Although in our study, grade > 3 hypertension was not reported in patients who developed grade > 3 cardiac events, patients treated with bevacizumab may have a significantly increased risk of developing high-grade hypertension which could potentiate cardiac ischemia[15]. In conclusion, our observation supports the emerging body of literature that the concurrent administration of the combination of the angiogenesis inhibitor bevacizumab with anthracycline is associated with increased risk of LVD, albeit reversible. older than 18 years with baseline cardiac left ventricular ejection fraction (EF) > 50% were eligible. Relevant exclusion criteria included clinically significant cardiovascular disease or peripheral vascular disease, including myocardial infarction, unstable angina (within 6 months prior to registration), NYHA Grade II or greater congestive heart failure, uncontrolled hypertension or a history of stroke within 6 months. Patients were treated with bevacizumab (15 mg/kg) and standard dose CHOP chemotherapy administered every 21 days for 6 8 cycles and those who achieved a complete response, partial response or stable disease received maintenance therapy with bevacizumab (15 mg/kg) every 3 weeks for 4 cycles. Cardiac function was monitored prospectively with EF determination at baseline, and at completion of 6 cycles A-CHOP prior to the start of bevacizumab maintenance. For patients eligible to receive bevacizumab maintenance, EF was Rabbit Polyclonal to GCVK_HHV6Z required to be > 50%. As the study was ongoing at the time of this report, we reviewed toxicity data (coded according to CTCAE Version 3.0.) for patients completing at least 6 cycles of A-CHOP. == Results and discussion == Between July 2006 and March 2009, 44 patients were treated on protocol. Median age was 59 years (range 19 81). Thirty patients received at least 6 cycles of A-CHOP, and within this group, 17 patients also received maintenance bevacizumab. As per study design, EF was assessed for all patients post 6 cycles A-CHOP. One or more designated cardiac events (total 8) were reported in 6 of 30 (20%) patients (90% CI: 9.1 35.7%), as summarized inTable I. One patient developed grade 2 ventricular tachycardia after 8 cycles of A-CHOP during cycle 5 of maintenance bevacizumab. Congestive heart failure (CHF), defined as grade 2 4 left ventricular dysfunction (LVD) was reported in 5 of 30 (17%) patients (90% CI: 5.6 34.7%) who were subsequently taken off study: 4 pts developed symptomatic CHF with grade > 3 LVD after 6 cycles of A-CHOP (including one after cycle 2 of maintenance bevacizumab) and 1 after 8 cycles of A-CHOP. Medical management of CHF was required in all patients, including a ventricular assist device in one patient with concomitant grade 4 arrhythmia. == Table I. == Characteristics of patients with cardiac events. IPI, International Prognostic Index; A-CHOP, Avastin-(cyclophosphamide, doxorubicin, vincristine, prednisone). This rate of CHF is higher than the reported rates of cardiomyopathy from doxorubicin (typically 1% to 2% for a cumulative doxorubicin Cucurbitacin E dose below 300 mg/m2, 7% at 575 mg/m2, and 21% at > Cucurbitacin E 700 mg/m2) and higher than those reported in studies evaluating R-CHOP or CHOP alone in patients with diff use large B cell lymphoma (DLBCL)[5,6]. The LVD improved to baseline within 6 months of discontinuing bevacizumab in 4 of 5 patients. Our cooperative group study has limitations since EF determination was according to individual institutional echocardiography protocols and not centrally reviewed. In addition, the ability to detect a cardiac event may vary among the institutions, which could result in biased adverse event recording. Also, the significance of low-grade events (grade 1 2) is not clear, and baseline cardiovascular risks, such as cholesterol, diabetes, thyroid disease and lung conditions were not prospectively evaluated. Additionally, due to limitations of study design, we cannot discern if there is incremental toxicity for patients who received > 300 mg/m2of doxorubicin. Bevacizumab as a single agent has not been associated with increased cardiac toxicity. Data suggest that MBC patients who have had anthracycline exposure prior to bevacizumab may have an increased incidence of CHF[7]. Limited data exist regarding the incidence of cardiac toxicity when bevacizumab is used in conjunction with anthracyclines and emerging data suggest an increased risk in both solid tumors and lymphomas. A phase II study in metastatic soft tissue sarcoma with doxorubicin followed Cucurbitacin E by bevacizumab reported that 6 of 17 (35%) patients who received total doxorubicin dose exceeding 300 mg/m2developed grade 2 or greater cardiac toxicity, despite the use of dexrazoxane[6]. The E2104 trial evaluated bevacizumab in combination with an anthracycline containing regimen as adjuvant therapy for breast cancer[8]. At a median follow-up of 14.6.
