He WM, Li WS. Investigating radiotherapy’s impact on intestinal perforation risk in gastrointestinal tumor patients treated with bevacizumab. World J Gastrointest Oncol 2025; 17(12): 110621 [DOI: 10.4251/wjgo.v17.i12.110621]
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 15, 2025 (publication date) through Dec 17, 2025
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World Journal of Gastrointestinal Oncology
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1948-5204
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He WM, Li WS. Investigating radiotherapy’s impact on intestinal perforation risk in gastrointestinal tumor patients treated with bevacizumab. World J Gastrointest Oncol 2025; 17(12): 110621 [DOI: 10.4251/wjgo.v17.i12.110621]
Wei-Mei He, Department of Pharmaceutical, Affiliated Hospital of Youjiang University of Ethnic Medicine, Baise 533000, Guangxi Zhuang Autonomous Region, China
Wen-Si Li, Department of Infirmary, Guilin Tourism University, Guilin 541006, Guangxi Zhuang Autonomous Region, China
Author contributions: He WM designed the research study; Li WS performed the research; and all authors thoroughly reviewed and endorsed the final manuscript.
Institutional review board statement: The research was reviewed and approved by Affiliated Hospital of Youjiang University of Ethnic Medicine, approval No. YYFY-LL-2023-60.
Informed consent statement: All research participants or their legal guardians provided written informed consent prior to study registration.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No other data available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Received: July 1, 2025 Revised: August 7, 2025 Accepted: October 15, 2025 Published online: December 15, 2025 Processing time: 163 Days and 0.2 Hours
Abstract
BACKGROUND
Gastrointestinal tumors are among the most common and deadly cancers globally, with radiotherapy and bevacizumab being key treatment strategies. Radiotherapy uses high-energy radiation to target DNA, reducing tumor size and alleviating symptoms. Bevacizumab, a targeted therapy, inhibits angiogenesis and tumor growth, particularly in advanced gastrointestinal cancers. However, both treatments can cause adverse gastrointestinal effects, such as intestinal mucosal damage and perforation. While research on the risk of intestinal perforation has grown, the underlying mechanisms remain underexplored. This study aims to compare the incidence of intestinal perforation and survival rates in patients treated with radiotherapy combined with bevacizumab vs bevacizumab alone.
AIM
To investigate the effect of radiotherapy on the risk of intestinal perforation in patients with colon cancer treated with bevacizumab.
METHODS
A total of 70 patients diagnosed with gastrointestinal malignancies admitted to our hospital from January 2023 to December 2024 were selected as research subjects. According to different treatment methods, 70 patients were divided into the bevacizumab only group (receiving bevacizumab treatment) and the bevacizumab + radiotherapy group (receiving radiotherapy combined with bevacizumab treatment), with 35 cases in each group. The two groups were compared in terms of clinical efficacy, incidence of intestinal perforation, serum tumor marker levels, overall survival and progression-free survival, levels of angiogenic factors, and adverse reactions.
RESULTS
Compared with the group treated with bevacizumab alone, the group treated with bevacizumab plus radiotherapy showed significant improvements in effective rate, overall survival, and progression-free survival (P < 0.05); the probability of intestinal perforation in the bevacizumab + radiotherapy group was 13.33%, while the probability of intestinal perforation in the bevacizumab group was 0. There was a statistically significant difference in the incidence of intestinal perforation between the two groups (P = 0.039). Following treatment, the levels of carbohydrate antigen (CA) 125, CA199, and CA153 in patients were significantly reduced (P < 0.05).
CONCLUSION
Radiation therapy may increase the risk of intestinal perforation in colon cancer patients receiving bevacizumab treatment. In clinical applications, the risks of combined use of radiotherapy and bevacizumab should be fully considered and personalized treatment plans should be formulated.
Core Tip: This study investigates the risk of intestinal perforation in gastrointestinal tumor patients treated with radiotherapy combined with bevacizumab vs bevacizumab alone. While radiotherapy and bevacizumab are essential for managing advanced gastrointestinal cancers, both treatments can cause gastrointestinal complications, including perforation. The study compares the incidence of intestinal perforation and survival outcomes, aiming to inform clinical decision-making and enhance patient safety.
Citation: He WM, Li WS. Investigating radiotherapy’s impact on intestinal perforation risk in gastrointestinal tumor patients treated with bevacizumab. World J Gastrointest Oncol 2025; 17(12): 110621
Gastrointestinal tumors are among the most prevalent and deadly malignancies globally, posing a serious health threat. With advancements in medical technology, treatments such as radiotherapy and biological therapy have become integral to their management. Radiotherapy uses high-energy radiation to destroy or inhibit tumor cell growth by targeting DNA, thereby reducing tumor volume and alleviating symptoms[1,2]. Bevacizumab, a targeted therapy, binds to the epidermal growth factor receptor, inhibits angiogenesis, and prevents tumor growth, showing effectiveness in advanced metastatic gastrointestinal cancers[3-5]. However, both treatments can lead to adverse effects, particularly in the gastrointestinal system, which is directly affected by radiotherapy. This can result in issues such as damaged intestinal mucosal barriers, gastrointestinal dysfunction, and perforation[6-8]. Although research on the risk of intestinal perforation due to these treatments has increased, studies on the mechanisms influencing this risk are still limited. This study aims to compare the incidence of intestinal perforation and survival rates in patients with gastrointestinal tumors treated with radiotherapy combined with bevacizumab vs those treated with bevacizumab alone, providing a scientific basis for clinical decision-making.
MATERIALS AND METHODS
General information
Seventy patients diagnosed with gastrointestinal malignancies admitted to our hospital from January 2023 to December 2024 were selected as the research subjects. According to different treatment methods, these 70 patients were divided into the bevacizumab only group (receiving bevacizumab treatment) and the bevacizumab + radiotherapy group (receiving radiotherapy combined with bevacizumab treatment), with 35 cases in each group. In the bevacizumab + radiotherapy group, there were 12 females and 23 males, ranging in age from 34 years to 73 years old, with an average age of (55.77 ± 9.70) years. Among them, there were 21 cases of stage III and 14 cases of stage IV malignant tumors; 13 cases of colorectal cancer, 16 cases of gastric cancer, and 6 cases of colorectal cancer. In the bevacizumab only group, there were 11 females and 24 males, ranging in age from 30 years to 75 years old, with an average age of (56.66 ± 11.73) years. Among them, 19 cases had stage III cancer and 16 cases had stage IV cancer; 12 cases had rectal cancer, 17 cases had gastric cancer, and 6 cases had colon cancer. There was no significant difference in gender, age, disease type and disease staging between the two groups of patients (P > 0.05), and they were comparable.
Inclusion criteria: (1) Confirmed as gastrointestinal malignant tumors by ultrasound, computed tomography, tumor markers, and biopsy pathological examination; (2) Unable to accept surgical treatment; and (3) No contraindications to radiotherapy (excluding those who can undergo surgical resection but do not accept surgery).
Exclusion criteria: (1) Combined with liver and kidney dysfunction, autoimmune diseases, cardiopulmonary dysfunction and other diseases; (2) Combined with systemic malignant tumors and lymph node metastasis; (3) Contraindications to the use of related drugs; and (4) Alcohol dependence, drug addiction or abuse history, mental disorders, etc. This study has been approved by the Ethics Committee of Affiliated Hospital of Youjiang University of Ethnic Medicine, approval No. YYFY-LL-2023-60. In addition, as this study is a retrospective study, the ethics committee has approved the waiver of patients’ relevant informed consent rights.
Methods
Bevacizumab only group: Patients only received bevacizumab treatment and did not receive radiotherapy. Bevacizumab (Suzhou Shengdia Biopharmaceutical Co., Ltd., National Medical Products approval No. S20210020, specification: 100 mg: 4 mL), bevacizumab 5 mg/kg, intravenous drip, once a week.
Bevacizumab + radiotherapy group: Patients received intensity modulated radiotherapy and bevacizumab treatment as outlined in the bevacizumab only group. Patients were asked to fast and take 500 mL of 0.9% sodium chloride injection orally 2 hours before treatment. The patient’s position was fixed with thermoplastic film, and both a computed tomography scan and image acquisition were performed to locate the treatment target area and organs at risk. The Primus-Hi linear accelerator (Siemens AG, Germany) 6 megavolt X-ray was used for radiotherapy, with irradiation field directions set to ≥ 4, single radiation dose of 1.8-2.2 Gy, total radiation dose of 60-66 Gy for the target area and positive lymph node area, and radiotherapy was carried out once a day, 5 times/week. Both groups were treated for two months.
Definition of intestinal perforation
The diagnosis of intestinal perforation is based on clinical manifestations, imaging examinations, and surgical pathology results. Clinical manifestations include sudden onset of abdominal pain, abdominal distension, nausea, vomiting, fever, etc., imaging examinations show signs of intestinal perforation, or surgical pathology results confirm intestinal perforation.
Observation indicators
Efficacy evaluation criteria: The efficacy was determined according to response evaluation criteria in solid tumors[9,10]: (1) Complete response (CR): The lesion disappeared and lasted for at least 4 weeks; (2) Partial response (PR): The lesion volume was reduced by at least 30% and lasted for at least 4 weeks; (3) Stable disease (SD): Between PR and disease progression; and (4) Progressive disease (PD): New lesions were found or the volume of the original lesions increased by more than 20%. Disease control rate = (CR + PR + SD) cases/total cases × 100%, total effective rate = (CR + PR) cases/total cases × 100%.
Incidence of intestinal perforation: The number and proportion of cases of intestinal perforation in the two groups of patients during radiotherapy and bevacizumab treatment and during the follow-up period after treatment were recorded and counted.
Survival status: The follow-up period was 1 year after the start of treatment, the patient’s survival time, recurrence and metastasis were recorded by telephone and outpatient visits. The overall survival (OS) rate and progression-free survival (PFS) rate were calculated.
Tumor markers: 3 mL of peripheral venous blood was collected from patients on an empty stomach in the morning, centrifuged for testing, and an enzyme-linked immunosorbent assay was used to detect carbohydrate antigen (CA) 125, CA199, and CA153 levels. Reference range: CA125 < 35 kU/L, CA153 < 25 U/mL, and CA199 < 37 U/mL. The instrument used was a Hitachi 7600-020 fully automatic biochemical analyzer.
Statistical analysis
SPSS 21.0 was used to analyze the data. The measurement data were expressed as mean ± SD, and the differences between the groups were analyzed by the t test. The enumeration data were expressed as frequency percentage, n (%), and the differences between the groups were analyzed by χ2 test. P < 0.05 indicated statistical significance.
RESULTS
Comparison of clinical efficacy between the two groups
Compared with the bevacizumab only group, the total effective rate in the bevacizumab + radiotherapy group was 54.29%, which was significantly higher than 28.57% in the bevacizumab only group (P = 0.029), Table 1.
Table 1 Clinical efficacy in the two groups, n (%).
Comparison of the incidence of intestinal perforation between the two groups
There was no statistically significant difference in the incidence of intestinal perforation between the bevacizumab only group and the bevacizumab + radiotherapy group (P = 0.038), Table 2.
Table 2 Incidence of intestinal perforation, n (%).
Compared with the bevacizumab only group, the OS of 76.67% and PFS of 73.33 in the bevacizumab + radiotherapy group were significantly higher than 56.67% in the bevacizumab only group (P < 0.05), Table 3.
Table 3 Comparison of survival between the two groups, n (%).
Comparison of serum tumor marker levels between the two groups
There was no significant difference in the levels of serum tumor-associated antigen 125, tumor-associated antigen 153, and tumor-associated antigen 199 between the two groups before treatment (P > 0.05); after treatment, the levels of serum tumor-associated antigen 125, tumor-associated antigen 153, and tumor-associated antigen 199 in the bevacizumab + radiotherapy group were significantly decreased compared with those in the bevacizumab only group (P < 0.05) , as shown in Table 4.
Table 4 Serum tumor marker levels in the two groups, mean ± SD.
Colorectal cancer is a common gastrointestinal cancer with a high incidence rate, poor prognosis and high mortality[11]. The early symptoms of colon cancer are often lacking in specificity, which means that most patients have already progressed to the middle or late stages of the disease by the time they seek medical treatment, thus missing the best opportunity for radical cure through surgery[12]. In addition, due to factors such as the possibility of tumor metastasis, the patient’s concurrent medical illness, or subjective resistance to surgical treatment, only 25% to 40% of all colon tumor patients can actually undergo surgical treatment[13,14]. Radiation therapy is one of the important treatment methods for inoperable gastrointestinal tumors. Intensity-modulated radiotherapy is based on conventional three-dimensional conformal radiotherapy. It divides the radiation field into smaller fields by adjusting the output dose of various points within the irradiation field cross-section, and then changes the specific dose intensity of each irradiation field independently. The target area is positioned more accurately, the irradiation dose is more precise, and the irradiation dose to the edge of the tumor target area is reduced. It has significant dosage-related advantages and is safer[15,16]. As a key angiogenic factor, vascular endothelial growth factor (VEGF) can promote the proliferation of vascular endothelial cells and accelerate the formation of new blood vessels. This process is crucial for the proliferation and infiltration of tumor cells. Therefore, targeted inhibition of VEGF has become a new strategy for clinical tumor treatment[17]. Bevacizumab, as the first United States Food And Drug Administration-approved humanized monoclonal antibody against VEGF, competitively binds to VEGF receptors on the surface of vascular endothelial cells, effectively inhibits VEGF activity, thereby hindering endothelial cell proliferation and inhibiting angiogenesis, exerting a significant anti-tumor effect[18,19]. The adverse reactions of bevacizumab include gastrointestinal reactions, proteinuria, poor wound healing, intestinal perforation, etc. Among them, intestinal perforation is a serious and rare adverse reaction[20]. Studies have shown[21] that the overall risk of intestinal perforation in the treatment of ovarian cancer with bevacizumab is 5.4%, while the risk of intestinal perforation in the treatment of colorectal cancer is 2.4%. Mubashir et al[22] evaluated the efficacy and safety of bevacizumab and found that the risk of gastrointestinal perforation was significantly increased in patients treated with bevacizumab, and the incidence of intestinal perforation was closely related to the dose of bevacizumab. Specifically, the relative risk of gastrointestinal perforation in patients who received 5 mg/kg bevacizumab per week was 2.67 (95% confidence interval: 1.14-6.26), while the relative risk in patients who received 2.5 mg/kg per week was 1.61 (95% confidence interval: 0.76-3.38). In addition, Shoji et al[23] also showed that the risk of gastrointestinal perforation in the high-dose group (5 mg/kg per week) was higher than that in the low-dose group (2.5 mg/kg per week). Although multiple clinical studies have suggested that bevacizumab, when used as a monotherapy or in combination with chemotherapy, may increase the risk of intestinal perforation in patients, whether radiotherapy further amplifies this risk remains controversial. A study analysis showed that the risk of perforation increases when bevacizumab is subsequently used in colorectal cancer patients who undergo pelvic radiotherapy[24]. The results of this study showed that the total effective rate in the bevacizumab + radiotherapy group after 2 months of treatment was 54.29%, which was higher than the 28.57% in the bevacizumab alone group; the 1-year OS was 76.67% and PFS was 73.33%, both higher than the group treated with bevacizumab alone. In addition, the incidence of intestinal perforation in the group receiving bevacizumab + radiotherapy was 11.43%, which was higher than the 0.00% in the group receiving bevacizumab alone. CA125, CA199, and CA153 are all biomarkers for colorectal cancer patients[25]. CA125 is a commonly used tumor marker for monitoring ovarian cancer. However, recent studies have shown that CA125 also has certain clinical value in gastrointestinal tumors and is an important and independent prognostic factor for CRC[26]. The increase in its level may be related to the progression of tumors or adverse treatment reactions. CA199 is mainly used for monitoring pancreatic, colon, and gastric cancer, and has certain value in determining liver metastasis[27]. In this study, compared with the group treated with bevacizumab alone, the levels of CA125, CA199, and CA153 were significantly reduced in the bevacizumab + radiotherapy group. This result suggests that radiotherapy combined with bevacizumab treatment may have a synergistic anti-tumor effect, thereby improving the efficacy. Radiotherapy can locally kill or inhibit tumor cells, enhance the vascular normalization effect of bevacizumab, improve drug delivery efficiency, and thus enhance anti-tumor activity[28]. Bevacizumab inhibits tumor angiogenesis by inhibiting the action of VEGF. The combination of the two may more effectively control tumor growth. Yang et al[29] believed that the survival rate of bevacizumab combined with radiotherapy was higher than that of bevacizumab alone, which is consistent with the results of the present study. The synergistic effect of radiotherapy and bevacizumab may help to more effectively control tumor growth and spread, thereby prolonging the survival time of patients. However, while the combined use of radiotherapy and bevacizumab improves the efficacy, it may also increase the risk of damage to normal tissues, especially intestinal tissues. The high-energy rays of radiotherapy can damage the intestinal mucosa and intestinal wall, which may cause ulcers and necrosis, and then cause intestinal perforation[30]. In addition, bevacizumab inhibits tumor angiogenesis by inhibiting the mitosis of tumor vascular endothelial cells, a mechanism that may damage intestinal blood vessels and affect the repair and regeneration capacity of intestinal tissues[31]. Therefore, the combined use of radiotherapy and bevacizumab may further aggravate intestinal damage, thereby significantly heightening the risk of intestinal perforation and leading to an increased incidence of adverse reactions. In summary, the results of this study show that while radiotherapy combined with bevacizumab has improved efficacy in colon tumors, it is necessary to be vigilant regarding serious complications such as intestinal perforation. Therefore, in clinical practice, patient screening should be optimized, such as avoiding patients with previous intestinal lesions or a high risk of radiation enteritis, developing personalized treatment plans and closely monitoring early signs of injury. In addition, exploring the adjustment of radiotherapy dose fractionation, such as intensity-modulated radiotherapy to reduce intestinal irradiation or bevacizumab administration timing, such as intermittent medication, may help balance efficacy and safety. This study is a single-center retrospective analysis with a small sample size and may have selection bias. Variables such as radiotherapy dose, target range and bevacizumab medication cycle are not fully standardized, which may affect the interpretation of the results. In the future, large-sample randomized controlled studies are needed to further verify the benefit-risk ratio of combined therapy. In addition, although precise 1:1 matching can improve intergroup comparability, non-randomization may weaken the internal validity and generalizability of research results, especially when faced with complex potential biases and difficult to control confounding factors. In future research, using randomized designs or further controlling for potential confounding factors may help better validate the reliability and broad applicability of this conclusion.
CONCLUSION
Radiation therapy may increase the risk of adverse reactions in cancer colon cancer patients receiving bevacizumab treatment. In clinical applications, the risks of combined use of radiotherapy and bevacizumab should be fully considered and personalized treatment plans should be formulated.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C, Grade C
Novelty: Grade B, Grade B, Grade C, Grade C
Creativity or Innovation: Grade C, Grade C, Grade C, Grade C
Scientific Significance: Grade C, Grade C, Grade C, Grade C
P-Reviewer: Hasbahceci M, MD, Professor, Türkiye; Morinaga T, PhD, Japan; Moyana T, MD, Professor, Canada S-Editor: Bai Y L-Editor: Webster JR P-Editor: Xu ZH
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