Capecitabine is an orally administered prodrug that converts preferentially to 5-fluorouracil within tumors, resulting in enhanced concentrations of 5-fluorouracil in tumor tissue. The use of capecitabine has shown efficacy in the metastatic setting for breast cancer, and more recently, efficacy as adjuvant therapy for triple-negative breast cancer (TNBC). Capecitabine has been shown to be well tolerated with minimal side effects, but the incidence of leukoencephalopathy is rare with a risk of less than one percent.
Case report
We report on a 34-year-old female patient with left TNBC, moderately differentiated, stage IIB that experienced symptoms of neurotoxicity following initiation of adjuvant chemotherapy with capecitabine.
Management and outcome
Naranjo Algorithm Assessment score of nine indicated patient had drug-induced leukoencephalopathy leading to discontinuation of capecitabine and resolution of the neurotoxicity symptoms.
Discussion
Early detection of capecitabine-induced neurotoxicity by magnetic resonance imaging is crucial as symptoms may be reversible to the condition that capecitabine is immediately discontinued.
DenkertCLiedtkeCTuttA, et al.Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet2017; 389: 2430–2442.
2.
FoulkesWDSmithIEReis-FilhoJS. Triple-negative breast cancer. N Engl J Med2010; 363: 1938–1948.
3.
WaksAGWinerEP. Breast cancer treatment: a review. JAMA2019; 321: 288–300.
4.
MasudaNLeeSJOhtaniS, et al.Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med2017; 376: 2147–2159.
5.
CassidyJTwelvesCVan CutsemE, et al.First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol2002; 13: 566–575.
6.
PirzadaNAAliIIDafarRM. Fluorouracilinduced neurotoxicity. Ann Pharmacother2000; 34: 35–38.
7.
SavareseDMGordonJSmithTW, et al.Cerebral demyelination syndrome in a patient treated with 5-fluorouracil and levamisole. Cancer1996; 77: 387–394.
8.
FigueredoATFawcetSEMolloyDW, et al.Disabling encephalopathy during 5-fluorouracil and levamisole adjuvant therapy for resected colorectal cancer. A report of two cases. Cancer Invest1995; 13: 608–611.
9.
Genentech USA. Inc.Capecitabine (package insert). South San Francisco: Genentech USA. Inc, 2015.
10.
HennessyBTGauthierAMMichaudLB, et al.Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature. Ann Oncol2005; 16: 1289–1296.
11.
NishijimaTFSuzukiMMussHB. A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat2016; 156: 227–236.
12.
NaranjoCABustoUSellersEM, et al.A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther1981; 30: 239–245.
13.
NiemannBRochlitzCHerrmannR, et al.Toxic encephalopathy induced by capecitabine. Oncology2004; 66: 331–335.
14.
YoshimuraKTokunagaSDagaH, et al.Capecitabine-induced leukoencephalopathy. Intern Med2019; 58: 621–622.
15.
ObadiaMLeclercqDWassermanJ, et al.Capecitabine-induced acute toxic leukoencephalopathy. Neurotoxicology2017; 62: 1–5.
16.
VidenovicASemenovIChua-AdajarR, et al.Capecitabine-induced multifocal leukoencephalopathy: a report of five cases. Neurology2005; 65: 1792–1794.
17.
BaehringJMFulbrightRK. Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry2008; 79: 535–539.
18.
EndoAYoshidaYNakashimaR, et al.Capecitabine induces both cardiomyopathy and multifocal cerebral leukoencephalopathy. Int Heart J2013; 54: 417–420.
19.
ShimoyamaRBanTMiyakeK. Early diagnosis of capecitabine-induced acute leukoencephalopathy by using diffusion-weighted MRI. Gan To Kagaku Ryoho2014; 41: 1251–1253.
20.
FantiniMGianniLTassinariD, et al.Toxic encephalopathy in elderly patients during treatment with capecitabine: literature review and a case report. J Oncol Pharm Pract2011; 17: 288–291.
21.
LyrosEWalterSKellerI, et al.Subacute reversible toxic encephalopathy related to treatment with capecitabine: a case report with literature review and discussion of pathophysiology. Neurotoxicology2014; 42: 8–11.
22.
CouchLGroteluschenDLStewartJA, et al.Capecitabine-related neurotoxicity presenting as trismus. Clin Colorectal Cancer2003; 3: 121–123.
23.
BougeaAVoskouPKilidireasC, et al.Capecitabine induced multifocal leukoencephalopathy: do we have always to switch off the chemotherapy. Case Rep Oncol Med2016; 2408269: 1–3.
24.
CouchLSBGroteluschenDLStewartJA, et al.Capecitabine related neurotoxicity presenting as trismus. Clin Colorectal Cancer2003; 3: 121–123.
25.
DeVitaVTJrHellmanSHRosenbergSA. Cancer principles & practice of oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001.
26.
VanCEFindlayMOsterwalderB. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol2000; 18: 1337–1345.
27.
RechtLDPrimaveraJM. Neurologic disorder in a 65-year-old man after treatment of colon cancer. N Engl J Med1999; 341: 512–519.
28.
WeissHDWalkerMDWiernikPH. Neurotoxicity of commonly used antineoplastic agents. N Engl J Med1974; 291: 75–81.
29.
AokiN. Reversible leukoencephalopathy caused by 5-fluorouracil derivatives presenting as akinetic mutism. Surg Neurol1986; 25: 279–282.
30.
BofillJSChavesMMorenoJA. Fluorouracil-induced aphasia. Ann Pharmacother2000; 34: 955.
31.
WilksABSaifMW. First case of foot drop associated with capecitabine in a patient with thymidylate synthase polymorphism. Cureus2017; 9: e995.
32.
TanMB-WMcAdoryLE. Capecitabine-induced leukoencephalopathy involving the bilateral corticospinal tracts. J Radiol Case Rep2016; 10: 1–10.
33.
TommasoNNicolettiTSpagniG, et al.Teaching neuroImages: transient mutism associated with splenium lesion in capecitabine-induced leukoencephalopathy. Neurology2019; 92: 1000–1001.
34.
DesmoulinFGilardVMalet-MartinoM, et al.Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos2002; 30: 1221–1229.
35.
HeierMSHeintzRFossaSD. Passage of 5′-dFUrd and its metabolites 5-FU and 5-FUH2 to CSF in a clinical phase 1 study. Acta Neurol Scand1986; 74: 240–244.
36.
NakagawaHYamadaMFukushimaM, et al.Intrathecal 5-fluoro-2′-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study. Cancer Chemother Pharmacol1999; 43: 247–256.
37.
KonstantinosMAlexandraGEfthimitosS, et al.Thymidine phsphorylase expression in patient with chronic viral hepatitis. Rom J Gastroenterol2005; 1: 27–31.
38.
ShimadaMHasegawaHRikimaruT. The significance of thymidine phosphrylase activity in hepatocellular carcinoma and chronic disease livers: a special reference to liver fibrosis and multicenter tumor occurrence. Cancer Lett2000; 148: 165–172.
39.
MoghaddamAZhangHTFanTP. Thymidine phosphorylase is a ngiogenic and promotes tumor growth. Proc Natl Acad Sci U S A1995; 92: 998–1002.
40.
EvrardACuqPCiccoliniJ, et al.Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human colorectal cancer cells transfected with thymidine phosphorylase. Br J Cancer1999; 80: 1726–1733.
41.
HeidelbergerCChaudhuriNKDannebergP, et al.Fluorinated pyrimidines: a new class of tumor inhibitory compounds. Nature1957; 179: 663–666.
42.
XiePMoJLLiuJH, et al.Pharmacogenomics of 5-fluorouracil in colorectal cancer: review and update. Cell Oncol (Dordr)2020; 43: 989–1001.
43.
ThierryLJean-MarcFFranckZ, et al.Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res2004; 10: 5880–5888.
MattisonLKFourieJDesmondRA, et al.Increased prevalence of dihydropyrimidine dehydrogenase deficiency in african-Americans compared with caucasians. Clin Cancer Res2006; 12: 5491–5495.
47.
TanMMcAdoryLE. Capecitabine-induced leukoencephalopathy involving the bilateral corticospinal tracts. J Radiol Case Rep2016; 10: 1–10.
48.
Renouf D and Gill S. Capecitabine-induced cerebellar toxicity. Clinical Colorectal Cancer 2006; 6: 70–71.
