Hypertriglyceridemia: An underdiagnosed side effect of Capecitabine chemotherapy

To the Editor

A 57-year-old patient was diagnosed with a stage II adenocarcinoma of the caecum.

He elected to have adjuvant chemotherapy with capecitabine, 2 500mg/m² divided in two daily doses for 14 days on a 21 day cycle for eight cycles. No significant comorbidities were reported.

He tolerated the treatment well, experiencing only grade1 nausea and grade1 palmar-plantar erythrodysesthesia after the fourth cycle of chemotherapy. After the sixth cycle, high levels of triglycerides were identified (891 mg/dl) as well as moderately elevated blood sugar (181 mg/dl); Hba1c was 8.9 mg/dl, with normal cholesterol. pretreatment baseline triglyceride levels were not measured but one year before they were 89 mg/dl. The patient was then prescribed omega-3 fatty acids 1 000 mg three times a day and metformin 500 mg twice daily (to lower the triglycerides and glucose levels respectively) and proceeded to the next cycle of capecitabine. At the end of the seventh cycle of chemotherapy, the level of triglycerides increased to 1 100 mg/dl. Omega-3 fatty acids were discontinued and bezafibrate 400 mg twice daily was commenced. One month after the end of the eighth cycle, triglyceride levels dropped to 152 mg/dl and glucose to 112 mg/dl.

Causes of secondary hypertriglyceridemia include uncontrolled diabetes mellitus, hypothyroidism, obesity and nephrotic syndrome. Several medications can also induce trglyceride elevation such as beta blockers, glucocorticoids, thiazides, estrogen, anti-psychotics and bile acid binding resins as well as drugs used in oncology, mainly tamoxifen, protease and mTOR inhibitors, some immunosuppressants, interferon, L-asparaginase and bexarotene [1]. According to the manufactuter's product information [2], capecitabine is rarely (>0.1% to <1%) associated with grade 3 (5–10-fold) or 4 (< 10-fold increase above the upper normal limit) elevation in serum triglycerides. Acute pancreatitis, which can be a complication of high triglycerides, has been reported as a side effect of capecitabine [3].

Sela and Heim report the case of a woman with metastatic breast cancer who developed severe hyper-triglyceridemia (3 090 mg/dl) after two cycles of capecitabine chemotherapy [4]. Koutras et al. report two cases (breast and colon cancer) with triglyceride levels (1 409 mg/dl and 1 510 mg/dl after seven and two cycles of treatment, respectively) [5] while Kurt et al. presented another two cases with breast and colon cancer with triglyceride levels of 916 mg/dl and 1 455 mg/dl after two and five cycles of chemotherapy, respectively [6]. They also retrospectively reviewed the data of 40 patients treated with capecitabine and found that average triglyceride levels increased significantly (137.1 ±76.3 vs. 204.5 ± 125.2 mg/dl; p < 0.001, before and after capecitabine respectively). Finally, Stathopoulos et al. observed hypertriglyceridemia in five of 12 patients whose triglyceride levels were tested, who were treated for advanced breast and colon cancer with capecitabine monotherapy [7]. An interesting observation in some of the cases described above, including our patient is the resistance of hypertriglyceridemia to the lipid lowering treatment when capecitabine was not withheld.

The etiology of capecitabine-induced hypertriglyceridemia is basically unknown. Capecitabine itself or its metabolites prior to the formation of 5-fluo-rouracil (5-FU) is probably responsible because 5-FU has been shown to decrease the level of serum lipids [8]. Hereditary lipoprotein lipase deficiency due to genetic polymorphisms or a drug-enzyme interaction could be the underlying pathogenic mechanism. Alterations in lipid profile and glucose levels observed in some patients raises the suspicion that these abnormalities may represent part of the metabolic syndrome. In addition to capecitabine, hypertriglyceridemia in this patient was probably exacerbated by uncontrolled diabetes.

In conclusion, cancer patients treated with capecitabine should be closely monitored for the development of hypertriglyceridemia especially those with already diagnosed dyslipidemia. It seems that this represents an underdiagnosed side effect of capecitabine chemotherapy and physicians need to be alert to identify these patients and apply the appropriate treatment early enough to avoid potential complications.