Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study

Background:5-Fluorouracil(5-FU)and capecitabine-associated cardiotoxicity ranging from asymptomatic electro-cardiography(ECG)abnormalities to severe myocardial infarction has been reported in a number of studies,but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date.In the present study,we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5-FU-and capecitabine-associated cardiotoxicity in cancer patients recruited from multiple centers in China.Methods:Among the 527 patients who completed the study,196 received 5-FU-based chemotherapy and 331 received capecitabine-based chemotherapy as either first-line or adjuvant therapy.Adverse events were reported during the treatment and up to 28 days of follow-up.Outcome measures included ECG,myocardial enzymes,cardiac troponin,brain natriuretic peptide and echocardiography.Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents.Results:In total,161 of 527 patients(30.6%)experienced cardiotoxicity.The incidence rate of cardiotoxicity was 33.8%(112/331)in the capecitabine group,which was significantly higher than the rate of 25%(49/196)in the 5-FU group(P=0.0042).110/527 patients(20.9%)suffered arrhythmia,105/527(19.9%)developed ischemic changes,while only 20/527 patients(3.8%)presented heart failure and 6/527 patients(1.1%)had myocardial infarction.Pre-existing cardiac disease,hypertension,capecitabine-based chemotherapy and duration of treatment were identified as sig-nificant risk factors associated with cardiotoxicity.The odds ratio were 15.7(prior history of cardiac disease versus no history),1.86(capecitabine versus 5-FU),1.06(5-8 versus 1-4 chemotherapy cycles)and 1.58(hypertension versus no hypertension),respectively.Conclusions:Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clini-cal practice.Close monitoring of patients is recommended,especially for those patients at high risk for cardiotoxicity.Possible risk factors are duration of treatment,capecitabine-based chemotherapy,pre-existing cardiac diseases and hypertension.Trial registration This study was initiated on January 22,2014 and has been retrospectively registered with the registra-tion number ChiCTR1800015434 .

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORCl and scavenging ROS

Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.