Vascular endothelial growth factor (VEGF) is expressed in many carcinomas; furthermore, it is known to be associated with invasion, metastasis of tumor, recurrence, and prognosis. Bevacizumab is a chimeric hominization immunoglobulin G1 monoclonal antibody directed against VEGF. Bevacizumab inhibits the neovascularization (formation and growth) in the tumor tissue and can delay tumor growth by inhibiting binding with a receptor developing in VEGF and vascular endothelial cells. The effect of not only neovascularization antagonism but also the effects to reduce tissue framework pressure of the tumor by making the vasculature of the tumor normalize and to improve antineoplastic accessibility to a tumor, was suggested [
6,
7]. High efficacy is shown by combination with antineoplastic and other molecular target drugs in various kinds of types of cancer. For breast cancer, bevacizumab with paclitaxel combined chemotherapy was authorized in Japan in September 2011.
While efficacy of bevacizumab is reported, characteristic and serious adverse events are being reported, including hypertension, proteinuria, hemorrhage, arterial thrombosis, protraction of wound healing, fistula formation, and gastrointestinal perforation [
8‐
12]. The potential of gastrointestinal perforation was reported for 0.9% of patients treated with bevacizumab, and the fatality rate of patients with gastrointestinal perforation treated with bevacizumab was reported to be as high as 20% [
8,
12]. Of gastrointestinal perforations induced by bevacizumab, 80% occur within 6 months after initial bevacizumab administration [
8]. The most common site of perforation is the colon, while small intestine ranked second and stomach ranked third [
8]. The risk factor of gastrointestinal perforation includes a high-dose administration of bevacizumab, a history of abdominal radiotherapy, carcinomatous peritonitis, colorectal cancer, renal cell carcinoma, colonic diverticulitis, peptic ulcer, and administration of steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) [
8]. It is considered that causes of bevacizumab-related gastrointestinal perforation are disorder of the structure and function of blood vessels, protraction of wound healing, and failure of tumor. Several mechanisms had been described to explain the development of gastrointestinal perforation as a result of bevacizumab. In the first, the inhibition of VEGF by bevacizumab could cause a decrease in vascular density, a disorder of vasoconstriction due to the release disorder of nitric monoxide, arterial thrombus, embolism as a result of failure of blood vessel structure, and disorder of functions [
6‐
13]. The second possible mechanism is related to gastrointestinal mucosa. Constant gastrointestinal wall proliferation and healing is dependent on microcirculation, protection with nitrous oxide, and normal platelet function, all of these depend on VEGF [
6‐
13]. Intestinal healing after damage such as surgery or ulcers is also dependent on these processes. From these mechanisms, NSAIDs are a risk factor of bevacizumab-related gastrointestinal perforation. The third possible mechanism is, ironically, the great efficacy of bevacizumab to reduce tumor volume [
6‐
13]. Tumor structure may provide some stability to the intestinal wall itself, and tumor death caused by bevacizumab creates perforation. There is no consensus for the pathological findings because gastrointestinal perforation cases caused by bevacizumab are rare and they could be caused by many mechanisms (as previously mentioned). A search using the terms “breast cancer,” “bevacizumab,” and “perforation” in PubMed for the period 1950 through to 2015, retrieved two case reports from France and 12 cases in clinical trials of bevacizumab: E2100, RIBBON-1, RIBBON-2, and AVADO. In total, only 14 cases were reported [
1‐
5]. The two cases in France were small intestinal perforation without intraabdominal cancer lesion [
1,
2].
In our case, when we performed diagnostic laparoscopy, all the intestinal tract and omentum formed an omental cake, and the whole peritoneum was thickened. A histopathological diagnosis of peritoneal dissemination of the breast cancer was made from a peritoneal sample. On the basis of these results, bevacizumab combined therapy was started; however, a small intestinal perforation occurred approximately 2 months after the initial bevacizumab administration. Therefore, an emergency operation was performed. In consideration of the intraoperative findings and onset time, bevacizumab was very effective and it was considered that the small intestinal perforation was caused by the failure of the tumor. For the gastrointestinal perforation caused by bevacizumab, it is safe that construction of enterostomy using oral tract from the perforation in consideration of protraction of wound healing [
14]. However, only a few cases in which the perforated tract was excised and anastomosis was performed at the same time and simple closure was performed, were reported [
15]. In our case, the perforations were 120 cm distant from Treitz ligament and located in upper small intestine, and serosa near perforations was considered almost normal, not edematous or inflammatory. Therefore, in consideration of worsening of quality of life caused by enterostomy, we performed a procedure of simple closure; however, in consideration of that she received treatment to elevate her blood pressure by peripheral vasoconstriction because she was critically ill with septic shock, in addition to protraction of wound healing by bevacizumab, the possibility of anastomotic leakage was enough. Therefore, we checked the drain finely and were able to re-operation at anytime, but, anastomotic leakage was not caused fortunately. Evading enterostomy with upper small intestine was considered a very big benefit to our patient. However, after all we should be very careful about a simple closure or resection and single-stage anastomosis. Scrupulous postoperative follow-up is necessary, including tight checking the drain, to ensure that a reoperation is performed immediately in the case of an emergency.