Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis

Cortés, Javier; Calvo, V.; Ramírez-Merino, Natalia; O’Shaughnessy, Joyce; Brufsky, Adam; Robert, Nicholas J.; Vidal, María; Muñoz, Eva; Pérez, Jose; Dawood, Shaheenah; Saura, Cristina; Cosimo, Serena Di; González-Martín, Antonio; Bellet, Meritxell; Silva, O.E.; Miles, David; Llombart, Antonio; Baselga, José

doi:10.1093/annonc/mdr432

Cited by 65 publications

(33 citation statements)

References 25 publications

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“…An increased incidence of cardiac events with decreases in left ventricular ejection fractions have been noted in other bevacizumab trials and particularly in trials in which anthracyclines have been combined with bevacizumab. [29][30][31][32] There are data from our trial as well as the literature that the decrease in LVEF may be reversible though the percentage who completely recover function, and the risk factors for left ventricular dysfunction are currently unknown. In our trial, the median age in patients with grade 2 or higher LVEF dysfunction was 68 years, the same as in our entire study group.…”

Section: Discussionmentioning

confidence: 91%

A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

Stopeck

Unger

Rimsza

et al. 2012

Blood

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S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progressionfree survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1-and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinical trials.gov as #NCT00121199. (Blood. 2012; 120(6):1210-1217)

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Section: Discussionmentioning

confidence: 91%

A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

Stopeck

Unger

Rimsza

et al. 2012

Blood

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“…While not active in melanoma (23), pan- creatic cancer (24,25), and prostate cancer (26), they have shown some effectiveness when combined with cytotoxic therapy in nonsmall cell lung cancer (27)(28)(29) and colorectal cancer (30), while the benefit in breast cancer remains controversial (31)(32)(33)(34). Among the main problems with these drugs are toxicity and rapid acquired resistance (35,36). In the present study, we showed that disruption of the interaction of RAS with PI3K p110α in host tissue impaired tumor-induced angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Murillo¹,

Zelenay²,

Nye³

et al. 2014

J. Clin. Invest.

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“…The activity of bevacizumab described here must be balanced with its adverse event profile. A meta-analysis of five randomized trials [5] showed the following to be more common when bevacizumab was added to chemotherapy in the treatment of breast cancer (all differences were statistically significant): proteinuria (odds ratio [OR], 27.68), hypertension (OR, 12.76), left ventricular dysfunction (OR, 2.25), and hemorrhagic events (OR, 4.07). Although these adverse events have the potential to cause complications, most patients do not seem to have a negative impact on their quality of life (QOL) with the addition of bevacizumab, and in the same meta-analysis there were no statistically significant differences for gastrointestinal perforation, vascular events, fatal events, or febrile neutropenia.…”

mentioning

confidence: 99%

Weighed, Measured, and Still Searching: Bevacizumab in the Treatment of Unselected Patients with Advanced Breast Cancer

Lopes

Dent

2011

The Oncologist

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In this issue of The Oncologist, Alvarez et al.[1] present a timely and comprehensive review of the data concerning bevacizumab in the treatment of patients with advanced breast cancer. The authors discuss the role of angiogenesis, including related therapeutic approaches as well as early clinical trials of bevacizumab, and appropriately focus on the randomized evidence. In summary, the three large first-line trials comparing chemotherapy alone with chemotherapy plus bevacizumabEastern Cooperative Oncology Group (ECOG) 2100, AVADO (Avastin and Docetaxel), and RIBBON-1 (Regimens in Bevacizumab for Breast Oncology)-met their primary endpoints and showed a statistically significant longer progression-free survival (PFS) duration. Pooled results demonstrated PFS intervals of 9.2 months and 6.7 months for patients treated with and without bevacizumab, respectively (hazard ratio, 0.64; 95% confidence interval [CI], 0.48 -0.69). The results were not homogenous, however, with median differences of 5.5 months in ECOG 2100 and 1.2-2.9 months in the other studies.The median, 1-year, and overall survival outcomes did not differ between the control and treatment arms in any of the individual trials or in the combined individual patient data metaanalysis [2]. Furthermore, there were no differences in any of the subgroups analyzed. The authors and the oncology community have raised potential hypotheses to explain this phenomenon, including the use of multiple further treatments upon progression, patients on placebo crossing over to receive bevacizumab, different interactions and potentials for synergism with each chemotherapy backbone, heterogeneous biology and sample populations, and the modest benefits of bevacizumab, among others [1,3,4]. The activity of bevacizumab described here must be balanced with its adverse event profile. A meta-analysis of five randomized trials [5] showed the following to be more common when bevacizumab was added to chemotherapy in the treatment of breast cancer (all differences were statistically significant): proteinuria (odds ratio [OR], 27.68), hypertension (OR, 12.76), left ventricular dysfunction (OR, 2.25), and hemorrhagic events (OR, 4.07). Although these adverse events have the potential to cause complications, most patients do not seem to have a negative impact on their quality of life (QOL) with the addition of bevacizumab, and in the same meta-analysis there were no statistically significant differences for gastrointestinal perforation, vascular events, fatal events, or febrile neutropenia. A larger meta-analysis of 16 randomized trials [6] with 10,217 patients, which included patients with other cancers, however, showed the addition of bevacizumab to be associated with a higher risk for fatal events (relative risk [RR], 1.33; 95% CI, 1.02-1.73; p ϭ .04; incidence, 2.9% versus 2.2% for bevacizumab versus chemotherapy alone). There was a higher risk for fatal events for individuals receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% versus 1.0%) but not for...

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Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis

Abstract: Bevacizumab did increase the risk of LVD and hemorrhagic events. The addition of bevacizumab to chemotherapy in patients with metastatic breast cancer was not associated with a significant increase in grade ≥ 3 arterial or venous thromboembolic events, GI perforation, or fatal events.

Cited by 65 publications

References 25 publications

A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Weighed, Measured, and Still Searching: Bevacizumab in the Treatment of Unselected Patients with Advanced Breast Cancer

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