, 2006; 17(9): 1379 - 1385. [Abstract] [Full Text] [PDF]

				D. Cameron, R. Bell, M. Aapro, and C. Zielinski What Are the Current Standards of Care and Recent Developments in the Management of Breast Cancer? Oncologist, September 1, 2006; 11(suppl_1): 1 - 3. [Full Text] [PDF]

				A. Wardley Capecitabine: Expanding Options for the Treatment of Patients with Early or Locally Advanced Breast Cancer Oncologist, September 1, 2006; 11(suppl_1): 20 - 26. [Abstract] [Full Text] [PDF]

				K. Gelmon, A. Chan, and N. Harbeck The Role of Capecitabine in First-Line Treatment for Patients with Metastatic Breast Cancer Oncologist, September 1, 2006; 11(suppl_1): 42 - 51. [Abstract] [Full Text] [PDF]

				W. P. McGuire Is it time for some new approaches for treating advanced ovarian cancer? J Natl Cancer Inst, August 2, 2006; 98(15): 1024 - 1026. [Full Text] [PDF]

				C. A. Hudis and E. P. Winer Cancer and leukemia group B breast committee: decades of progress and plans for the future. Clin. Cancer Res., June 1, 2006; 12(11): 3576s - 3580s. [Abstract] [Full Text] [PDF]

				B. Ramaswamy, A. D. Elias, N. T. Kelbick, A. Dodley, M. Morrow, M. Hauger, J. Allen, C. Rhoades, K. Kendra, H. X. Chen, et al. Phase II Trial of Bevacizumab in Combination with Weekly Docetaxel in Metastatic Breast Cancer Patients. Clin. Cancer Res., May 15, 2006; 12(10): 3124 - 3129. [Abstract] [Full Text] [PDF]

				D. A. Sica Angiogenesis Inhibitors and Hypertension: An Emerging Issue J. Clin. Oncol., March 20, 2006; 24(9): 1329 - 1331. [Full Text] [PDF]

				S. B. Wedam, J. A. Low, S. X. Yang, C. K. Chow, P. Choyke, D. Danforth, S. M. Hewitt, A. Berman, S. M. Steinberg, D. J. Liewehr, et al. Antiangiogenic and Antitumor Effects of Bevacizumab in Patients With Inflammatory and Locally Advanced Breast Cancer J. Clin. Oncol., February 10, 2006; 24(5): 769 - 777. [Abstract] [Full Text] [PDF]

				D. G. McNeel, J. Eickhoff, F. T. Lee, D. M. King, D. Alberti, J. P. Thomas, A. Friedl, J. Kolesar, R. Marnocha, J. Volkman, et al. Phase I Trial of a Monoclonal Antibody Specific for {alpha}v{beta}3 Integrin (MEDI-522) in Patients with Advanced Malignancies, Including an Assessment of Effect on Tumor Perfusion Clin. Cancer Res., November 1, 2005; 11(21): 7851 - 7860. [Abstract] [Full Text] [PDF]

				D. R. D'Adamo, S. E. Anderson, K. Albritton, J. Yamada, E. Riedel, K. Scheu, G. K. Schwartz, H. Chen, and R. G. Maki Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas J. Clin. Oncol., October 1, 2005; 23(28): 7135 - 7142. [Abstract] [Full Text] [PDF]

				A. Goldhirsch, J. H. Glick, R. D. Gelber, A. S. Coates, B. Thurlimann, H.-J. Senn, and and Panel Members Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005 Ann. Onc., October 1, 2005; 16(10): 1569 - 1583. [Abstract] [Full Text] [PDF]

				J. O'Shaughnessy Extending Survival with Chemotherapy in Metastatic Breast Cancer Oncologist, October 1, 2005; 10(suppl_3): 20 - 29. [Abstract] [Full Text] [PDF]

				W. P. Tew, D. P. Kelsen, and D. H. Ilson Targeted Therapies for Esophageal Cancer Oncologist, September 1, 2005; 10(8): 590 - 601. [Abstract] [Full Text] [PDF]

				S. Motl Bevacizumab in combination chemotherapy for colorectal and other cancers Am. J. Health Syst. Pharm., May 15, 2005; 62(10): 1021 - 1032. [Abstract] [Full Text] [PDF]

				R. S. Herbst, A. Onn, and A. Sandler Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256. [Abstract] [Full Text] [PDF]

				J. Feliu, P. Escudero, F. Llosa, M. Bolanos, J.-M. Vicent, A. Yubero, J.-J. Sanz-Lacalle, R. Lopez, L. Lopez-Gomez, E. Casado, et al. Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study J. Clin. Oncol., May 1, 2005; 23(13): 3104 - 3111. [Abstract] [Full Text] [PDF]