Chemotherapy-induced cardiotoxicity in children

Introduction: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents.

Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology.

Expert opinion: There is no ‘safe’ anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.     

Phase II study of esorubicin (4 ′ deoxydoxorubicin) in anthracycline naive patients with ovarian cancer

Summary Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4 deoxydoxorubicin at a dose of 30 mg/m² intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4 deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.N. Colombo is a recipient of a fellowship from the American-Italian Foundation for Cancer Research.     

Genome‐wide association study of genetic variants related to anthracycline‐induced cardiotoxicity in early breast cancer

We performed a genome‐wide association study to investigate the association between single nucleotide polymorphisms and anthracycline‐induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m²‐300 mg/m²) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty‐seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m² [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23‐4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11‐5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E?06), rs11894115 (MPP4, P = 4.71E?06), rs58328254 (RPL7, P = 6.09E?06), and rs117299725 (PRUNE2, P = 8.53E?06), although none of these variants reached the Bonferroni‐corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E?07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.     

A four gene signature predicts benefit from anthracyclines: evidence from the BR9601 and MA.5 clinical trials

Chromosome instability (CIN) in solid tumours results in multiple numerical and structural chromosomal aberrations and is associated with poor prognosis in multiple tumour types. Recent evidence demonstrated CEP17 duplication, a CIN marker, is a predictive marker of anthracycline benefit. An analysis of the BR9601 and MA.5 clinical trials was performed to test the role of existing CIN gene expression signatures as predictive markers of anthracycline sensitivity in breast cancer.Univariate analysis demonstrated, high CIN25 expression score was associated with improved distant relapse free survival (DRFS) (HR: 0.74, 95% CI 0.54-0.99, p = 0.046). High tumour CIN70 and CIN25 scores were associated with aggressive clinicopathological phenotype and increased sensitivity to anthracycline therapy compared to low CIN scores. However, in a prospectively planned multivariate analysis only pathological grade, nodal status and tumour size were significant predictors of outcome for CIN25/CIN70. A limited gene signature was generated, patients with low tumour CIN4 scores benefited from anthracycline treatment significantly more than those with high CIN4 scores (HR 0.37, 95% CI 0.20-0.56, p = 0.001). In multivariate analyses the treatment by marker interaction for CIN4/anthracyclines demonstrated hazard ratio of 0.35 (95% CI 0.15-0.80, p = 0.012) for DRFS. This data shows CIN4 is independent predictor of anthracycline benefit for DRFS in breast cancer.     

蒽环类抗肿瘤药化疗患者心肌99Tcm-MIBI清除率变化

目的探讨用蒽环类抗肿瘤药（ATC）化疗患者心99^Tc^m-MIBI清除率变化及其在ATC心脏毒性监测中的价值。方法14例接受ATC化疗的患者化疗前和化疗第6周期后1周行99^Tc^m-MIBI静态平面及门控SPECT显像。比较化疗前后99^Tc^m-MIBI早期与晚期清除率及左心室射血分数（LVEF）的差异。结果ATC治疗患者化疗前早期及晚期心肌99^Tc^m-MIBI清除率分别为（17．92±5．86）％和（17．05±5．17）％，化疗后为（21．27±7．14）％和（19．67±6．41）％，化疗前后相比差异均有统计学意义（t值分别为-2．611，-2．824，P均〈0．05）。化疗前后LVEF变化差异无统计学意义（t=1．719，P〉0．05）。结论ATC化疗患者心肌99^Tc^m-MIBI清除率的变化有助于监测ATC所致的心肌损害，且其早于LVEF的改变。     

Echocardiographic evaluation of cardiac function in paediatric oncology patients treated with or without anthracycline

Using Doppler echocardiography, we studied the left ventricular systolic and diastolic function in 124 healthy control children (group C), 110 oncology patients who had received anthracycline (group A), and 76 oncology patients who had received chemotherapy not including anthracycline (group N), at rest and after supine bicycle exercise. The mean dosage of anthracycline that group A patients received was 219 ± 95 mg/m². Impaired systolic function was detected in 29% of the patients in group A and 4% in group N. Figures for impaired diastolic function for group A and N were 27% and 28% respectively. Abnormal diastolic function was detected more frequently in the first two years after chemotherapy in both groups. Four parameters measured at rest appeared to be specifically abnormal in group A but not in group N. These were ejection fraction, fractional shortening, rate-corrected velocity of circumferential fiber shortening (VCFC) and left ventricle peak systolic wall stress (LVWS). After exercise more parameters were abnormal in group N patients when compared to normal children, but abnormalities of VCFC and LVWS remained specific for group A. In conclusion, abnormalities of diastolic function were common among paediatric oncology patients no matter whether they had received anthracycline treatment or not. Abnormalities of systolic function were more specific to anthracycline toxicity. VCFC and LVWS were the most sensitive measurements for differentiating group N patients from group A patients.