Case Report

Oncology Pharmacy Practice

J Oncol Pharm Practice 18(1) 152154 ! The Author(s) 2011 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155211401455 opp.sagepub.com

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Retinal vein thrombosis in a patient with metastatic colon cancer receiving XELOX chemotherapy combined with bevacizumab pre-hepatic resection
Peter Gilbar
Cancer Care Services, Toowoomba Hospital, PMB 2, Toowoomba, Australia

Natacha Sorour
Cancer Care Services, Toowoomba Hospital, PMB 2, Toowoomba, Australia

Abstract Retinal vein thrombosis is a common vascular occlusive disorder of the retina responsible for varying degrees of vision impairment. It is an adverse effect rarely associated with cancer and its treatment. We report the case of a patient with metastatic colon cancer who developed central retinal vein thrombosis (CRVT) in the right eye following two cycles of chemotherapy with capecitabine and oxaliplatin (XELOX) plus bevacizumab given prior to hepatic resection. Despite cessation of chemotherapy, vision has not improved. The etiology of the CRVT in this case is not clear due to risk factors for venous thrombotic events including colonic malignancy and previous major surgery. However, the proximity of chemotherapy administration to the initial development of symptoms suggests the possibility of a medication-related cause, with bevacizumab and capecitabine the most likely suspects.

Keywords Bevacizumab, capecitabine, colon cancer, oxaliplatin, retinal vein thrombosis

Introduction
Central retinal vein thrombosis (CRVT) is a common vascular occlusive disorder of the retina which can precipitate various degrees of visual loss. The pathogenesis of CVRT is multifactorial with both local factors and systemic diseases being etiologically important. Known risk factors include systemic vascular disease, hypertension, diabetes mellitus, hyperlipidemia, glaucoma, and primary and secondary hypercoagulable states, including malignancy.1 Several medications have been implicated in the development of retinal vein thrombosis (RVT), including medroxyprogesterone,2 interferonalpha, riboviran,3 and iniximab.4

hemicolectomy and anastomosis for an obstructing lesion at the splenic exure. Histology showed a moderately dierentiated adenocarcinoma inltrating through the bowel wall and into pericolic fat. Twelve of 30 sampled lymph nodes contained metastatic carcinoma. Computed tomography (CT) showed a 1.3-cm lesion in segment ve of the liver and this was conrmed on positron emission tomography. Neoadjuvant chemotherapy was commenced with XELOX (oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 given orally twice daily for 14 days) plus bevacizumab 7.5 mg/kg IV; all repeated every 3 weeks. Ondansetron and dexamethasone were prescribed for 2 days as anti-emetics. Following two cycles, the patient
Corresponding author: Peter Gilbar, Department of Pharmacy, Toowoomba Health Services, PMB 2 Toowoomba 4350, Australia. Email: peter_gilbar@health.qld.gov.au

Case report
Following Caucasian positive colonoscopy, a 50-year man underwent a laparoscopic old left

Gilbar and Sorour was referred to a metropolitan tertiary hospital, where distal pancreatectomy, splenectomy, and segment ve liver dissection were performed. Histology conrmed adenocarcinoma in the resected hepatic metastasis and clear resection margins. At a follow-up appointment, 6 weeks post-surgery, the patient described loss of vision in the right eye. Subsequent questioning revealed that he had suered transient blurred and decreased vision in his right eye following each of his two chemotherapy cycles which he had not previously reported. This lasted for 3 days post-cycle one and for 45 days following his second cycle. In each instance, visual problems started the day following chemotherapy. A persistent reduction in vision dated from the time of surgery. He was referred to an ophthalmologist who found a relative aerent pupillary defect with acuity in the right eye of 6/36. Further examination revealed signicant right disc edema with associated fundal hemorrhages, dilated and tortuous retinal veins, and macular edema, consistent with a diagnosis of CRVT. CT of the brain and orbits showed no abnormalities. No specic ophthalmic intervention was suggested with vision deemed unlikely to improve. Anticoagulation was not felt to be benecial at this stage. The case was discussed with oncology colleagues and a decision was made not to proceed with adjuvant chemotherapy, given the risk that potential further thrombosis involving the left eye would render the patient legally blind. He is currently being monitored closely for signs of disease recurrence.

153 safety and ecacy of two doses of bevacizumab plus uorouracil/leucovorin versus uorouracil/leucovorin alone, one case of RVT was reported in the control arm.8 Capecitabine is an oral uropyrimidine which is converted to uorouracil in tumor tissue via a threestep enzymatic process.9 Data pooled from ve randomized controlled trials involving 1745 patients showed that combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk of an arterial thromboembolic event but not for venous thromboembolic events.10 The rate of Grade 3/4 venous thromboembolism was 9.97% among bevacizumab-treated patients and 9.85% among the control group which involved various treatments with capecitabine, uorouracil/leucovorin, oxaliplatin, paclitaxel, and carboplatin. The incidence of particular venous thromboembolic events, specically RVT, was not mentioned. A systematic review and meta-analysis of 15 randomized trials, involving 7956 patients, assessed the risk of venous thromboembolism associated with the use of bevicizumab.11 In a variety of advanced solid tumors, the incidence of all-grade and high-grade venous thromboembolism were 11.9% and 6.3%, respectively, with a relative risk (RR) of 1.29 and 1.38 compared to controls. In colorectal cancer, this was 19.1% (RR 1.19) and 7.3% (RR 1.56), respectively. The etiology of the RVT in this case is not clear. The patient had risk factors for venous thromboembolic events with the colonic malignancy and previous major surgery. However, the proximity of chemotherapy administration to the initial development of symptoms lends itself to the probability of a medicationrelated event. Anti-neoplastic therapy, involving all three drugs both alone and in various combinations, has been implicated in the development of venous thrombosis, though not specically CRVT. The FU pro-drug, capecitabine, presents as a possible suspect as FU has been reported to cause CVRT. Oxaliplatin appears to be the least likely drug cause as in phase II single agent studies of oxaliplatin in colorectal cancer, involving 134 patients, there were no reports of thromboembolic events.12,13 The possible role of bevacizumab as an aetiological cause in this patients CVRT is uncertain but seems the most likely culprit due to its propensity for causing venous thromboembolic events both alone and in conjunction with chemotherapy. While visual loss had occurred prior to major surgery following completion of neo-adjuvant therapy, this may have contributed to the severity of the event. In conclusion, RVT is a potentially serious complication of chemotherapy. Although rare, clinicians using bevacizumab and/or uoropyrimidines should be aware of this possibility.

Discussion
Clinically signicant hemostatic abnormalities, such as thrombosis and hemorrhage, may aect as many as 15% of cancer patients.5 The incidence of (CRVT) due to malignancy is unknown but has been reported in a patient with colon cancer.6 Previous medical history in our patient was not signicant for thrombotic risk factors other than cancer and surgery. He took no regular medications, was a life-long non-smoker, and had no other vascular risk factors. In a retrospective study of 206 cancer patients, 7.3% had proven venous thromboembolism during or within 3 months after chemotherapy. The incidence was specically high in colorectal cancer patients treated with the combination of uorouracil (FU) and leucovorin, with 6 of 39 (15%) aected.7 One case of RVT was reported in an ovarian cancer patient, seemingly due to carboplatin and cyclophosphamide. Thrombosis is a possible adverse eect of oxaliplatin, capecitabine, and bevacizumab; however, despite an extensive literature search, we were unable to nd any cases of RVT specically linked to any of these medications. In a phase II study investigating the

154 References
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Journal of Oncology Pharmacy Practice 18(1)

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