In the JournalsPerspective

Daunorubicin linked to lower cardiomyopathy risk than doxorubicin in childhood cancer survivors

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.

 

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.

 

    Perspective

    Etan Orgel, MD, MS

    The study by Feijen and colleagues explores the long-term cardiac impact after exposure to anthracycline (and anthraquinone) chemotherapies for treatment of many common childhood cancers. Prior to this study, data for the comparative cardiotoxicity of these agents were limited, with dosing-equivalency guidelines more akin to commonly held beliefs than founded in robust data. The authors are to be commended for assembling the largest single cohort to date, including dosing and cardiac data from decades of follow-up of over 28,000 childhood cancer survivors. This allowed the first definitive characterization of relative cardiotoxicity for each drug. 

    The findings clearly demonstrate that many of the dose-equivalency ratios so firmly ingrained into treatment regimens and screening guidelines either under- or overestimate the cardiac “cost” of therapy. In the case of mitoxantrone, the study found the risk for cardiotoxicity to be more than twofold greater than previously believed. Improved precision in estimating cardiac risk is essential to integrate potentially cardiotoxic multiagent and multimodal therapy into a cohesive treatment plan. Inaccurate cumulative estimates for cardiotoxicity may even preclude the use of potentially life-saving treatments due to concerns for excessive toxicity risk.

    As the authors note, these findings impact patients well beyond therapy. Data-driven updates to evidence-based guidelines for cardiac screening in adult survivors of childhood cancer are in process among oncology consortia.

    Yet, while the relative dose-toxicity relationship is now clear, it is nonetheless notable that only a small percentage of anthracycline-exposed patients are expected to develop clinically significant cardiotoxicity before age 40 years (cumulative incidence of 3.4%). In fact, only 399 cases were identified in the entire 28,000-plus cohort. The authors suggest greater dose-dependent risk might prompt incorporation of yet-unproven dexrazoxane cardioprotection or liposomal drug formulations. However, the low incidence might suggest the opposite. Perhaps there is a need to instead re-examine our tolerance for higher cumulative doses in the context of still-challenging cure rates in many anthracycline-sensitive cancers.

    As acknowledged by the authors, although the study focuses on “late anthracycline toxicity,” one might also wonder if the data cutoff at age 40 years is really “late enough” for an aging survivor population.  Does anthracycline usage in children and adolescents result in a greater predisposition to heart problems in their 40s, 50s and beyond?

    Most crucially, however, sensitivity to cardiotoxicity is likely multifactorial and not solely related to age and dose. The current study, therefore, contributes a key piece to unlock this puzzle, but exploration of the genetic variability underlying individual susceptibility to dose-dependent cardiotoxicity is urgently needed. 

    Serious and debilitating treatment-related side effects manifest well past the bounds of childhood and adolescence. This leads to an underappreciation of late effects by many pediatric providers while simultaneously placing the burden of care upon the adult medical community.

    Studies such as this are essential to open a window into the lives of childhood cancer survivors. The glimpse provided will promote improved screening for toxicities resulting from intensive chemotherapy from the distant past and, hopefully, better risk-adapted regimens to prevent toxicities in the future.  The current study is an important first step toward that day.

    Etan Orgel, MD, MS

    Children’s Center for Cancer and Blood Diseases <br>
    Children’s Hospital Los Angeles

    Disclosure: Orgel reports no relevant financial disclosures.