Bevacizumab is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Numerous reports have shown that this drug exhibits significant efficacy in the treatment of various cancer types, including metastatic colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma, cervical cancer and ovarian cancer. Bevacizumab can positively improve key indicators such as a patient's overall survival (OS) time, progression-free survival (PFS) time and objective response rate (ORR) (1–5). The core mechanism of action lies in the binding of bevacizumab to VEGF with high affinity, blocking the interaction between VEGF and receptors on the surface of endothelial cells, thereby effectively inhibiting tumor angiogenesis (6,7). Although this drug has demonstrated notable efficacy in clinical applications, its related adverse reactions cannot be ignored. A phase III clinical trial evaluated the safety of continued bevacizumab treatment in 245 breast cancer patients who experienced disease progression after receiving bevacizumab combined with chemotherapy. The most common grade 3 or higher adverse events were hypertension (13%), neutropenia (12%) and hand-foot syndrome (11%) (8). A phase II clinical trial evaluated the efficacy of adding bevacizumab to the cisplatin-paclitaxel treatment regimen in 150 patients with advanced cervical cancer. Among these, the most common grade 3/4 adverse events were neutropenia (25%), anemia (19%), hypertension (14%) and the occurrence of ≥1 perforation/fistula event (13%) (4). However, a literature search reveals that reports on esophageal perforation caused by bevacizumab during the treatment of lung cancer are extremely rare (9). The present report describes in detail the clinical diagnosis and treatment process of a patient with advanced lung cancer who developed esophageal perforation while receiving bevacizumab treatment, and systematically analyzes its occurrence mechanism and management strategies. The aim of the study is to provide references for clinical diagnosis and treatment, enhancing the awareness of and clinical management ability for this rare adverse reaction of the drug, and optimizing the risk early warning mechanism during the treatment process.

The present report describes the case of a patient with advanced lung cancer who had a history of chronic gastritis. In the early stage, the patient received 4 cycles of chemotherapy with 700 mg bevacizumab combined with pemetrexed and carboplatin, as well as intensity-modulated radiotherapy (total dose of 40 Gy/20 fractions). Later, the dose of bevacizumab was adjusted to 800 mg + the original chemotherapy regimen. Esophageal perforation occurred during the 6th cycle of treatment. After comprehensive treatments, such as esophageal covered stent implantation under endoscopy, the condition of the patient improved in the short term.

From the results of the present report, combined with a literature analysis, we hypothesize that the pathogenesis is associated with the synergistic effect of multiple risk factors. The anti-angiogenic effect of bevacizumab as a key therapeutic drug, the duality of the vascular normalization effect and the toxic effect of bevacizumab are worthy of in-depth discussion. This drug blocks the phosphorylation of VEGFR-2 by binding to VEGF-A with high affinity, which inhibits tumor angiogenesis whilst also impairing the physiological vascular repair mechanism (12,13). Thawani et al (14) reported that even if patients did not receive local treatments (radiotherapy or surgery) and only used bevacizumab, it could also cause a tracheoesophageal fistula. When perforation occurred in the patients, the median dose of bevacizumab used was 733 mg, which was close to the median dose of 800 mg for the risk threshold of gastrointestinal perforation reported in the literature (15). The odds ratio was 2.8 (P=0.03), suggesting that high-dose medication may be an important predisposing factor. ii) The synergistic damage effect of combined radiotherapy and chemotherapy is another risk factor. During the radiotherapy process for lung cancer, there is an association between the length of time after the completion of radiotherapy and the occurrence of esophageal fistula. According to previous studies, the time span from the end of radiotherapy to the appearance of esophageal fistula varies greatly. The condition may occur as soon as ~4 months after the end of radiotherapy (16) or as late as 21 months (17). Previous case reports by Nishie et al (18) and Wang et al (19) have indicated that during the treatment of lung cancer, esophageal perforation may be induced in patients who did not receive radiotherapy when treated with bevacizumab combined with chemotherapy. However, in the present case, the situation was more complex, as the patient not only received bevacizumab combined with chemotherapy but also sequentially underwent radiotherapy. Specifically, the mean esophageal dose of the patient was 18 Gy, and the maximum esophageal dose was 36 Gy. The mean dose at the location of the later esophageal perforation was 21 Gy, and the maximum esophageal dose was 33 Gy. Radiotherapy is likely to cause chronic inflammation and fibrosis of the esophageal mucosa (20). When the adverse effects caused by radiotherapy are superimposed on the anti-angiogenic effect of bevacizumab, the tolerance of tissues may be further weakened (21). Furthermore, the regimen of pemetrexed combined with carboplatin used in the patient in the present case may have exacerbated the damage to the esophageal mucosa (22). The Aspergillus flavus infection (confirmed by tNGS) that occurred in the patient later could have caused pulmonary inflammation and the severe cough (23,24). This may have increased the pressure on the esophageal wall through mechanical stress and become a direct predisposing factor for perforation (25). Spigel et al (26) performed two independent phase II clinical trials on 34 patients with small cell lung cancer (29 patients) and non-small cell lung cancer (5 patients). The research revealed that the combination of bevacizumab with radiotherapy and chemotherapy markedly increased the risk of a tracheoesophageal fistula in patients with lung cancer (incidence rate, 2.3 vs. 0.0%, respectively). The treatment regimen of the patient in the present case included the combination of bevacizumab with radiotherapy and chemotherapy, which may have increased the risk of tracheoesophageal fistula. Another risk factor associated with the pathogenesis of perforation is the superimposed impact of underlying diseases and predisposing factors. The previous chronic gastritis of the patient in the present case may have led to acid reflux, which could have chronically stimulated the esophageal mucosa to form chronic inflammation and reduce the resistance of local tissues (27). Zhou et al (15) performed a retrospective analysis of 8 cases of bevacizumab-related gastrointestinal perforation, reporting that 62.5% of the patients had underlying digestive tract diseases, which was consistent with the situation in the present case. Moreover, when the patient in the present case coughed, the intrathoracic pressure suddenly increased (up to 50–100 mmHg) (28,29), which may have caused damage to the weak areas of the esophageal wall (25). Especially when the mucosa has already been damaged by radiotherapy or drugs, it is easy for a full-thickness rupture to form and create a fistula.

In view of the serious consequences of tracheoesophageal fistula (the patient in the present case eventually died due to advanced cancer), the following management strategies should be considered when bevacizumab is used clinically: i) Screening of high-risk factors: Patient medical history should be collected in detail, with a focus on basic conditions such as the history of digestive tract diseases (such as chronic gastritis and ulcers), radiotherapy history and chronic cough. For patients who are due to receive bevacizumab combined with radiotherapy, the radiation dose received by the esophagus should be strictly evaluated. Furthermore, the superimposed use of high-dose drugs (such as ≥800 mg per time) plus radiotherapy and chemotherapy should be avoided if possible. ii) Baseline assessment and monitoring: For patients at moderate-to-high risk of esophageal perforation (such as those with combined radiotherapy, chemotherapy and bevacizumab, or those with a history of digestive tract diseases), gastroscopy is recommended before treatment (30) to exclude esophageal mucosal damage. During the treatment, swallowing functions (such as swallowing pain, a foreign body sensation and a choking cough) and respiratory symptoms (an aggravated cough and shortness of breath) should be closely monitored. When abnormalities occur, an esophageal fistula should be immediately screened for (upper gastrointestinal contrast radiography or endoscopy is preferred). iii) Principles of emergency treatment: Once a tracheoesophageal fistula is diagnosed, bevacizumab should be immediately stopped, fasting started, and anti-infection and nutritional support treatments should be administered. Minimally invasive methods such as endoscopic stent implantation should be prioritized to close the fistula and improve the quality of life of the patient.

In conclusion, we hypothesize that the esophageal perforation in the present case was the result of the synergistic effect of multiple factors, including drug dosage, radiation dose to the esophagus, esophageal damage caused by chemotherapy, underlying digestive tract diseases and mechanical stress damage. Clinically, individualized risk assessments for high-risk groups are needed, and treatment indications and dosages should be strictly controlled and combined with close symptom monitoring and imaging evaluations, in the hope of the early identification and management of this rare but potentially fatal complication.