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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7135-7142 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.16.139 Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue SarcomasFrom the Gastrointestinal Oncology Service and Developmental Chemotherapy Service, Department of Medicine and Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT; and Investigational Drug Branch, Clinical Trials Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD Address reprint requests to David D'Adamo, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: dadamod{at}mskcc.org
PURPOSE: To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. RESULTS: A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. CONCLUSION: The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.
Soft-tissue sarcomas (STSs) are malignant tumors of mesenchymal origin. Approximately 9,400 cases are diagnosed annually in the United States, accounting for fewer than 1% of all malignancies.1 Surgery, with or without adjuvant radiation therapy, is the mainstay of treatment for patients with early-stage disease. Despite surgical excision, between 40% and 60% of patients develop locally recurrent or metastatic disease. Although pulmonary metastasectomy can be curative for 15% to 30% for selected patients with lung-only disease,2 the majority of patients with metastatic sarcomas succumb in this setting, with a median survival time of 12 to 18 months. Complete responses to chemotherapy for recurrent or metastatic STSs are rare. Most tumors rapidly develop drug resistance and patients develop progressive disease within months. For most patients, palliation is the main objective of treatment. Doxorubicin is the mainstay of treatment for metastatic sarcomas, with response rates of between 10% and 30%.3-5 The addition of ifosfamide and/or dacarbazine increases response rate without prolonging survival, at the cost of increased toxicity.6 Accordingly, patients with advanced and metastatic disease are appropriate candidates for investigational therapies. The recombinant human monoclonal antibody bevacizumab is a novel antineoplastic agent that binds human vascular endothelial growth factor (VEGF). Bevacizumab has demonstrated safety in phase I studies administered as a single agent.7 As a single agent it is most promising in renal cell carcinoma, with a response rate of 10%, but with significant benefit in time to progression versus placebo in a randomized trial.8 In other diseases, bevacizumab shows activity in combination with standard chemotherapy. In advanced non–small-cell lung cancer, a randomized phase II trial showed a trend towards increased response rate and time to progression when bevacizumab was combined with paclitaxel and carboplatin.9 A large randomized trial was conducted in patients with metastatic breast cancer, who had received prior therapy both with an anthracycline and a taxane.10 Patients were treated with capecitabine and either bevacizumab or placebo. Although no survival benefit was demonstrated, the combination did have a significantly higher response rate. The disease in which bevacizumab has had the greatest impact is metastatic colorectal cancer. After a randomized phase II study showed encouraging results when low-dose bevacizumab was combined with fluorouracil and leucovorin,11 Hurvitz et al conducted a large randomized phase III trial of irinotecan, bolus fluorouracil, and leucovorin with bevacizumab or placebo.12 The addition of bevacizumab demonstrated increased response rate, time to progression, and a 4.7 month increase in overall survival, leading to its approval by the US Food and Drug Administration for the treatment of metastatic colon cancer. The rationale for this trial was to improve the efficacy of single-agent doxorubicin when combined with bevacizumab. STSs are highly vascular tumors. Several studies have shown correlation between prognosis and surrogates for angiogenesis, including microvessel density and circulating VEGF and basic Fibroblast Growth Factor (bFGF).13,14 Neo-angiogenesis is also required for development of metastatic disease.15 The aim of this study was to test the safety and efficacy of bevacizumab in combination with doxorubicin for the treatment of metastatic STS.
Patient Eligibility Eligible patients had histologically confirmed metastatic STS, with measurable disease. Patients were anthracycline naive and had zero to one prior treatment regimens for metastatic disease. Other inclusion criteria included an age of at least 18 years, recovery from prior chemotherapy or radiation, Karnofsky performance status of at least 80%, and a cardiac ejection fraction (EF) of at least 50%. Adequate hematologic, hepatic, and renal function (including proteinuria of no more than 500 mg per day) were also required. Patients with brain metastases, deep venous thrombosis, pulmonary embolism or other condition requiring anticoagulation, clinically significant cardiovascular disease, active infection or nonhealing wound, recent surgery within 21 days or needle biopsy within 7 days, another malignancy (except for basal cell carcinoma of the skin or cervical carcinoma-in-situ) diagnosed within 5 years, and pregnant women were all excluded. Written informed consent was required. 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 requirements.
Therapy
Patients with National Cancer Institute Common Toxicity Criteria version 2.0 grade 4 toxicity for neutrophils or leukocytes lasting 7 days or longer, or who experienced a neutropenic fever, were re-treated after a dose reduction (60 mg/m2 level-1 dose, 50 mg/m2 level-2 dose) and resolution of toxicity to
Study Parameters
Statistical Considerations Secondary objectives were to determine time to treatment failure, time to progression, overall survival, and to further characterize the toxicity profile of bevacizumab given with doxorubicin in this group of patients. Time to treatment failure was defined as time from treatment start date to off-study date; progression or death while on-study or a major toxic event were considered treatment failures. Time to progression was defined as time from treatment start date to date of progression or last follow-up. Overall survival was defined as time from treatment start date to death or last follow-up. Time to treatment failure, time to progression, and overall survival were determined using Kaplan-Meier estimators.18
Patient Characteristics and Disposition The study was conducted in two centers in North America. Patient characteristics are presented in Table 1. Notably, 13 patients (76%) were female and 11 patients (65%) had leiomyosarcoma, seven of uterine origin; leiomyosarcoma typically constitute only 20% to 30% of all STSs. All patients enrolled received at least one course of combination therapy and were assessable for toxicity. One patient completed only one cycle of therapy before stopping for toxicity, but is included in an intention to treat analysis regarding response.
Efficacy of Therapy Two of 17 patients, both with uterine leiomyosarcoma, had PR as assessed by RECIST (31% decrease and 45% decrease in unidimensional disease for 12 cycles and 15 cycles, respectively). There were no complete responses. The overall response rate was 12% (95% CI, 1% to 36%). An additional 11 patients (65%) had stable disease for 12 weeks or greater. Median time to treatment failure (progression of disease or excess toxicity) was 4 months (Fig 1). Median time to progression was 8 months (Fig 1). Two patients have not progressed, both with 10 months of follow-up. Median overall survival is 16 months (Fig 1B) with 13 patients still alive as of September 2004, with follow-up ranging from 3 months to 21 months.
Safety and Toxicity The toxicity of bevacizumab and doxorubicin was similar to that reported for single-agent doxorubicin (Table 2). There was modest nausea and vomiting, well controlled with standard antiemetics. There were no cases of grade 3 to 4 nausea or vomiting. Alopecia was universal. Hematologic toxicity was typical for this dose of doxorubicin. There were two cases of febrile neutropenia, and no septic deaths. No filgrastim or pegfilgrastim was used in the initial therapy of these patients, but was added routinely in subsequent cycles after episodes of febrile neutropenia. The toxicity of doxorubicin at 75 mg/m2 is significant and all eight patients staying on study more than four cycles required protocol-mandated doxorubicin dose reductions.
Toxicities typically ascribed to bevacizumab were not frequently observed. There were no cases of proteinuria greater than grade 1. There was no hypertension greater than grade 1. Bleeding was minor, with several patients reporting self-limited epistaxis. There was one case of grade 2 vaginal bleeding in a patient with uterine leiomyosarcoma that was attributed to progression of disease. No patients required transfusions. There were no bowel perforations. There were no arterial embolic complications such as cerebrovascular accident or myocardial infarction. There was one upper extremity deep venous thrombosis in a previously radiated field. Three patients received eight cycles of bevacizumab maintenance therapy after a cumulative dose of doxorubicin of 600 mg/m2. Two patients received one cycle each of bevacizumab only during combination therapy, while doxorubicin was held for anthracycline-related toxicity. The toxicity of these 10 cycles of bevacizumab monotherapy (Table 3) was quite modest. One patient experienced transient elevation of liver enzymes on therapy, in the setting of stable liver metastases.
One patient died of recurrent bilateral pneumothoraces, possibly treatment related. She had innumerable pulmonary nodules, many of which were pleural based. After two cycles of bevacizumab and doxorubicin she developed bilateral pneumothoraces that required chest tube placement. CT scan showed stable disease in the chest. After this first episode resolved, she was re-treated with bevacizumab and doxorubicin, complicated again by lung collapse. She was admitted to an outside facility, where she declined chest tube placement and subsequently expired.
Cardiac Toxicity
The mainstay of treatment for metastatic STS is the anthracycline doxorubicin. The addition of other agents such as ifosfamide, dacarbazine or cyclophosphamide, vincristine, and dactinomycin has shown an increase in response rate, without an advantage in overall survival.5,6,19 There have been no new agents approved for the treatment of metastatic nongastrointestinal stromal tumor sarcomas since the use of ifosfamide became widely accepted in the late 1980s. Because the growth of sarcomas is in part dependent on neoangiogenesis, sarcomas provide an attractive model for testing combination cytotoxic and antiangiogenic therapy. Preclinical models of sarcomas have shown little activity for antiangiogenic therapy per se but at least additive if not synergistic effects when combined with conventional chemotherapy. This study was designed to test if the addition of the anti-VEGF antibody bevacizumab could increase the response rate of STS to doxorubicin and to define the toxicities of this combination regimen. The combination of bevacizumab and doxorubicin failed to increase the response rate of STS from 20% to 40%. That our trial design was overly optimistic is underscored by randomized studies in colon cancer and breast cancer showing only a 10% increase in response rate when bevacizumab was added to either capecitabine or an irinotecan, fluorouracil, and folinic acid combination. The observed response rate, 12%, was relatively low for single-agent doxorubicin. However, other studies, using outside review of radiographs, show that the response rate to doxorubicin may be as low as 10%.20 Additional studies have identified a dose response to doxorubicin, but it cannot be claimed that the doxorubicin dose in this study, 75 mg/m2 every 3 weeks, was inadequate. The variability of patient histology is a well recognized factor that can affect the response rate to any given chemotherapy agent for STSs,19 emphasizing the need for subtype-specific studies of chemotherapy agents in this heterogeneous group of diseases. Another question for future studies is the observation of prolongation of response and prolonged stable disease in patients enrolled in this study. In the pivotal trial in metastatic colon cancer, the increase in time to progression with bevacizumab was 4 months, more than that observed in any other phase III trial in colon cancer; whereas, the increase in response rate was modest, from 35% to 45%.12 The time to progression and overall survival in this study of patients with metastatic STS were encouraging, but the number of patients on trial was too small to draw any firm conclusions. Patient responses in this trial were evaluated using RECIST. RECIST works well with spherical tumors. However, STSs are often irregular, with variable areas of necrosis, and can be larger cranio-caudally than they are transversely or in an anterior-posterior axis. Sarcomas could progress or respond more in the short axis rather than in the long axis. Furthermore, for large tumors such as sarcomas, growth is potentially limited anatomically by the body cavity or muscle group in which it resides. These are all factors that make difficult the accurate measurement of sarcomas using standard axial CT imaging for at least some patients, exemplified in this study by one patient with stable disease by RECIST but a confirmed PR by WHO criteria. In a study of gastrointestinal stromal tumor, Choi et al21 found response by fluorodeoxyglucose-positron emission tomography and decrease in tumor vascularity provided valuable additional information for determining overall tumor response, in conjunction with RECIST. Another patient with a large synovial sarcoma of the leg with lung and abdominal metastases received 5 cycles of combination therapy and had stable disease by RECIST. Like the patient with bilateral pneumothoraces and tumor cavitation, there was almost complete central necrosis of the tumor mass, with only a small rim of viable tumor on the outside of the mass, recapitulating animal models of antiangiogenic therapy22 (Fig 3). The patient was taken off study for toxicity and 2 months later, after treatment with gemcitabine, the tumor had collapsed in on itself and met criteria for PR. This observation raises the issue of the sequence and dose of chemotherapy and antiangiogenic therapy. As pointed out by Jain, perhaps the goal of antiangiogenic therapy should be normalization of vasculature ("euangiogenesis") as opposed to overtly inhibiting23 all new blood vessel formation.
Regarding toxicity and adverse events unique to this study, although pneumothorax resulting from treatment is an exceedingly rare phenomenon, there is at lease one case report of a patient with leiomyosarcoma with lung metastases who developed recurrent pneumothoraces while receiving CyVADIC chemotherapy, a doxorubicin-based combination regimen.24 Of greater importance is the observation that the combination of doxorubicin and bevacizumab resulted in an unacceptably high exacerbation of the cardiomyopathy associated with the anthracycline doxorubicin. The reported rates of cardiomyopathy from doxorubicin are 1% to 2% for a cumulative doxorubicin dose below 300 mg/m2, rising to 7% at a doxorubicin dose of 575 mg/m2, and 21% at a cumulative dose greater than 700 mg/m2. The observed 35% rate of grade 2 or greater cardiotoxicity with the combination of bevacizumab and doxorubicin is greater than would have been expected in this patient population. Of the patients who experienced this adverse event, none had received prior chest radiotherapy or high-doses of alkylating agents (two risk factors for increasing the risk of anthracycline associated cardiomyopathy). It is interesting to speculate on the mechanism of this toxicity. It is known that VEGF is crucial for angiogenesis and revascularization of cardiac tissue following myocardial infarction.25,26 Some of the earliest gene therapy trials involved delivery of VEGF to damaged myocardium to relieve angina.27 VEGF is essential to embryonic development, because VEGF is one of the only genes that is embryonic lethal even with only one copy deleted.28 Cardiac malformations are prominent in the developmental abnormalities of VEGF knockout mice. What is unusual about the cardiac toxicity observed in our study is that it was seen at low cumulative doses as well as at higher doses. This suggests that doxorubicin can cause cardiac toxicity even at low doses, but that this damage can be repaired in a VEGF-dependent fashion, not becoming clinically apparent until later. The fact that the cardiomyopathies observed here were largely reversible is consistent with this model. Presumably, after discontinuation of bevacizumab, VEGF levels would return to normal allowing repair of damaged myocardium. An alternative explanation is that the cardiac assessment was done too close to the time of chemotherapy, which resulted in stunned myocardium without overt permanent damage to the myocardium. This is not the first report of cardiomyopathy associated with antiangiogenic therapy. Sunitinib (SU1248), a vascular endothelial growth factor receptor inhibitor, is reported to have a low incidence (< 10%) of cardiomyopathy with extended use, which was also largely reversible.29 There were no reports of grade 3 or grade 4 cardiotoxicity associated with its use. Karp et al investigated the use of bevacizumab with mitoxantrone and cytarabine in patients with relapsed or poor risk leukemia.30 There were two cases of fatal cardiomyopathy in their study. In patients who received two cycles of therapy, the incidence of significant decline in EF was 7%. Interestingly, this toxicity was most frequently observed in patients with secondary myelodysplastic syndrome, who had previously received substantial cumulative dose of anthracyclines. The recently reported trial of Miller et al of capecitabine with or without bevacizumab did note an increase in grade 3 and grade 4 cardiac toxicity on the bevacizumab-containing arm (7 v 2 patients).10 All patients on that trial had received prior anthracycline treatment. Because routine evaluation of LVEF was not required by that trial, it cannot be determined whether there was also an increase in grade 2 toxicity, which we are reporting in this study. Ongoing studies of bevacizumab and doxorubicin in locally advanced breast cancer have not noted substantial decline in EF. This trial achieved high peak concentrations of both doxorubicin (75 mg/m2 q 3 weeks) and bevacizumab (15 mg/kg every 3 weeks), so there may be a dose-response associated with this toxicity. The combination of doxorubicin and bevacizumab is toxic at this dose and schedule, and a worrisome combination to consider without modification of the treatment scheme. Although the response rate is not higher than that expected for single-agent doxorubicin, time to progression and overall survival data are encouraging and suggest further investigation of alternative antiangiogenic strategies for the treatment of STSs. Preclinical and animal studies have suggested that antiangiogenic therapy should not have the typical acute toxicities of cytotoxic chemotherapy. Nonetheless, as these agents enter clinical practice we are now observing new toxicities, specifically hypertension, deep venous thrombosis, pulmonary embolism, cerebrovascular accidents, myocardial infarction, hemorrhage, bowel perforation, and now, apparent acceleration of cardiomyopathy. Although the clinical use of antiangiogenic agents is promising, as observed with the results of bevacizumab in colon cancer, it cannot be recommended that they should be incorporated routinely into other regimens without appropriate safety and efficacy studies.
The authors indicated no potential conflicts of interest.
We thank Judith Karp, MD, for useful discussions. We are grateful to patients and their families for their participation in this trial.
Supported in part by Grants No. PPG P01 CA47179 and N01-CM17105, as well as the Dibner Fund for Sarcoma Research and Abolish Cancer Today. D.R.D. and S.E.A. contributed equally to this study. This study was presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005 2. Chao C, Goldberg M: Surgical treatment of metastatic pulmonary soft-tissue sarcoma. Oncology (Huntingt) 14:835-841; discussion 842-844, 847, 2000
3. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-1275, 1993 4. Cruz AB Jr, Thames EA Jr, Aust JB, et al: Combination chemotherapy for soft-tissue sarcomas: A phase III study. J Surg Oncol 11:313-323, 1979[Medline] 5. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995
6. Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993
7. 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
8. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003
9. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004
10. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005
11. 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
12. 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
13. Yoon SS, Segal NH, Olshen AB, et al: Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma. Ann Oncol 15:1261-1266, 2004 14. Potti A, Ganti AK, Tendulkar K, et al: Determination of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas and the role of overexpression in leiomyosarcoma. J Cancer Res Clin Oncol 130:52-56, 2004[CrossRef][Medline] 15. Folkman J: Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333:1757-1763, 1995
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21. Choi H, Charnsangavej C, de Castro Faria S, et al: CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: A quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol 183:1619-1628, 2004
22. de Candia P, Solit DB, Giri D, et al: Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors. Proc Natl Acad Sci USA 100:12337-12342, 2003
23. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005 24. Fenlon HM, Carney D, Breatnach E: Case report: Bilateral recurrent tension pneumothorax complicating combination chemotherapy for soft tissue sarcoma. Clin Radiol 51:302-304, 1996[CrossRef][Medline]
25. Xu X, Li J, Simons M, et al: Expression of vascular endothelial growth factor and its receptors is increased, but microvascular relaxation is impaired in patients after acute myocardial ischemia. J Thorac Cardiovasc Surg 121:735-742, 2001 26. Soeki T, Tamura Y, Shinohara H, et al: Serial changes in serum VEGF and HGF in patients with acute myocardial infarction. Cardiology 93:168-174, 2000[CrossRef][Medline]
27. Losordo DW, Vale PR, Symes JF, et al: Gene therapy for myocardial angiogenesis: Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 98:2800-2804, 1998 28. Ferrara N, Carver-Moore K, Chen H, et al: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439-442, 1996[CrossRef][Medline] 29. Demetri GD, Desai J, Fletcher JA, et al: SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol, 2004 ASCO Annual Meeting Proceedings 22 (abstr 3001):195, 2004
30. Karp JE, Gojo I, Pili R, et al: Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: Therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 10:3577-3585, 2004 Submitted February 17, 2005; accepted June 14, 2005. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
National Cancer Institute Common Toxicity Criteria version 2.0 grade 1. Patients whose doxorubicin was held because of doxorubicin-related toxicity received bevacizumab at 5 mg/kg/wk until re-treatment with both agents. The cumulative doxorubicin dose was capped at 600 mg/m2 (with dexrazoxane). Patients with continued clinical response or stable disease were eligible to receive single-agent bevacizumab until disease progression. All patients received standard supportive care including antiemetics, blood transfusions, erythropoietin, and antibiotics as medically indicated. 
