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To the Editor:

Inflammatory bowel diseases (IBDs) are usually considered chronic conditions, often moving in spurts, which can never be declared cured. Current therapies for IBDs mainly consist of salicylates, corticosteroids, antitumor necrosis factor (TNF) agents, and surgery. Colorectal cancer (CRC) may complicate the natural history of IBDs. Indeed, several studies have suggested that patients with Crohn's disease (CD) have an increased risk of CRC.1 Basically, CD patients have an estimated 20 times greater risk than in a control population.1 Also, patients with a past history of CD represent 2% of patients with CRC.2

The optimal treatment of advanced CRC includes 5-fluorouracil doublets combined with anti-EGFR or anti-VEGF agents. Bevacizumab, a humanized IgG1 monoclonal antibody to VEGF, exerts clinical activity and improves survival in metastatic CRC patients.3 However, bleeding occurs in 3.1% of patients receiving bevacizumab,3 and represents a serious concern for its use in patients with IBD. Furthermore, we have previously reported exacerbation of hemorrhagic rectocolitis in patients receiving sunitinib and sorafenib, two oral multikinase inhibitors targeting the VEGF pathway.4 Hence, the safety of bevacizumab in IBD patients is uncertain, and few data are available in the literature.

We report on two patients with IBD who received bevacizumab-based chemotherapy for metastatic CRC. The first patient is a 47-year-old man with a 2-year history of CD controlled with oral corticosteroids and 5-aminosalicylate, with two exacerbations per year. During a screening colonoscopy the patient was diagnosed with a right colon carcinoma and pancolitis in September 2008. He was treated by subtotal colectomy followed by 12 cycles of FOLFOX adjuvant chemotherapy until April 2009. Six months later a peritoneal recurrence was diagnosed. The patient received first-line chemotherapy combining 5-FU, irinotecan, and bevacizumab (5 mg/kg every 2 weeks), allowing complete tumor response. For a total of 14 cycles of bevacizumab he did not experience any acute CD outbreak. At the time of this report the patient is still alive without evidence of disease.

The second patient is a 57-year-old woman with a 14-year history of CD with pancolitis who underwent colectomy. Four years later she was diagnosed with rectal carcinoma. She subsequently underwent curative surgical resection with ileostomy. Three years later she developed peritoneal recurrence and was subsequently started on capecitabine, oxaliplatin, and bevacizumab as part of a phase III clinical trial. She received two cycles of this regimen and developed severe (grade 4) diarrhea, without bleeding or inflammatory syndrome. The grade 4 digestive toxicity was considered as being triggered by capecitabine,5 and possibly worsened by ileostomy. Therefore, the patient was excluded from the study and chemotherapy was changed to 5-FU plus oxaliplatin. The patient experienced disease progression after 4 cycles and she died of disease 20 months later. Importantly, no acute CD outbreak was observed while the patient was under bevacizumab.

In our experience, bevacizumab did not worsen CD in metastatic CRC patients. In contrast, we observed exacerbation of IBD-related symptoms in patients receiving the multikinase inhibitors sunitinib and sorafenib.4 Importantly, these tyrosine kinase inhibitors target not only the VEGF signaling pathway, but also the PDGF receptors. The PDGF signaling pathway was shown to be critically involved in the pathophysiology of IBDs,6, 7 suggesting that the deleterious effects of sorafenib and sunitinib might be related to PDGFR inhibition and not VEGFR inhibition. Our safety data with bevacizumab, an anti-VEGF agent, are consistent with this hypothesis.

Further clinical reports are required to determine whether bevacizumab can be safely used in cancer patients with IBDs.

REFERENCES

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  • 1
    Weedon DD, Shorter RG, Ilstrup DM, et al. Crohn's disease and cancer. N Engl J Med. 1973; 289: 10991103.
  • 2
    Winawer SJ, Schottenfeld D, Flehinger BJ. Colorectal cancer screening. J Natl Cancer Inst. 1991; 83: 243253.
  • 3
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350: 23352342.
  • 4
    Loriot Y, Boudou-Rouquette P, Billemont B, et al. Acute exacerbation of hemorrhagic rectocolitis during antiangiogenic therapy with sunitinib and sorafenib. Ann Oncol. 2008; 19: 1975.
  • 5
    Ducreux M, Bennouna J, Hebbar M, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2010 [Epub ahead of print].
  • 6
    Krzystek-Korpacka M, Neubauer K, Matusiewicz M. Platelet-derived growth factor-BB reflects clinical, inflammatory and angiogenic disease activity and oxidative stress in inflammatory bowel disease. Clin Biochem. 2009; 42: 16021609.
  • 7
    Kumagai S, Ohtani H, Nagai T, et al. Platelet-derived growth factor and its receptors are expressed in areas of both active inflammation and active fibrosis in inflammatory bowel disease. Tohoku J Exp Med. 2001; 195: 2133.

Romain Coriat MD, MSc* †, Olivier Mir MD, MSc*, Sarah Leblanc MD†, Stanislas Ropert XX*, Catherine Brezault MD, MSc†, Stanislas Chaussade MD, PhD†, François Goldwasser MD, PhD*, * CERIA (Centre for Research on Angiogenesis Inhibitors) Department of Medical Oncology Cochin Teaching Hospital Paris Descartes University Paris, France, † Gastroenterology Unit Cochin Teaching Hospital Paris Descartes University Paris, France.