Radiotherapy combined with bevacizumab in gastrointestinal cancers: Balancing efficacy against the risk of intestinal perforation

Abstract

The combination of radiotherapy with bevacizumab represents a promising therapeutic strategy for advanced gastrointestinal cancers. While this combination leverages synergistic mechanisms to enhance antitumor efficacy, it also poses significant safety concerns, particularly regarding the risk of intestinal perforation. This letter discusses the current understanding of this dual effect and underscores the importance of careful patient selection, advanced radiotherapy techniques, and vigilant toxicity monitoring to optimize clinical outcomes.

Key Words: Radiotherapy; Bevacizumab; Gastrointestinal cancers; Intestinal perforation; Combination therapy; Toxicity management

Core Tip: The combination of radiotherapy and bevacizumab in gastrointestinal cancers offers enhanced efficacy but requires careful management due to an increased risk of intestinal perforation. Strategic patient selection and advanced radiotherapy techniques are essential to balance benefits and risks.

TO THE EDITOR

We read with interest the study by He and Li[1] investigating the risk of intestinal perforation with the combination of radiotherapy and bevacizumab in gastrointestinal cancers. The authors address a highly relevant and complex clinical question regarding the safety profile of combining targeted therapy (bevacizumab) with radiotherapy in this setting. Their work provides valuable real-world evidence in an area where clear clinical guidelines are still evolving.

The biological rationale for this approach is well-founded. Radiotherapy induces localized tumor cell death through multiple mechanisms, including DNA damage and modulation of cell fate decisions[2], while bevacizumab inhibits angiogenesis by targeting vascular endothelial growth factor[3]. The combination of radiotherapy and bevacizumab can offer potential clinical advantages in selected settings, such as glioblastoma[4]. Although this synergistic approach may amplify antitumor responses, it simultaneously raises valid safety concerns, particularly regarding overlapping gastrointestinal toxicities. Existing literature provides some insight into this risk; a meta-analysis of bevacizumab trials reported a gastrointestinal perforation rate of approximately 0.9%[5], while abdominal radiotherapy has been associated with severe complications, including perforation, in 4%-8% of patients[6]. However, data specifically addressing the risk of their combination remain limited and are particularly scarce in gastrointestinal cancers.

The study is undoubtedly insightful, as it addresses the critical issue of combining radiotherapy with bevacizumab in patients with gastrointestinal cancers. However, we would like to highlight an important inconsistency in the manuscript that warrants clarification. While the Abstract section focuses specifically on colon cancer, the Methods section describes a cohort that includes patients with both colorectal and gastric cancers. The considerable biological and anatomical differences between these malignancies—including variations in their natural history, treatment approaches, and inherent perforation risks—may significantly influence the interpretation of the results. Analyzing them together without appropriate stratification could introduce confounding factors.

In light of these considerations, we wish to highlight several key aspects of clinical management that may help navigate the challenges associated with this combination.

First, refined patient selection is crucial. Not all patients are suitable candidates for combined-modality therapy. Those with pre-existing intestinal pathologies, extensive surgical histories, or poor performance status may be at a disproportionately higher risk of complications. A thorough baseline assessment, including detailed imaging and careful evaluation of bowel health, is indispensable. Furthermore, conducting comprehensive pre-treatment assessments and incorporating molecular and genetic profiling can aid in identifying suitable candidates and personalizing treatment plans.

Second, the adoption of advanced radiotherapy techniques, such as intensity-modulated radiotherapy, allows for maximal tumor targeting while minimizing exposure to adjacent healthy bowel. Minimizing the volume of irradiated intestine is one of the most effective strategies for reducing treatment-related gastrointestinal toxicity. Additionally, utilizing precision radiotherapy techniques like stereotactic body radiotherapy and applying adaptive radiotherapy approaches that adjust treatment based on patient response can further enhance targeting accuracy and therapeutic outcomes.

Third, the temporal sequencing of therapies should be carefully considered. As the sequence of bevacizumab and radiotherapy administration has been shown to influence the incidence of adverse events in some trials[7], modifying the treatment schedule to limit concurrent exposure or to include phased treatment interruptions presents a viable strategy to reduce intestinal toxicity while maintaining therapeutic efficacy.

Finally, for future clinical studies, if feasible, a subgroup analysis comparing the risk of intestinal perforation between patients with colorectal cancer and those with gastric cancer would be highly valuable. Such an analysis could help determine whether the primary risk remains consistent across different tumor origins.