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Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation.

Tol J, Cats A, Mol L, Koopman M, Bos MM, van der Hoeven JJ, Antonini NF, van Krieken JH, Punt CJ - Invest New Drugs (2008)

Bottom Line: Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported.The majority (89%) of events developed early during treatment.Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

ABSTRACT
Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.

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Related in: MedlinePlus

Gastric ulcer at endoscopy in patient 1
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Fig1: Gastric ulcer at endoscopy in patient 1

Mentions: Eighteen patients presented with a symptomatic GI ulcer (Fig. 1) (n = 6), perforation (n = 8) or a perforated ulcer (n = 4; Table 1). Patient characteristics are shown in Table 2. Median age was 64 years (range 50–73). The incidence of GI ulcer, perforation, or perforated ulcer development in the present study was 0.8%, 1.0% and 0.5% respectively. The overall risk of the development of an ulcer with or without perforation, or a perforation with or without an ulcer was 1.3% and 1.6%, respectively. The incidence of events was higher in the cetuximab treatment arm (ulcers: two versus four; perforation: five versus three; perforated ulcers: three versus one, respectively). However the small difference in a low number of events does not allow further conclusions. Four ulcers developed in the upper digestive tract and two ulcers developed in the lower digestive tract, of which one at the site of anastomosis at 5 months after colon resection. All eight perforations were located in the lower digestive tract, of which six at the site of the primary tumour or local recurrence. One perforated ulcer developed in the duodenum, two at the site of primary anastomosis 16 months and 3 years after rectum resection, respectively, and one patient developed multiple ulcers, perforations and perforated ulcers along the entire digestive tract. Both patients who developed a perforated ulcer at the site of the anastomosis following anterior resection previously underwent preoperative radiotherapy on the pelvic region. Sixteen (89%) events (five ulcers, seven perforations and all four perforated ulcers) developed within the first 15 weeks after the start of treatment. The histological diagnosis was confirmed upon pathologic review in all 13 patients of whom tissue specimens were available (five ulcers, four perforations and all four perforated ulcers). One tumour showed deep ulceration with necrosis at the side of perforation (patient 15). Since no tissue was available from 4 perforations, the presence of ulceration surrounding the perforation could not be assessed in these patients. As bevacizumab is an inhibitor of angiogenesis, and as we presumed that the inhibition of angiogenesis was related to the development of ulcers and perforations, special attention was focussed at the blood vessels surrounding the ulcer or perforation. No special features were seen and the expected neovascularisation which accompanies ulceration was present. Additional CD68 immunostaining for macrophages (performed on tissue of 10 patients), CD31 and CD34 for assessing vascularity (one patient) and CMV staining (three patients) did not reveal any abnormalities. No Helicobacter pylori colonisation was found in the gastric and duodenal biopsies by histology. In all five patients developing a perforation with a primary tumour in situ, the perforation was located within the primary tumour. Seven perforations occurred in patients after resection of the primary tumour (58%), in whom the anastomosis was the site of perforation in three patients. In order to assess other known risk factors for ulceration, the use of relevant comedication (protonpump inhibitors (PPI), non-steroidal anti-inflammatory drugs (NSAID) and steroids) was recorded. Out of seven patients with localisation of an ulcer or perforation in the upper abdominal tract, two patients used NSAID in combination with prophylactic use of PPI at the time of randomisation and a third patient used PPI for unknown indication. Three patients used oral steroids at the time of randomisation.Fig. 1


Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation.

Tol J, Cats A, Mol L, Koopman M, Bos MM, van der Hoeven JJ, Antonini NF, van Krieken JH, Punt CJ - Invest New Drugs (2008)

Gastric ulcer at endoscopy in patient 1
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2480515&req=5

Fig1: Gastric ulcer at endoscopy in patient 1
Mentions: Eighteen patients presented with a symptomatic GI ulcer (Fig. 1) (n = 6), perforation (n = 8) or a perforated ulcer (n = 4; Table 1). Patient characteristics are shown in Table 2. Median age was 64 years (range 50–73). The incidence of GI ulcer, perforation, or perforated ulcer development in the present study was 0.8%, 1.0% and 0.5% respectively. The overall risk of the development of an ulcer with or without perforation, or a perforation with or without an ulcer was 1.3% and 1.6%, respectively. The incidence of events was higher in the cetuximab treatment arm (ulcers: two versus four; perforation: five versus three; perforated ulcers: three versus one, respectively). However the small difference in a low number of events does not allow further conclusions. Four ulcers developed in the upper digestive tract and two ulcers developed in the lower digestive tract, of which one at the site of anastomosis at 5 months after colon resection. All eight perforations were located in the lower digestive tract, of which six at the site of the primary tumour or local recurrence. One perforated ulcer developed in the duodenum, two at the site of primary anastomosis 16 months and 3 years after rectum resection, respectively, and one patient developed multiple ulcers, perforations and perforated ulcers along the entire digestive tract. Both patients who developed a perforated ulcer at the site of the anastomosis following anterior resection previously underwent preoperative radiotherapy on the pelvic region. Sixteen (89%) events (five ulcers, seven perforations and all four perforated ulcers) developed within the first 15 weeks after the start of treatment. The histological diagnosis was confirmed upon pathologic review in all 13 patients of whom tissue specimens were available (five ulcers, four perforations and all four perforated ulcers). One tumour showed deep ulceration with necrosis at the side of perforation (patient 15). Since no tissue was available from 4 perforations, the presence of ulceration surrounding the perforation could not be assessed in these patients. As bevacizumab is an inhibitor of angiogenesis, and as we presumed that the inhibition of angiogenesis was related to the development of ulcers and perforations, special attention was focussed at the blood vessels surrounding the ulcer or perforation. No special features were seen and the expected neovascularisation which accompanies ulceration was present. Additional CD68 immunostaining for macrophages (performed on tissue of 10 patients), CD31 and CD34 for assessing vascularity (one patient) and CMV staining (three patients) did not reveal any abnormalities. No Helicobacter pylori colonisation was found in the gastric and duodenal biopsies by histology. In all five patients developing a perforation with a primary tumour in situ, the perforation was located within the primary tumour. Seven perforations occurred in patients after resection of the primary tumour (58%), in whom the anastomosis was the site of perforation in three patients. In order to assess other known risk factors for ulceration, the use of relevant comedication (protonpump inhibitors (PPI), non-steroidal anti-inflammatory drugs (NSAID) and steroids) was recorded. Out of seven patients with localisation of an ulcer or perforation in the upper abdominal tract, two patients used NSAID in combination with prophylactic use of PPI at the time of randomisation and a third patient used PPI for unknown indication. Three patients used oral steroids at the time of randomisation.Fig. 1

Bottom Line: Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported.The majority (89%) of events developed early during treatment.Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

ABSTRACT
Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.

Show MeSH
Related in: MedlinePlus