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Capecitabine-related cardiotoxicity: recognition and management

Muhammad Wasif Saif, MD, Megumi Tomita, MD, Leslie Ledbetter, RN, and Robert B. Diasio, MD the other hand, the most common grade 3 tox-icities were lymphopenia (44%); diarrhea (12%); proved by the US Food and Drug Ad-ministration (FDA) for first-line therapy HFS (11%); hyperbilirubinemia (9%); fatigue in patients with stage III or IV colorectal (8%); stomatitis (7%); and abdominal pain, nau- cancer when single-agent fluoropyrimidine thera- sea, vomiting, ileus, and dehydration (4%); grade py is preferred. It also is approved as monotherapy 4 toxicity reported in the same population was for treating metastatic breast cancer in patients mainly hematologic and included lymphopenia resistant to both anthracycline- and paclitaxel- (15%), neutropenia (2%), and thrombocytopenia based regimens or in those for whom further an- thracycline treatment is contraindicated; in ad- Cardiovascular toxicities related to 5-fluoro- dition, it may be used with docetaxel (Taxotere) uracil (5-FU) are rare but potentially significant; after failure of prior anthracycline-based che- they are manifested by signs and symptoms of motherapy.1–6 The drug also has been studied in myocardial ischemia and angina.10 This adverse patients with prostate, pancreatic, renal cell, and reaction has not been reported frequently with the use of capecitabine11—but the potential for All patients with colorectal or breast cancer who have received 2,500 mg/m2/d of capecitabine At the University of Alabama, Birmingham in two divided doses for 14 days followed by 1 Comprehensive Cancer Center, we observed two drug-free week have experienced adverse events. patients (Table 1; Patients 3 and 4) who developed Effects occurring in more than 25% of these pa- cardiotoxicity during capecitabine administration. tients included anemia, nausea, vomiting, diar- Thereafter, we performed a literature review that rhea, abdominal pain, hand-foot syndrome (HFS), identified reports of capecitabine-associated car- fatigue/weakness, dermatitis, and hyperbilirubi- diotoxicity (Tables 2 and 3).12–19 This prompted nemia. The most common grade 3 toxicities in us to perform a retrospective review of patients colorectal cancer patients were hyperbilirubine- treated with capecitabine between April 2003 and mia (18%); HFS (17%); diarrhea (13%); abdomi- November 2004 under one oncologist who treated nal pain (9%); and nausea, vomiting, ileus, and breast cancer and another who specialized in gas- fatigue (4%); the most common grade 4 toxicities trointestinal (GI) oncology after receiving institu- were hyperbilirubinemia (5%) and neutropenia tional review board approval. Herein, we report and diarrhea (2%). Other grade 4 adverse events our experience with seven cases of cardiotoxicity that occurred in 1% or fewer included vomiting, associated with the use of capecitabine.
stomatitis, abdominal pain, constipation, ileus, Data Analysis
anorexia, dehydration, cough, venous thrombo-sis, and anemia. In patients with breast cancer, on A search of the pharmacy database identified patients treated with capecitabine for a solid ma-lignancy during this period; in addition, a review of electronic charts was performed. When a car- diac event in a patient on capecitabine was iden- Correspondence to: M. Wasif Saif, MD, Associate Professor, tified, the individual’s paper chart was searched Yale University School of Medicine, Section of Medical On- for details including, but not limited to, laboratory cology, 333 Cedar Street, FMP 116, New Haven, CT 06520; tests (eg, cardiac enzymes), electrocardiogram telephone: (203) 737-1875; fax: (203) 785-3788; email: wasif.
(ECG), multiple gated acquisition (MUGA) scan, and reports of a stress test, if performed. Six pa- 2008 Elsevier Inc. All rights reserved.
Capecitabine-related Cardiotoxicity: Recognition and Management Table 1
Description of Seven Patients Developing Capecitabine-Associated Cardiotoxicity
Abbreviations: XRT = radiation therapy; ECG = electrocardiogram; F = female; M = male; CK = creatinine kinase; CK–MB = creatine kinase–myocardial band isoenzyme; LVEF = left ventricular ejection fraction; NTG = nitroglycerin; SL = sublingual; Tc-99m MIBI - technetium-99m sestamibi; MUGA = multiple gated acquisition; LCA = left coronary artery; RCA = right coronary artery; EF = ejection fraction; TTE = transthoracic echocardiogram; LVH = left ventricular hypertrophy; RVH = right ventricular hypertrophy; RVEF = right ventricular ejection fraction; N/A = not available; CAD = coronary tients were identified from our clinic; a seventh patient was using an ex vivo radioisotopic assay using lysates of peripheral referred to our institution for deoxypyridinoline (DPD) assay blood mononuclear cells.20,21 To minimize variation resulting after developing cardiac side effects when using capecitabine from a circadian rhythm in DPD activity, 60 mL of whole blood was drawn from a peripheral vein into heparinized vacu- Cardiotoxicity was defined as angina-like symptoms, includ- tainers at approximately 12 pm. Peripheral mononuclear cells ing chest pain, shortness of breath, palpitations, abnormal car- were isolated by separation on a Ficoll gradient and washed diac enzyme results, ischemic changes or arrhythmia on ECG, three times in an ice bath. The lysed cells then were centri- and abnormal stress test or cardiac catheterization results. Pa- fuged to remove cellular debris, and the cytosol was collected. tients’ histories were searched to rule out any other etiologies Subjects were considered to be DPD-deficient by radioassay for similar symptoms, such as esophageal spasm, etc.
when their peripheral blood mononuclear cell DPD activity Data collected included age, gender, diagnosis, dose of was < 0.18 nmol/min/mg protein.22–24 capecitabine used, predisposing risk factors, presenting symp- toms, laboratory results on cardiac enzyme levels, ECGs, echo-cardiograms, and results of stress tests and cardiac catheteriza- INCIDENCE
tions. Risk factors for ischemic heart disease were smoking, diabetes, hypertension, hypercholesteremia, and family history Overal , 7 of the 78 (9%) patients developed clinical symp- of ischemic heart disease. Information about discontinuation toms suggesting cardiac toxicity during capecitabine treatment.
of capecitabine and response to further medical management DEMOGRAPHICS
(eg, aspirin, nitrates, β-blockers, and calcium antagonists) also The median age was 63 years (range, 32–89 years). Further, 48 patients were male, and 30 were female; 63 were white, and MEASURING DPD TO EXPLORE PHARMACOGENETICS
Results of a DPD assay were collected from the Department The demographic characteristics of the seven patients who of Pharmacology and Toxicology. DPD activity was measured developed cardiac toxicity possibly related to capecitabine are Saif, Tomita, Ledbetter, and Diasio Table 1
Description of Seven Patients Developing Capecitabine-Associated Cardiotoxicity
Abbreviations: XRT = radiation therapy; ECG = electrocardiogram; F = female; M = male; CK = creatinine kinase; CK–MB = creatine kinase–myocardial band isoenzyme; LVEF = left ventricular ejection fraction; NTG = nitroglycerin; SL = sublingual; Tc-99m MIBI - technetium-99m sestamibi; MUGA = multiple gated acquisition; LCA = left coronary artery; RCA = right coronary artery; EF = ejection fraction; TTE = transthoracic echocardiogram; LVH = left ventricular hypertrophy; RVH = right ventricular hypertrophy; RVEF = right ventricular ejection fraction; N/A = not available; CAD = coronary described in Tables 1 and 4. This group included two males m²/d), and the remaining three patients received capecitabine and five females (mean age, 50 years; range, 39–65 years). The monotherapy (1,500–2,000 mg/m²/d). Patients developed car- diagnoses of these patients included stage IV breast cancer diac events after being on capecitabine for a median of 3.5 (Patients 1 and 7), locally advanced rectal cancer (Patients 3, 4, 5, and 6), and stage IV pancreatic cancer (Patient 2).
LABORATORY TESTS
SYMPTOMS
DPD activity was measured in Patients 1, 3, 4, and 7; all of Symptoms in all seven patients who developed cardiotox- these levels were normal (range, 0.182–0.688 nmol/min/mg icity included substernal chest pain and chest discomfort as- sociated with dyspnea, diaphoresis, or palpitations that led to Cardiac enzyme analyses were available for Patients 1, 3, 5, 6, and 7. Patients 1, 6, and 7 had elevated creatine kinase (CK) levels and/or CK–myocardial band (CK–MB) levels. RISK FACTORS
However, none of the patients had significantly elevated tro- No patients had pre-existing documented heart disease (ie, ponin levels (range, 0.1– 0.2 ng/mL; Table 1).
ischemic heart disease, myocardial infarction, arrhythmia, hy-pertension). Patient 6 had cardiac risk factors (ie, smoking, ADDITIONAL TESTS
family history of heart disease). Patient 7 had breast cancer Among five patients who underwent ECG when experi- and had used anthracycline and paclitaxel previously. Patient encing pain, only three showed abnormalities. Patient 1 had 3 had a remote history of smoking, and Patient 2 had a history sinus tachycardia with hyper T waves in anterolateral leads, Patient 6 had T-wave inversion in leads III and IV, and Pa-tient 7 experienced atrial fibrillation with a rapid ventricular DOSE AND RESPONSE DURATION OF CAPECITABINE
rate. Two patients did not have an ECG done on the day that All four rectal cancer patients received concomitant radio- they experienced chest pain; their subsequent ECGs did not therapy with a radiosensitizing dose of capecitabine (1,650 mg/ show any abnormalities. An ECG initially was not performed Capecitabine-related Cardiotoxicity: Recognition and Management Table 2
Reported Cases of Patients Developing Cardiotoxicity Secondary to Capecitabine
Abbreviations: 5-FU = 5-fluorouracil; F = female; M = male; N/A = not available; NTG = nitroglycerin; ECG = electrocardiogram; IV = intravenous; Tc-99m MIBI = technetium-99m sestamibi from Patient 4; however, an ECG performed on this patient daily. Other patients were placed on 81 mg of aspirin if they Patients 1 and 3 underwent cardiac stress tests, which RECHALLENGE
showed no evidence of ischemic disease. Patient 6 underwent cardiac catheterization, which revealed nonobstructive coro- Rechallenge using a lower dose of capecitabine was attempt- nary artery disease. A MUGA scan was performed in Patients ed in Patients 4, 5, and 6, who were diagnosed with advanced 6 and 7; no abnormalities were observed.
rectal cancer and were undergoing concurrent capecitabine and radiation therapy. The rechallenge dose of capecitabine was MEDICAL TREATMENT
lowered from 1,650 mg/m2/d to 1,200 mg/m2/d. Patient 6 devel- All patients had complete resolution of their symptoms af- oped recurrent chest pain with no ECG or enzymatic changes ter discontinuing capecitabine therapy. Patient 1 was treated after receiving five rechallenge doses of capecitabine. There- with 81 mg of aspirin, sublingual nitrates, and 12.5 mg of fore, capecitabine was stopped indefinitely in this patient.
metoprolol tartrate twice daily. Patient 6 received 82 mg of as- Patients 4 and 5 tolerated capecitabine with no recurrent pirin, 25 mg of an extended-release formulation of metoprolol cardiac symptoms and continued treatment for the duration succinate once daily, and 20 mg of atorvastatin (Lipitor) once Saif, Tomita, Ledbetter, and Diasio Table 3
Reported Series of Patients Developing Cardiotoxicity Secondary to Capecitabine
1,189 patients received capecitabine monotherapy 153 patients treated with capecitabine and oxaliplatin; chemoradiation given for rectal cancer and chemotherapy given for advanced colon cancer) MORTALITY
conclusion to be made. The association between cardiac dis- There were no cardiac-related deaths.
ease and risk factors with capecitabine-induced cardiotoxicity still is uncertain; however, close monitoring for cardiac abnor- Discussion
malities in patients with heart disease should be undertaken The incidence and risk factors associated with capecitabi- ne-induced cardiotoxicity are poorly defined. Our retrospec-tive chart review revealed that cardiotoxicity associated with SIGNS AND SYMPTOMS
capecitabine administration appeared to be a potentially sig- A 6% incidence of chest pain and a 0.1% incidence of nificant side effect akin to that noted with use of 5-FU (Table tachycardia and arrhythmia in patients using capecitabine 5).25 However, the incidence and severity of this toxicity are alone have been reported (Table 3).27 In our study, all patients developed angina-like symptoms. Akin to previous case re-ports,12,13,28 angina-like symptoms were the predominant pre- INCIDENCE
sentation in our review. ECG abnormalities suggesting isch- In our retrospective study, 9% of patients treated with capecitabine for a solid malignancy had cardiac events; no other obvious etiology was noted in five of these patients.
RISK FACTORS/USE WITH OTHER CARDIOTOXIC AGENTS
Van Cutsem et al’s18 retrospective analysis of 1,189 patients In a review of the published literature from 1969–2000 per- given capecitabine monotherapy noted a low incidence (3%) taining to 5-FU–related cardiotoxicity,29 we found that 19% of of capecitabine-related cardiotoxicity, including grade 3/4 car- patients who developed cardiotoxicity had a history of cardiac diotoxicity occurring in 0.8% of patients in the capecitabine arm and 0.7% in the 5-FU/leucovorin (LV) arm. One death related to capecitabine occurred in a patient with a history of ischemic heart disease. Heart failure developed in one patient in the 5-FU/LV arm. In breast cancer studies, cardiotoxicity occurred at a similar incidence (3%) in taxane-pretreated breast cancer patients without treatment-related death. How- ever, details concerning the temporal relationship of these toxicities with capecitabine treatment were not described.
Ng’s group19 examined cardiotoxicity in 153 patients treated with capecitabine and oxaliplatin (Eloxatin) in two prospec- tive advanced colorectal cancer trials. Ten patients (6.5%) developed cardiac events. One patient (0.7%) died suddenly, one patient developed cardiac failure with raised troponin I levels, and another developed ventricular tachycardia. The remaining seven patients (4.6%) experienced angina; one of three patients with elevated troponin I levels developed ven- The incidence of cardiotoxicity in our study was higher than that reported by prior investigators, although the retro- spective nature of the study and the small sample size allow no *Both received antianginal therapy and had complete resolution of symptoms.
Abbreviation: ECG = electrocardiogram Capecitabine-related Cardiotoxicity: Recognition and Management Table 5
Summary of 5-FU and Capecitabine-induced Cardiotoxicity
More common in those with CAD; mechanism is Risk increased for CAD, prior chest XRT, concomitant cisplatin therapy; rate- and dose- dependent; vasospasm is possible mechanism Abbreviations: CAD = coronary artery disease; XRT = radiation therapyAdapted from Eskilsson and Albertsson25 disease, and an additional 10% of patients had cardiac risk fac- fact, in a manner similar to that described by Aksoy et al,17 tors. In the present study, none of the seven patients with car- exertional chest pain was reproduced with capecitabine ther- diotoxicity had a history of heart disease, although Patient 6 apy in Patient 6; the fact that the patient had nonobstruc- had cardiac risk factors. Sledge et al30 also found no increased tive coronary disease and no evidence of myocardial injury cardiac toxicity among metastatic breast cancer patients receiv- suggested that coronary spasm was induced by capecitabi- ing first-line treatment with 1,000 mg/m2 of capecitabine twice ne, since coronary spasm has been linked to the etiology of daily on days 1–15 (28 doses) and 15 mg/kg of bevacizumab However, spasm cannot account for all reported adverse cardiac effects; an animal study searched for alternative DOSE EFFECT?
mechanisms. Groups of six rabbits were treated with differ- Because of the limited variance in dosages and small sam- ent doses and schedules of 5-FU; their hearts were removed ple size, we were unable to conclude whether capecitabine- shortly after death or scheduled sacrifice for macroscopic and related cardiotoxicity was related to dose. A larger study may microscopic examination. Following a single 50-mg/kg dose of 5-FU, all animals rapidly developed a massive hemorrhagic myocardial infarct with spasms of the proximal coronary arter- HISTORY OF 5-FU CARDIOTOXICITY
ies. Repeated 15-mg/kg infusions of 5-FU induced left ven- Aksoy et al17 and Frickhofen et al14 both described patients tricular hypertrophy, foci of myocardial necrosis, thickening with prior 5-FU–related angina who developed similar symp- of intramyocardial arterioles, and disseminated apoptosis in toms when subsequently switched to capecitabine. This find- myocardial cells of the epicardium and endothelial cells of the ing suggested that capecitabine may induce angina similar to distal coronary arteries.33 In discussing these results, Tsibiribi that experienced with 5-FU and that a history of 5-FU cardio- et al33 suggested that spasm of the coronary arteries is not the toxicity may be considered a risk factor for such effects related only mechanism of 5-FU cardiotoxicity—apoptosis of myocar- dial and endothelial cells may result in inflammatory lesions Capecitabine use is suggested to mimic continuous infusion of 5-FU. In a past report, Saif et al29 found that the cardiotox- A PHARMACOGENETIC EXPLANATION?
icity was higher with an infusional regimen (74%) than with a bolus dose (21%) of 5-FU.
Accumulation of 5-FU or its cardiotoxic metabolites due to DPD deficiency may increase the risk of 5-FU–related cardio- PATHOGENESIS
toxicity, although the relationship between fluoropyrimidine As with 5-FU, the precise mechanism of capecitabine-related cardiotoxicity and DPD deficiency is unknown.
cardiotoxicity is not clearly defined. Prior or concomitant radia- Milano et al20 observed that only 5% of DPD-deficient pa- tion therapy may contribute to the effect, since 5-FU has radia- tients developed 5-FU–related cardiotoxicity. In our retrospec- tion-sensitizing properties; other theories include elicitation of tive study, 56% of patients who developed cardiotoxicity were an autoimmune response due to the formation of a complex tested for DPD levels; however, no deficiency was noticed.
of 5-FU and cardiac cells, cardiotoxic impurities in the 5-FU MANAGEMENT
formulation, coronary spasm, direct myocardial ischemia due to endothelial damage, changes in platelet aggregation, abnormal- If it develops, cardiotoxicity is managed according to stan- ities of coagulation protein (eg, elevated level of fibrinopeptide dard practice. Administration of prophylactic coronary vaso- A [FPA]), and significant decrease in protein-C activity.29 dilators (eg, nitrates, calcium-channel blockers) to prevent None of the seven patients in this study sustained myo- coronary artery spasm has been investigated.29 Eskilsson and cardial injury detected by troponin level. However, Patients Albertsson25 treated 58 patients receiving 5-FU infusions with 1 and 6 had ECG changes suggesting ischemic events. In 120 mg of verapamil given three times daily and found that Saif, Tomita, Ledbetter, and Diasio prophylactic calcium-channel blockers had no significant protective effect against cardiotoxicity. Consistent with these findings, our Patient 6 derived no benefit from prophylactic Cardiac disease, risk factors, cardiotoxic β-blocker therapy or aspirin use, as he developed recurrent angina with capecitabine rechallenge at a reduced dose.
Jensen and Sorenson34 performed a retrospective study of 668 patients treated with 5-FU or capecitabine for GI cancers to identify risk factors associated with cardiotoxicity induced Pretreatment
by 5-FU or capecitabine. They found that cardiotoxicity oc-curred in 29 cases (4.3%). For patients with and without pre- existing cardiovascular disease, the number of cases of grades 2–4 cardiotoxicity according to National Cancer Institute Common Toxicity Criteria was 0, 10, and 2 cases and 3, 14, and 0 cases, respectively (P = 0.16). In three patients, an in- tercurrent decrease in renal clearance to < 30, 48, and 71 mL/ symptoms or signs manifest during capecitabine administration min–1 led to markedly increased cardiotoxicity. Chemotherapy dose reduction to 70% or 50%, either alone or with antiangi-nal medication, prevented cardiotoxicity during subsequent chemotherapy in 9 (60%) and 3 (20%) cases out of 15 assess- able patients (P = 0.001), respectively. To abolish symptoms of cardiotoxicity, sublingual nitroglycerin was efficient for 15 patients and inefficient for 2 patients (P = 0.001). The au-thors concluded that cardiac and renal comorbidities are risk factors for 5-FU–induced cardiotoxicity and that rechallenge with a modified 5-FU–based chemotherapy regimen supported used in combination with other agents known to cause electrolyte disturbance) by symptomatic medical treatment is feasible.
Much like 5-FU, capecitabine has not been linked to par- treatment
ticular risk factors related to the development of cardiotox- icity. Still, the potential morbidity and mortality of this rare side effect are significant. Therefore, it may be reasonable to recommend careful monitoring and evaluation for patients Treat with conventional therapy for such receiving capecitabine, particularly for those having a his- tory of coronary artery disease or strong cardiac risk factors. This issue is particularly important when patients are treated with capecitabine and bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, which increases the risk for arterial thromboembolism itself.29 If a patient develops symptoms suggesting a cardiac etiology, Perform only if clinically important and capecitabine should be discontinued immediately, antiangi- nal therapy should be initiated, and a prompt cardiac work-up should be conducted. A rechallenge with capecitabine or Rechallenge
another fluoropyrimidine should be reserved only for patients having no alternative therapeutic alternatives and should be administered in a supervised environment.34 Conclusion
Figure 1 Treatment Algorithm for the Management
Cardiotoxicity associated with capecitabine is similar to that noted with use of intravenous fluoropyrimidines. The incidence and risk factors associated with capecitabine-induced cardio-toxicity, however, are poorly defined. Patients commonly pres-ent with angina-like symptoms; however, arrhythmia might oc- tients having cardiac risk factors or receiving other concomitant cur with capecitabine. Patients require prompt evaluation and cardiotoxic agents (Figure 1). Importantly, caution should be discontinuation of the drug to prevent serious consequences.
used in patients being considered for rechallenge with capecitabi- Thus, a high index of suspicion for cardiac toxicity should ne. Further studies aiming at the pathophysiologic mechanisms be maintained during capecitabine treatment, particularly in pa- of cardiotoxicity and preventive measures are needed.
Capecitabine-related Cardiotoxicity: Recognition and Management References
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Hyperventilation Syndrome, Treatment With L-Tryptophan and Pyridoxine; Predictive Values of Xanthurenic Acid Excretion. M.J.A.J.M. Hoes, M.D.1, P. Colla2, H. Folgering, M.D., Ph.D.3 Abstract Introduction A case is made for the pathophysiological The hyperventilation syndrome (HVS) is a importance of the cerebral serotonergic functional syndrome (van Dis, 1978) caused

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