Bevacizumab has been used as a promising drug for metastatic colorectal cancer in combination with chemotherapeutic agents. However, it has a few serious adverse effects, such as intestinal bleeding or perforation. The purpose of this study is to identify the clinical characteristics of intestinal perforation induced by bevacizumab in colorectal cancer patients.
From January 2007 to June 2018, a total of 488 patients underwent chemotherapy with bevacizumab for metastatic colorectal cancer. Medical records were reviewed retrospectively.
Nine patients (1.8%) were identified with intestinal perforation induced with bevacizumab. The median age was 59 years (range, 36–68 years). The primary tumor site was the sigmoid colon in six patients, the rectum in three patients. The liver was the most common metastatic organ (7 patients). Perforation sites were primary tumor site of the colorectum in four patients and the small bowel in five patients. Intestinal perforation was developed after a median of 3 chemotherapy cycles (range, 1–15 cycles), and a median of 7 days (range, 3–32 days) after chemotherapy. One patient expired due to sepsis.
Bevacizumab induced intestinal perforation is a lethal adverse effect in patients with colorectal cancers. The characteristics of intestinal perforation varied according to perforation site, previous chemotherapy cycles, and clinical course. Careful monitoring is necessary with the use of bevacizumab in conjunction with chemotherapeutic agents.
Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor, is an antiangiogenic agent approved for the treatment of multiple solid tumors. It has shown promise as a clinical agent against metastatic colorectal cancer, and particularly in combination with chemotherapy [
From January 2007 to June 2018, a total of 488 patients underwent chemotherapy with bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA, USA) with metastatic colorectal cancers. Medical records were reviewed retrospectively. The study was approved by the Institutional Review Board of Kosin University Gospel Hospital (IRB 2019-01-013) and performed in accordance with the principles of the Declaration of Helsinki.
The use of chemotherapy was applied in patients younger than 75 years of age and having appropriate bone marrow, liver, and renal function (hemoglobin >10 g/dL, leukocyte count >4,000/mm3, platelets >100,000/mm3, bilirubin <2.0 mg, aspartate transaminase/alanine transaminase <1.25 normal value, creatinine <1.25×normal value). The activity level was applied to patients with 0 to 2 using Eastern Cooperative Oncology Group criteria.
Bevacizumab was administered by intravenous infusion at 5 mg/kg in combination with irinotecan (FOLFIRI) at 130–180 mg/m2 by 2-hour infusion with 5-fluorouracil at 400 mg/m2 by bolus infusion followed by 600 mg/m2 continuous infusion for 22 hours, and with leucovorin at 20 mg/m2, every 2 weeks. With a FOLFOX regimen, bevacizumab was administered with oxaliplatin (FOLFOX) at 85 mg/m2 by 2-hour infusion with 5-fluorouracil at 400 mg/m2 by bolus infusion followed by 600 mg/m2 continuous infusion for 22 hours, and with leucovorin at 20 mg/m2.
For the patients with intestinal perforation induced by bevacizumab, clinical characteristics were reviewed such as perforation sites, surgery of intestinal perforation, postoperative complication, chemotherapy cycles, and interval between chemotherapy and intestinal perforation.
Of the 488 patients, nine patients (1.8%) were identified with intestinal perforation induced by bevacizumab. The median age was 59 years (range, 36–68 years). Primary tumor site was the sigmoid colon in six patients, the rectum in three patients. The liver was the most common metastatic organ in seven patients. Six patients underwent resection of primary tumor. Perforation sites were the colorectum in four patients, the small bowel in five patients (3 in the jejunum and 2 in the ileum). Primary tumor site perforation was in three patients. Intestinal perforation developed after a median of three chemotherapy cycles (range, 1–15 cycles; 3–4 cycles in 4 patients), and a median of 7 days (range, 3–32 days) after chemotherapy. Chemotherapy with bevacizumab was 3rd line in case 1 and 2nd line in case 8. Stoma formation was done in six patients (
In one patient, two events of intestinal perforation developed at 3-month intervals. There was no chemotherapy after the first event of intestinal perforation. The 2nd event of a colo-vesical fistula at the sigmoid colon developed. Hartmann’s procedure and omentopexy were performed. The colo-vesical fistula developed after a total of 11 cycles of chemotherapy (FOLFIR) with bevacizumab, 134 days after chemotherapy.
For bevacizumab induced intestinal perforation, the commonly suggested predisposing factors are peptic ulcer disease, diverticulitis, chemotherapy-induced colitis, a history of abdominal radiation, abdominal carcinomatosis and bowel obstruction [
The pathophysiologic mechanism by which bevacizumab leads to bowel perforation is unknown. There are several possible mechanisms [
Scappaticci et al. [
In conclusion, intestinal perforation induced bevacizumab is uncommon, though a serious and fatal adverse effect. Although the pathophysiology is not completely understood, careful observation is imperative for those patients who are administered bevacizumab in combination chemotherapy. Awareness of signs and symptoms of peritonitis with abdominal pain, nausea, and vomiting is necessary, especially after 3–4 cycles and within 7–10 days after bevacizumab administration. If intestinal perforation is diagnosed, bevacizumab administration should be ceased immediately and then resuscitation and early surgical intervention should be undertaken.
No potential conflict of interest relevant to this article was reported.
Characteristics of bevacizumab induced intestinal perforation in colorectal cancer
Characteristic | Patients (n=9) |
---|---|
Sex (male:female) | 6:3 |
| |
Age (yr) | 59 (36–68) |
| |
Primary tumor site (colon:rectum) | 6:3 |
| |
Metastasis site | |
Liver | 7 |
Lung | 1 |
Peritoneum | 3 |
Ovary | 1 |
| |
Resection of primary tumors (yes:no) |
6:3 |
| |
Perforation site (small bowel:colorectum) |
5:4 |
| |
Perforation at primary tumor sites | 3 |
| |
Concurrent chemotherapy regimen | |
FOLFOX | 4 |
FOLFIRI | 5 |
| |
Bevacizumab, total use (cycle) | 3 (1–15) |
| |
Interval between chemotherapy and perforation (day) | 7 (3–32) |
| |
Previous history of intestinal obstruction (yes:no) | 4:5 |
Values are presented as median (range).
Low anterior resection in 5 cases, sigmoidectomy in 1 case, colostomy in 1 case.
The jejunum in 3 cases, the ileum in 2 cases, the sigmoid colon in 2 cases, the rectum in 1 case and anastomotic site in the rectum in 1 case.
Case review of small bowel perforation induced with bevacizumab
Characteristic | Case 1 | Case 2 | Case 3 | Case 4 | Case 5 |
---|---|---|---|---|---|
Sex | Female | Male | Male | Male | Male |
Age (yr) | 48 | 68 | 36 | 67 | 65 |
Primary tumor locations | Sigmoid colon | Rectum | Rectum | Sigmoid colon | Sigmoid colon |
Metastasis sites | Ovary, peritoneum | Liver, peritoneum | Liver | Liver | Liver |
Surgery for primary tumor | Sigmoid colon resection | LAR | LAR | LAR | LAR |
Perforation sites | Ileum | Jejunum | Ileum | Jejunum | Jejunum |
Perforation at tumor sites | No | No | No | No | Yes |
Perforation surgery | Small bowel resection & ileostomy | Primary closure & jejunum ostomy | Small bowel resection & ileostomy | Small bowel resection | Small bowel resection |
Postoperative complications | None | Expired | None | Leakage | None |
Bevacizumab concurrent chemotherapy regimen | FOLFOX | FOLFIRI | FOLFOX | FOLFIRI | FOLFIRI |
Bevacizumab, total use (cycle) | 1 | 4 | 3 | 11 | 3 |
Interval between chemotherapy and perforation (day) | 7 | 3 | 4 | 32 | 11 |
Previous history of intestinal obstruction | No | No | No | No | Yes |
Preoperative CEA | 854.3 | 2,476 | 6.2 | 5.2 | 4.2 |
LAR, low anterior resection; CEA, carcinoembryonic antigen.
Case review of the colorectum perforation induced with bevacizumab
Characteristic | Case 6 | Case 7 | Case 8 | Case 9 |
---|---|---|---|---|
Sex | Male | Female | Male | Female |
Age (yr) | 46 | 59 | 59 | 41 |
Primary tumor locations | Rectum | Sigmoid colon | Rectum | Sigmoid colon |
Metastasis sites | Liver | Peritoneum | Liver, lung | Liver |
Surgery for primary tumor | None | Colostomy | LAR | None |
Perforation sites | Rectum | Sigmoid colon | Rectum | Sigmoid colon |
Perforation at tumor sites | Yes | Yes | No |
Yes |
Perforation surgery | Hartmann’s colostomy | Peritoneal irrigation & drainage | Ileostomy | Sigmoid colon resection & ileostomy |
Postoperative complications | Paralytic ileus | Paralytic ileus | None | None |
Concurrent chemotherapy regimen | FOLFIRI | FOLFOX | FOLFOX | FOLFIRI |
Bevacizumab, total use (cycle) | 2 | 14 | 15 | 3 |
Interval between chemotherapy and perforation | 25 | 7 | 20 | 4 |
Previous history of intestinal obstruction | Yes | Yes | No | Yes |
Preoperative CEA | 1,082 | 6.8 | 12.8 | 12.4 |
LAR, low anterior resection; CEA, carcinoembryonic antigen.
Rectum perforation at proximal site from the tumor site.