Anthracycline-based chemo poses cardiac hazard in Asian children

Use of anthracycline class of chemotherapeutic drugs for treating childhood cancer may trigger cardiotoxic effects in a number of children, according to data from a multiethnic Southeast Asian cohort study.

“Our study reaffirms that freedom from symptoms does not ensure normal heart function and suggests that children with abnormal ventricular systolic function have higher mortality risk compared to those with normal systolic function,” said a team of Singapore-based researchers.

In a group of 458 paediatric oncology patients (median age at diagnosis, 5.8 years) treated with anthracycline at KK Women's and Children's Hospital, 32 (7 percent) developed cardiotoxicity over a 4-year follow-up. Specifically, 12 children (2.6 percent) showed signs of clinical heart failure, while the rest (4.4 percent) were asymptomatic. [Front Pediatr 2021;doi:10.3389/fped.2021.639603]

More than half of the children (53 percent) presented with late cardiotoxicity, such that the event occurred >1 year after completion of chemotherapy. Cardiotoxicity was associated with a much higher total all-cause mortality rate (46.9 percent vs 19.2 percent; p<0.001), with three children (9.4 percent) dying from end-stage heart failure.

Median cumulative doxorubicin isotoxic dose was 200 mg/m², and one-third of the cohort received a cumulative dose of ≥250 mg/m² (high dose). Commensurate with the demographics of Singapore, the majority of patients were ethnically Chinese (65.2 percent), followed by Malay (16.4 percent), Indian (10 percent), and others (8.3 percent). Leukaemia was the most common disease (57.2 percent), while lymphoma was the most frequent solid tumour (18.3 percent).

Interestingly, traditional factors such as female sex, age at diagnosis, and cumulative doxorubicin equivalent dose failed to predict cardiotoxicity on logistic regression analysis. The only patient factor associated with higher risk of cardiotoxicity was ethnicity.

Pharmacoethnicity in cardiotoxicity

“Although there was no one statistically significant ethnic predisposition to developing cardiotoxicity, we noticed that there was a higher proportion of non-Chinese/Malay/Indian (‘others’) among those with [versus without] cardiotoxicity (28.1 percent vs 6.8 percent; p<0.001),” the researchers pointed out.

“Others” in multiracial Singapore predominantly comprise those of Caucasian descent and, in the current study, included foreign nationals (eg, Filipino and Vietnamese, among others). The racial breakdown of the current study cohort is said to be representative of the local population, with a Chinese majority and minority groups comprising of Malays, Indians, and others. [https://www.singstat.gov.sg/-/media/files/publications/population/population2019.pdf]

“While the elevated risk of this ‘others’ racial group may not be immediately intuitive owing to its heterogeneity, what is apparent in our study is that children from the main ethnic groups (Chinese, Malay, and Indian) showed no racial predilection to cardiotoxicity. There were also no significant differences between gender, age at diagnosis, cumulative anthracycline dose and irradiation between the patients of the main ethnic groups and others,” according to the researchers. “[This highlights] the importance of pharmacoethnicity in the development of cardiotoxicity.”

Asian burden

Taken together, the findings contribute to better understanding of the Asian burden of the cardiotoxic effects of anthracyclines to aid development of measures to prevent or reduce the risk of cardiac disease, they said.

Similar epidemiological studies in Asian populations are few and have smaller sample sizes compared to their Western counterparts. In Beijing, for example, the frequency of anthracycline-induced heart failure was 1.5 percent, which is lower than that seen in the Singaporean cohort. Meanwhile, a South Korean cohort reported a 2.1-percent incidence of symptomatic heart failure, similar to the current data. [Pediatr Hematol Oncol 2018;35:111-120; Cancer Res Treat 2019;51:357-367]

“In a separate South Korean study … 2.7 percent (7/258) of their total cohort developed clinical congestive heart failure, which is similar to our data. Overall, there appears to be congruency of the incidence of heart failure in Asian populations,” the researchers stated. [J Chemother 2012;24:292-296]

“Clinically, it suggests the importance of having a systematic, periodic echocardiographic surveillance in these patients and better understanding of the Asian reaction to anthracyclines in order to achieve improved long-term patient outcomes especially in the impending era of personalized medicine,” they continued.

The researchers called for further studies to determine the optimal interval of such surveillance and establish the most sensitive echocardiographic index for prediction of long-term cardiac outcome.