A case of HCC successfully treated with infliximab‐steroid sequential therapy for small bowel perforation due to atezolizumab/bevacizumab combination therapy

Abstract Background Although reports of gastrointestinal perforation after immune‐related adverse events (irAE) enteritis are rare, the anti‐ vascular endothelial growth factor (VEGF) effect of bevacizumab may be involved in gastrointestinal perforation. We report a rare case of gastrointestinal perforation in a patient with hepatocellular carcinoma treated with atezolizumab/bevacizumab combination therapy and infliximab before steroid use. Case A 72‐year‐old man, who received seven courses of atezolizumab/bevacizumab for hepatocellular carcinoma due to hepatitis B, was admitted to our department with idiopathic abdominal pain and diarrhea (grade 2 [G2]). Computed tomography (CT) and colonoscopy confirmed edema in the gastrointestinal tract. Perforation of the jejunum was observed in a CT performed on the third day and an emergency operation was performed. Intraoperative findings showed severe edema of the jejunum and leakage of feces into the abdominal cavity. The patient was diagnosed with irAE enteritis comprehensively with severe wall thickening on CT and colonoscopy, negative stool culture, and pathological findings of CD8‐positive cells. Infliximab was administered before initiating steroids, to prevent reperforation. The enteritis improved by the 22nd day; however, CT performed on the 35th day of illness showed relapse of gastrointestinal wall thickening and G2 diarrhea symptoms; therefore, prednisolone (PSL) 60 mg/day was started on the 36th day of illness. After introducing PSL, enteritis did not reoccur, and the patient was discharged on the 63rd day of illness after admission. Conclusion There are no reports of gastrointestinal perforation by atezolizumab/bevacizumab for hepatocellular carcinoma, and prior administration of infliximab. We therefore report the clinical course and management.


| INTRODUCTION
The anti-PD-L1 antibody, an immune checkpoint inhibitor, exerts an antitumor effect mainly by maintaining the activation of T cells by inhibiting the binding of PD-1 and PD-L1. 1 Anti-vascular endothelial growth factor (VEGF) inhibitors have become the mainstay of cancer treatments where tumor growth is attributed to abundant neovascularization. Therefore, a combination therapy with atezolizumab and bevacizumab is considered as one of the standard treatment options for unresectable hepatocellular carcinoma (HCC). 2 However, immune-related adverse events (irAEs), which can develop in various organs, have become a matter of concern. [3][4][5] Although reports of gastrointestinal perforation after irAE enteritis are rare, the anti-VEGF effect of bevacizumab may be involved in gastrointestinal perforation. 6,7 Herein, we report a rare case of gastrointestinal perforation in a 72-year-old man with HCC being treated with atezolizumab/bevacizumab combination therapy.

| CASE REPORT
A 72-year-old man was admitted to the Department of Gastroenterology and Hepatology of our institute with the chief complaints of abdominal pain and diarrhea. The patient received a total of seven courses of atezolizumab/bevacizumab from October 2021 for HCC (Child Pugh grade A; Table 1) and subsequently developed idiopathic abdominal pain and diarrhea. He was treated with intestinal regulators for several days before being admitted to our hospital. The patient had a medical history of esophageal varices (Lm,F2,Cb,RC0 ! post endoscopic variceal ligation) and portal vein thrombosis with no significant familial history and no smoking and drinking habits. At the time of referral, the patient was being orally administered famotidine (40 mg/day), entecavir hydrate (0.5 mg/day), warfarin potassium (2 mg/day), rifaximin (600 mg/day), and L-isoleucine, leucine, and valine (12.45 mg/day).
Physical examination at the time of admission revealed the following features: height, 165 cm; weight, 59.0 kg; body temperature, 37.5 C; blood pressure, 120/70 mmHg; pulse, 90 beats/min; and respiratory rate, 16 breaths/min. No rebound tendernesss in the middle of the abdomen was noted, but the liver was palpable by two lateral fingers and lower limb edema was observed. The blood test showed a marked increase in C-reactive protein level (Table 2). In addition, albumin and platelet count levels were decreased, indicating liver cirrhosis. The

| DISCUSSIONS
IrAEs is a problem peculiar to immune checkpoint inhibitors and is caused due to an autoimmune reaction. IrAEs can occur in all organs, and in addition to colitis, endocrine abnormalities, rashes, interstitial pneumonia, liver damage, 3-5 and infrequent but fatal side effects have also been reported. 8 However, perforation of the gastrointestinal tract is extremely rare, as in this case. 6 On the third day after admission, jejunal perforation was observed, and emergency surgery was performed. After two doses of infliximab at two-week intervals, improvement of enteritis and disappearance of free air were confirmed. Thereafter, grade 2 diarrhea relapsed and the patient was administered on PSL (60 mg/day.) The patient was discharged on the 63rd day after admission. CRP, C-reactive protein; PSL, prednisolone gastrointestinal perforation in bevacizumab combination chemotherapy is 0.9%-3.6%, and the onset time is often within 6 months after the start of administration. 9 Additionally, Cao et al. reported that the frequency of gastrointestinal perforation with chemotherapy without bevacizumab is 0.13% (2/1508), whereas that in the bevacizumab group is 1.0% (15/14912). 10 The mortality rate of gastrointestinal perforation is reported to be as high as 21.5%. 9 These reports reported the incidence of colorectal cancer, especially at the infiltration site of colorectal cancer. On the other hand, there is also a report that perforation occurred in the small intestine without cancer infiltration, 11 and there is a possibility of perforation risk regardless of the presence or absence of cancer infiltration.
Perforation of the esophagogastric junction has also been reported in combination therapy with atezolizumab/bevacizumab. 12 However, this case had a history of intra-abdominal stereotactic ablative radiotherapy (SABR), which is a major difference from our case.
In In other words, it is highly possible that inflammation of the gastrointestinal tract and delayed wound healing due to VEGF inhibition interacted, leading to gastrointestinal perforation.