January 31, 2019
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Daunorubicin linked to lower cardiomyopathy risk than doxorubicin in childhood cancer survivors

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Daunorubicin appeared associated with a lower cardiomyopathy risk than doxorubicin among childhood cancer survivors, according to a multicenter cohort study published in JAMA Oncology.

Results also showed epirubicin appeared about equivalent to doxorubicin in terms of cardiotoxicity risk.

Additionally, researchers found that the current hematologic-based doxorubicin dose equivalence ratio of mitoxantrone — 4:1 — may substantially underestimate the correlation between the anthraquinone and long-term cardiomyopathy risk.

“With 5-year survival of childhood cancer now reaching nearly 85%, balancing the potential long-term adverse effects of otherwise effective cancer treatments is an important consideration,” Elizabeth A.M. Feijen, PhD, of the department of pediatric oncology at Emma Children’s Hospital/Academic Medical Center of University of Amsterdam, and colleagues wrote. “For many treatments, the traditional assumption has been that the antileukemia potency of an agent is proportional to its acute hematologic toxicity and, by extension, proportional to toxicity in other organ systems. However, data in both pediatric and medical oncology supporting this assumption in relation to cardiotoxicity are limited.”

Feijen and colleagues sought to ascertain the optimal doxorubicin dose-equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or mitoxantrone.

The researchers reviewed medical records on 28,423 childhood cancer survivors (46.4% female; median age at cancer diagnosis, 6.1 years; range, 0-22.7) from three studies, abstracting cumulative doses of the anthracyclines doxorubicin, daunorubicin, epirubicin and idarubicin, as well as mitoxantrone, along with data on chest radiotherapy exposure.

Cardiomyopathy (severe, life-threatening or fatal) by age 40 years served as the primary outcome. Researchers assessed cardiomyopathy risk in agent-specific Cox proportional hazards models adjusted for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone.

Among the childhood cancer survivors, 9,330 received doxorubicin at a median dose of 181 mg/m2 (interquartile range [IQR], 119-320), 4,433 patients received daunorubicin at a median dose of 120 mg/m2 (IQR, 99-208), 342 patients received epirubicin at a median dose of 300 mg/m2 (IQR, 240-400); 241 received idarubicin at a median dose of 36 mg/m2 (IQR, 20-40) and 265 received mitoxantrone at a median dose of 40 mg/m2 (IQR, 26-72).

In total, 1,857 patients (7.4%) received more than one type of anthracycline or anthraquinone agent, and 87 patients (0.4%) received more than two types.

At median follow-up of 20 years, the researchers observed 399 cases of grade 3 to grade 5 cardiomyopathy by age 40 years, for a cumulative incidence of 3.4% (95% CI, 3.1-3.8). Of these, 229 (56.2%) received doxorubicin only, and 81 received other anthracyclines or mitoxantrone. Forty-five cases involved chest radiotherapy without any known anthracycline or mitoxantrone treatment, and 44 cases had no apparent history of chest radiotherapy or cardiotoxic chemotherapy.

Researchers also estimated an agent-specific cardiomyopathy equivalence ratio in relation to doxorubicin for each dose category as a ratio of the HRs. A weighted mean then established the overall agent-specific equivalence ratio across all dose categories.

In relation to doxorubicin, results showed mean equivalence ratios between the HRs of 0.6 (95% CI, 0.4-1) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Researchers could not calculate idarubicin-specific estimates due to the rarity of outcomes.

Even after multiplying doses by a factor of four to account for differences in therapeutic doses, mitoxantrone appeared associated with a greater risk for cardiomyopathy than doxorubicin, with a mean equivalence ratio of 10.5 (95% CI, 6.2-19.1). These data suggest mitoxantrone is “approximately 2.6 times more cardiotoxic than what the conventional fourfold multiplier would suggest,” according to the researchers.

The mitoxantrone-doxorubicin linear dose response model had a ratio of 13.8 (95% CI, 8-21.6), but researchers observed evidence for nonlinearity with a dose of 300mg/m2 or higher.

When researchers restricted analyses to doxorubicin doses of less than 300mg/m2 and mitoxantrone doses of less than 75mg/m2, the linear dose-response ratio remained high at 8.1 (95% CI, 0.5-16.1).

“Although our data were not based on randomized comparisons of children treated with various anthracyclines or anthraquinones, our findings would suggest that the commonly used doxorubicin conversion ratios for daunorubicin (approximately 1) and mitoxantrone (approximately 4) should be reconsidered and perhaps revised (downward and upward, respectively),” the researchers wrote.

The investigators noted several limitations to the study, including the relative scarcity of significant cardiomyopathy in children and the study’s reliance on the Childhood Cancer Survival Study, which utilizes self-reports supplemented with death records.

“This large cohort study of 28,423 childhood cancer survivors with detailed cancer treatment exposures found that compared with doxorubicin, the anthraquinone mitoxantrone was associated with more cardiotoxic risk than current guidelines would suggest, whereas the anthracycline daunorubicin was associated with less cardiotoxic risk,” the researchers wrote. “The cardiotoxicity equivalence ratios determined in the present study for the most commonly used cancer agents may influence the choice of agents when designing new protocols.” – by Jennifer Byrne

Disclosures: Feijen reports grant funding from the European Union 7th Framework Programme for Research, Technological Development and Demonstration during the study. Please see the study for all other authors’ relevant financial disclosures.