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Hypertriglyceridemia and hyperglycemia induced by capecitabine: A report of two cases and review of the literature Gao-hua Han and Jun-Xing Huang J Oncol Pharm Pract published online 29 April 2014 DOI: 10.1177/1078155214532508 The online version of this article can be found at: http://opp.sagepub.com/content/early/2014/04/29/1078155214532508

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Case Report

Hypertriglyceridemia and hyperglycemia induced by capecitabine: A report of two cases and review of the literature

J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214532508 opp.sagepub.com

Gao-hua Han and Jun-Xing Huang

Abstract Background: Capecitabine is a tumor-activated oral fluoropyrimidine used in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. Methods: Two patients with colorectal carcinoma who developed capecitabine-induced hypertriglyceridemia (including a patient who developed hyperglycemia concurrently) were described, treatment modalities were discussed, and the literatures were reviewed. Results: The first patient, a 43-year-old man, developed hyperlipidemia and hyperglycemia after two cycles of XELOX regimen chemotherapy for colorectal cancer. His triglyceride was 2.47 mmol/L (normal range 0.34–1.7 mmol/L) and total cholesterol was 6.93 mmol/L (normal range 3.12–5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58–11.9 mmol/L and 2 h postprandial glucose was 14.5–17.2 mmol/L) and glucose was positive in the urine(3+). The second patient, a 47-year-old woman, developed abnormalities in the lipid profile after the sixth cycle of XELOX regimen chemotherapy for colorectal cancer. Her serum triglyceride was 2.41 mmol/L (normal range 0.34–1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12–5.9 mmol/L). The profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. The Naranjo score for capecitabine-induced hypertriglyceridemia was 9 (definite). An analysis of the underlying pathogenic mechanisms was provided. Conclusion: It is important of physicians and pharmacists to be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia induced by capecitabine.

Keywords Hypertriglyceridemia, hyperglycemia, capecitabine, colorectal carcinoma

Introduction Capecitabine (Xeloda), a prodrug of cytotoxic agent 5-fluorouracil (5-FU), is commonly used in the treatment of metastatic gastric cancer, breast cancer, and colorectal carcinoma. It is associated with a variety of common adverse effects including diarrhea, plantarpalmar erythrodysesthesia, and nausea but infrequently associated with severe hypertriglyceridemia, especially rarely with hyperglycemia. When looking at the literature, we found disruptions in the lipid profile in 21 cases from 10 papers1–10 and concomitant hyperglycemia in five cases from four papers.1,3,8,9 In this report, we present two patients with capecitabine-induced

hypertriglyceridemia (CI-HTG), including one patient with concomitant hyperglycemia and review the literature (published reports).

Department of Oncology, The People’s Hospital of Taizhou, Taizhou Medical School, Jiangsu and Nantong University, Jiangsu, China Corresponding author: Jun-Xing Huang, Department of Oncology, The People’s Hospital of Taizhou, Taizhou Medical School, Jiangsu and Nantong University, No. 210, Yingchun Road, Taizhou 225300, Jiangsu Province, China. Email: [email protected]

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Case report Case 1 A 43-year-old man with colorectal cancer. The patient had received rectectomy for stage III colon cancer. Postoperative pathology examination showed that signet ring cell carcinoma had been invaded through the rectum wall to the adipose tissue with seven lymph nodes positive in a total of 12. The patient was started on first-line chemotherapy with raltitrexed (3 mg/m2, every 21 days) and oxaliplatin (130 mg/m2, every 21 days). After two cycles of chemotherapy, he received concurrent radiotherapy. There was no hyperlipidemia, obesity, or diabetes mellitus in the patient’s medical history. Before the initiation of chemotherapy, the patient’s lipid profile and blood glucose levels were in the normal range. After the third cycle of chemotherapy and radiotherapy, severe marrow depression appeared (white blood cell count was 0.9  109/L), and then XELOX was performed as the fourth and fifth cycle chemotherapy regimen, including capecitabine (1000 mg/m2 bid d1–14, every 21 days) and oxaliplatin (130 mg/m2, every 21 days). Before the XELOX regimen, his lipid profile and blood glucose levels were still normal. After one cycle of XELOX regimen chemotherapy, his triglyceride and total cholesterol serum levels were normal, while the low-density lipoprotein cholesterol level rose to 3.4 mmol/L (normal range 0–3.12 mmol/L) and the blood glucose was 5.8 mmol/L (normal range 3.89–5.9 mmol/L). Three weeks later, after two cycles of XELOX regimen chemotherapy, the lipid profile evaluation revealed elevation of triglycerides (2.47 mmol/L, normal range 0.34–1.7 mmol/L) and total cholesterol levels (6.93 mmol/L, normal range 3.12–5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58–11.9 mmol/L and 2 h postprandial glucose was 14.5–17.2 mmol/L) and glucose was positive in the urine(3+). Changes in diet, weight gain, alcohol intake, and other causes of acute hyperlipidemia were excluded. The patient did not receive steroids during treatment. In a further laboratory examination, glycosylated hemoglobin was 5.1% and islet cell antibody, insulin antibody, and glutamic acid hydroxyl enzyme antibody showed negative. XELOX regimen was terminated and the alternative FOLFOX4 regimen was administered for two cycles without lipidlowering drug or hypoglycemic drug. Two months later, levels of triglycerides and cholesterol decreased rapidly and fell to levels of 1.45 mmol/L and 5.6 mmol/L, respectively. The patient’s blood glucose remained higher than normal level (fasting blood glucose was 6.53–7.25 mmol/L), but glucose was negative in the urine.

A 47-year-old woman with adenocarcinoma at the junction of rectum and sigmoid colon. Postoperative pathology examination revealed invasive, poorly differentiated adenocarcinoma, grade III, T3N1M0. After surgery, a six-cycle XELOX regimen was administered, including capecitabine (1000 mg/m2 bid d1-14, every21 days) and oxaliplatin (130 mg/m2, every 21 days). Radiation therapy was refused by the patient. The lipid profile at the beginning of chemotherapy was in normal range. There was no history of diabetes mellitus or hyperlipidemia. Hyperlipidemia and anemia were found before the seventh cycle of capecitabine; her serum triglyceride level was 2.41 mmol/L (normal range 0.34–1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12–5.9 mmol/L) and the hemoglobin was 70 g/L. At the same time, a cumulative peripheral neurotoxicity was observed (grade 3 neurotoxicity presented as numbness of lower limb and plantar heel pain). Due to the side reaction, only oral capecitabine was given in the remaining two cycles of chemotherapy regimen (capecitabine 750 mg/m2 bid d1-14, every 21 days) without lipid-lowering drug. After the eighth cycle of chemotherapy, the lipid profile evaluation revealed reduction of triglycerides (2.07 mmol/L, normal range 0.34–1.7 mmol/L) and cholesterol (6.52 mmol/L, normal range 3.12– 5.9 mmol/L). Diet control (restrictive daily intake of carbohydrates) and appropriate physical exercises were advised; her abnormal triglyceride and cholesterol were restored to normal levels within two months after the chemotherapy. In following up, the patient had a normal lipid profile and a normal glucose level.

Discussion Capecitabine is an orally administered, enzymeactivated fluoropyrimidine carbamate designed to generate high levels of 5-FU in tumor cells.11 Hypertriglyceridemia is a rare side effect of capecitabine treatment. By National Cancer Institute Common Toxicity Criteria, grade 3 or 4 hypertriglyceridemia is listed as an uncommon (0.1% to 1%) toxicity.12 The mechanism of CI-HTG is basically unknown. It may be due to capecitabine-induced reduction in the activity of lipoprotein lipase and hepatic triglyceride lipase.13 It is well known that capecitabine is metabolized by carboxylesterase to 5-deoxy-5-fluorocytidine which is then converted by cytidine deaminase to 5-deoxy-5-fluorouridine and finally converted by thymidine phosphorylase to 5-FU.14 Because a previous study investigating the effect of 5-FU on serum lipid levels showed a significant reduction of the total cholesterol in both patients and animals,13

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Table 1. Scores for individual axes of the Naranjo Adverse Drug Reactions Probability Scale. Axis Previous reports on the reaction Temporal illegibility in the onset of the reaction Inprovement after drug withdrawal Positive re-challenge Exclusion of alternative causes for the adverse drug reaction Placebo response Drug concentration and monitoring Dose relationship Previous exposure and cross reactivity Presence of any objective evidence Results

Numerical score

Yes

No

Unknown

0–1 1–2 0–1 1–2 1–2 0–1 0–1 0–1 0–1 0–1

1 2 1 2 1 1 1 1 1 1

0 1 0 1 2 1 0 0 0 0

0 0 0 0 0 0 0 0 0 0

CI-HTG score

CI-HGC score

+1 +2 +1 +2 +2 0 0 +1 0 0 9

+1 +2 +1 0 0 0 0 0 0 0 4

CI-HTG: capecitabine-induced hypertriglyceridemia. The adverse drug reaction are assigned to a probability category on the basis of the total score as ‘‘definite’’ ¼ 9, ‘‘likely’’ ¼ 5–8, ‘‘possible’’ ¼ 1–4, ‘‘unlikely’’ ¼ 0.

hypertriglyceridemia may be attributed either to capecitabine itself or to precursor of 5-FU. The second possible underlying pathogenic mechanism of CI-HTG may be pancreatic damage/pancreatitis caused by capecitabine.15 It is possible that capecitabine may cause low-grade undetected pancreatic inflammation, and this inflammation may be the reason for the observed hyperglycemia and hypertriglyceridemia. The first case of our patients received raltitrexed and oxaliplatin treatment before XELOX regimen; therefore, it may be argued that the hypertriglyceridemia in this case may be a side effect of raltitrexed or oxaliplatin. However, this possibility can be ruled out as the laboratory tests of the subject showed normal lipid profiles before and after the chemotherapy with raltitrexed and oxaliplatin. Hypertriglyceridemia was presented after two cycles of XELOX, and when capecitabine was withdrawn, hypertriglyceridemia was controlled whilst the oxaliplatin was continued, indicating that capecitabine was involved in hypertriglyceridemia. According to Naranjo’s Adverse Drug Reaction Probability Scale, The Naranjo score for CI-HTG was 9 (definite) (Table 1). CI-HTG occurred between the second and the eighth cycle of capecitabine treatment, especially commonly occurred after the sixth cycle of capecitabine.2,4,7,9–12 The disruptions in the lipid profile of our patients conformed to this published observation. Capecitabine-induced hyperglycemia (CI-HGC) is very rare. Garg et al.9 reported the first case of capecitabine-induced hypertriglyceridemia and diabetes. Merely five cases have been thus far reported. The pathogenesis of capecitabine-induced hyperglycemia is unclear. According to the negative expression of antibodies associated with diabetes (such as islet cell

antibody, insulin antibody, and glutamic acid hydroxyl enzyme antibody) when hyperglycemia emerged in the first case of our patients, it is obvious that there has no diabetes mellitus induced by capecitabine. No previous evidence was found to imply that capecitabine may disturb the metabolism of glucose. The underlying mechanism may be that capecitabine lowered the threshold for diabetes in a patient with altered glucose homeostasis. The Naranjo score for capecitabine-induced hyperglycemia was 4 (possible) (Table 1). According to the literatures, in the cases of severe CI-HTG, the treatment of capecitabine should be discontinued and the lipid-lowering agents such as statins be administered.2,3,7–14 But in our cases, the profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. It implied that the mild CI-HTG should be reversible.

Conclusion Although the incidence is low, it is highly likely that dyslipidemia was caused by capecitabine (the Naranjo score was 9). As the lipid profile is not routinely performed in cancer patients, CI-HTG may remain underestimated. It is important for physicians and pharmacists to be aware of possible dyslipidemia; therefore, monitoring of the lipid profile should be considered in cancer patients receiving capecitabine.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Conflict of interest None declared.

Acknowledgments The authors are grateful to Dr Xueliang Han for his assistance with the manuscript preparation.

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