Annals of Oncology Advance Access originally published online on August 22, 2008
Annals of Oncology 2008 19(11):1975; doi:10.1093/annonc/mdn566
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letters to the editor |
Acute exacerbation of hemorrhagic rectocolitis during antiangiogenic therapy with sunitinib and sorafenib
Angiogenic inhibitors (AIs) have been found to increase survival and are approved in advanced renal cell carcinoma [1, 2]. Consequently, most of these patients will routinely receive these two tyrosine kinase inhibitors, sorafenib and sunitinib.The toxicity of these agents requires a deeper mechanistic understanding so that prevention and intervention strategies can be formulated. Here, we report the case of a man who was suffering from severe acute hemorrhagic rectocolitis (HRC) while treating with sunitinib and thereafter with sorafenib.
A 57-year-old man with a 20-year history of hemorragic rectocolitis controlled with oral corticosteroids and 5-aminosalicylates had one exacerbation per year. This patient was diagnosed a high-grade clear-cell renal carcinoma in September 2006 and was treated by right nephrectomy and surrenalectomy for recurrence in May 2007. Sunitinib was initiated in August 2007 as a standard regimen (50 mg/day for 4 weeks every 6 weeks) for pulmonary and left adrenal metastases. On the 11th day of the first course of sunitinib, he developed severe bloody diarrhea, left abdominal pain and generalized weakness. His body temperature was 37.8°C and he had lost 4 kg during the previous 11 days. Blood tests reveal lymphopenia (650/mm3), thrombocytopenia (83 000/mm3) and C-reactive protein elevation to 179 ng/ml. Stool cultures were negative. Contrast-enhanced computed tomography of the abdomen revealed marked left colon wall thickening and dilatation suggesting an acute ulcerative colitis associated with aspect of chronic colitis. A sigmoidoscopy examination revealed diffuse involvement of the rectum and sigmoid with erythema, petechia and swollen mucosa without deep ulceration. A rectal biopsy showed features of acute colitis with cryptitis, crypt abscess, lymphocytic infiltration and neutrophils infiltration and chronic colitis consistent with a diagnosis of ulcerative colitis. The patient recovered under oral corticosteroids and oral mesalamine. He was discharged 2 weeks later. At the end of September 2007, in replacement for sunitinib he was given sorafenib, another vascular endothelial growth factor receptor inhibitor at dose of 400 mg twice daily. Ten days later, he developed symptomatic hand–foot syndrome leading to discontinuation of sorafenib. Rechallenge at a dose of 400 mg/day resulted in the reappearance of similar symptoms at day 10. Then, he was given sorafenib at dose 200 mg daily. Two weeks later, he developed subsequent HRC exacerbation with 12 bloody stools/day and definitively discontinued antiangiogenic therapy. The patient recovered without sequelae.
In our case, the onset of HRC exacerbation was clearly associated with sunitinib and sorafenib because clinical, radiological and histopathological findings were suggestive of HRC exacerbation and there were positive dechallenge and rechallenge tests. This strongly suggests that antiangiogenic therapies worsen HRC. These clinicopathological typical findings indicate that AIs may induce HRC acute exacerbation. Both immunological hypersensitivity and vascular abnormalities are implicated in the pathogenesis of HRC, and vascular endothelial growth factor appears as regulator of mucosal immune-driven angiogenesis [3, 4]. Intestinal damage might be followed by either physiological or pathological angiogenesis. On the basis of animal models, AIs were proposed as treatments for HRC [3, 4]. Patients with cancer and HRC treated with AIs will need close collaboration between oncologists and gastroenterologists with aggressive supportive treatment.
Department of Oncology, Faculty of Medicine, Paris Public Assistance Hospital, Cochin Hospital, Paris V University, Paris, France
* (E-mail: y.loriot{at}voila.fr)
References
1. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med (2007) 356:125–134.
2. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med (2007) 356:115–124.
3. Binion DG, West GA, Volk EE, et al. Acquired increase in leucocyte binding by intestinal microvascular endothelium in inflammatory bowel disease. Lancet (1998) 352:1742–1746.[CrossRef][Web of Science][Medline]
4. Gaya DR, Russell RK, Nimmo ER, Satsangi J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet (2006) 367:1271–1284.[CrossRef][Web of Science][Medline]
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