Relationship Between Safety and Cumulative Bevacizumab Dose in Patients With Metastatic Colorectal Cancer Who Received Long-term Bevacizumab Treatment

Abstract

Background/Aim: Bevacizumab-based chemotherapy is the standard treatment for metastatic colorectal cancer (mCRC) but has several specific adverse events. The cumulative bevacizumab dose (CBD) increases with longterm treatment as it is often used beyond the first disease progression, based on existing evidence. However, the association between CBD and the frequency and severity of adverse events in mCRC patients who received bevacizumab for long-term treatment remains unclear. Patients and Methods: Among the mCRC patients who received bevacizumab-based chemotherapy between March 2007 and December 2017 at the University of Tsukuba Hospital, those who continued treatment for more than 2 years were eligible for the study. The onset and worsening of proteinuria, hypertension, bleeding, and thromboembolic events were assessed to determine their relationship with CBD. Results: Of the 109 patients who received bevacizumab-based chemotherapy, 24 were included in the study. Grade 3 proteinuria was observed in 21 (88%) and 9 (38%) patients. The severity of proteinuria markedly increased after administering >100 mg/kg of CBD and progressed to grade 3 at concentrations exceeding 200 mg/kg. Thromboembolic events were observed in three (13%) patients, and two of them developed acute myocardial infarction after receiving a CBD of >300 mg/kg. Grade 2 or higher hypertension and grade 1 bleeding were observed in 9 (38%) patients and in 6 (25%) patients, respectively, regardless of the CBD. Conclusion: Proteinuria and thromboembolic events occurred and worsened in mCRC patients when the bevacizumab dose exceeded the threshold dose.Colorectal cancer is the third leading cause of cancer-related deaths worldwide and the second leading cause of cancerrelated deaths in Japan (1). For metastatic colorectal cancer (mCRC), bevacizumab, an angiogenesis inhibitor, is used as the standard treatment in fluoropyrimidine combination with oxaliplatin or irinotecan-based doublet chemotherapy, which is generally administered at 2.5 mg/kg/week (2). The median progression-free survival time with first-line chemotherapy, including bevacizumab, is 8-15 months (2-4). In addition, the significance of continuing bevacizumab treatment even after disease progression has been proven in a previous randomized phase III trial; bevacizumab is frequently used as a second-line treatment after failure of bevacizumab-based first-line therapies (5-7). Although the long-term administration of bevacizumab has shown a survival benefit, the increased incidence and severity of bevacizumab-related adverse events (AEs) remain a concern.Bevacizumab-related AEs included proteinuria, hypertension, arterial or venous thrombosis, bleeding, gastrointestinal perforation, and delayed wound healing (2). Several studies have investigated the association between bevacizumab treatment duration and bevacizumab-related AEs. The severity of proteinuria and cardiovascular events increases with longterm use of bevacizumab (8). A similar relationship has been shown between the risk of protein...

Forecasting Survival Rates in Metastatic Colorectal Cancer Patients Undergoing Bevacizumab-Based Chemotherapy: A Machine Learning Approach

“…Our analyses suggest that an increase in 'Antibiotic Days' is positively correlated with cancer progression and mortality in mCRC patients, emphasizing the importance of not only considering the use of antibiotics but also paying attention to their duration. This phenomenon can be correlated to the cumulative bevacizumab dose (CBD) caused by increasing the 'Antibiotic Days' as it was reported in another study [75] considering the terminal half-life of bevacizumab is relatively long (about 20 days) in both men and women [76].…”

The effective combination therapies with irinotecan for colorectal cancer

“…The inclusion of bevacizumab to irinotecan-based backbone chemotherapy regimens is a standard choice for first-line treatment for mCRC patients ( Garcia et al, 2020 ). However, adverse events of proteinuria and thromboembolism occurred in mCRC patients chronically treated with bevacizumab when the dose of the drug exceeded the threshold dose ( Fukuda et al, 2023 ). Adding bevacizumab to first- and second-line therapy increased costs by $60,000 and $40,000, respectively, and prolonged median OS by 6 weeks for both, but bevacizumab was more cost-effective in second-line therapy due to the shorter duration of therapy ( Goldstein et al, 2015 , 2017 ).…”