Author + information
- Melissa M. Hudson, MD∗ ( and )
- Matthew J. Ehrhardt, MD, MS
- Division of Cancer Survivorship, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- ↵∗Address for correspondence:
Dr. Melissa M. Hudson, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, Tennessee 38105.
Treatment for childhood, adolescent, and young adult cancers has evolved over past decades with efforts to improve disease control and reduce long-term and late-onset therapy-related complications. Contemporary treatment strategies use risk- and response-stratified interventions, balancing the use and intensity of specific agents and modalities with what is known about cancer pathophysiology, patient risk features such as age at diagnosis and sex, and the results of early therapy response assessments, which are increasingly guided by blood and imaging biomarkers (1). This approach has produced 5-year overall survival rates exceeding 80% across all diagnoses, with extended survival beyond this milestone anticipated for most patients (2). However, as most present protocols still largely include cytotoxic chemotherapeutic agents alone or in combination with radiation, the spectrum of therapy-related complications has evolved over time, and the more recently treated survivors still experience a high risk of therapy-related complications known to adversely impact health-related quality of life and increase the risk of premature mortality (3).
Cancer therapy-related cardiac disease represents an important cause of late morbidity and mortality in childhood, adolescent, and young adult cancer survivors, most commonly related to anthracycline chemotherapy and chest-directed radiation therapy (4). Anthracycline-associated cardiotoxicity includes cardiomyopathy, which may include a period of asymptomatic left ventricular dysfunction followed by subsequent heart failure, and exhibits an exponential increase in risk with increasing lifetime cumulative dose that is highest among children treated with doses of 250 mg/m2 or higher and lowest among those treated with doses below 100 mg/m2 (5). Younger age at exposure and genetic variation affect risk, as heart failure has been reported in individuals treated with doses below 250 mg/m2 (6).
Chest-directed radiation exposure to cardiovascular structures increases the risk of cardiomyopathy, conduction defects, atherosclerotic heart disease, and myocardial infarction (4). Chest radiation-related cardiac injury also demonstrates a dose-related pattern with risk level that is highest among individuals exposed to doses of 35 Gy or more; however, this appears negligible at doses below 15 Gy (5). The volume of the heart exposed should also be considered, because low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (50% or greater heart volume) or high doses (20 Gy or greater) to small cardiac volumes (0.1% to 29.9%) have each been reported to significantly increase the rate of cardiac disease compared to unexposed survivors (6). Importantly, individuals treated with combined modality therapy including anthracycline chemotherapy and chest-directed radiation, an approach often used for adolescent and young adult malignancies such as Hodgkin lymphoma, are at particularly high risk of cardiomyopathy (5).
Recognition of the late toxicity associated with chemotherapy and radiation has been a major stimulus for modification and risk stratification of contemporary treatment protocols, with a particular emphasis on both improving reproductive potential and minimizing cardiotoxicity in survivors. Consider Hodgkin lymphoma, a disease for which early treatment success was associated with substantial risk for cardiotoxicity and infertility. Evolution of treatment regimens that balance dose intensity with cumulative exposures has resulted in strategies adapted for risk of relapse and early treatment response, resulting in more moderate exposure to potentially gonadotoxic alkylators, cardiotoxic anthracyclines, and both gonado- and cardiotoxic radiation for most individuals (7). Not only have such strategies significantly lowered 15-year all-cause and cardiac-related mortality among long-term childhood cancer survivors over time, but these strategies have also resulted in an emerging population of young female survivors with preserved reproductive potential (8). Accordingly, health care providers are challenged to continue to provide ongoing vigilance in assessing survivors at risk of cancer therapy-related cardiac dysfunction, which may manifest years after treatment and be precipitated by comorbid conditions common in an aging population and physiological stressors such as pregnancy, labor, and delivery.
In this issue of JACC: CardioOncology, Nolan et al. (9) summarize the results of a well-executed systematic review and meta-analysis that aimed to determine the incidence of peripartum-associated left ventricular dysfunction or heart failure and associated therapy-related risk factors. This topic is relatively understudied and is of substantial clinical importance in view of the increasing numbers of long-term survivors with preserved reproductive potential, the large proportion (estimated at 60%) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy, and the clinical implications for obstetrical management. The 6 studies discussed in the report (9) have limitations, most notably smaller sample sizes, that challenge generalizability of the results. Combined data from all studies indicated that cancer therapy-related cardiac dysfunction, defined as asymptomatic left ventricular dysfunction or heart failure developing during pregnancy or within 12 months of delivery, is a rare event that occurs in 1.7% of patients overall among 2016 pregnancies; however, the prevalence was 28.4% among those with a history of cancer therapy-related cardiac dysfunction, representing a 40-fold excess risk compared to those without a history of cancer therapy-related cardiac dysfunction, and provides compelling evidence that that group of patients would benefit from specialized obstetrical care. All but 1 event occurred in women exposed to anthracycline therapy, precluding subgroup analysis of treatment factors contributing to risk of cancer therapy-related cardiac dysfunction that could be used to stratify the risk of perinatal care. Until further information is available, vigilance is advised in assessing women treated with any potentially cardiotoxic agent or modality.
The authors used the collective data gained regarding risk and risk factors to inform a pre-pregnancy assessment algorithm (9). Adhering to the algorithm assumes that knowledge of cancer history, cardiac events experienced during therapy, and cancer therapy-related risk factors are available. Ideally this information is provided by the treating oncology team and detailed in a cancer treatment summary and survivorship care plan. In reality, this information may be more challenging to obtain, but communication with an oncology team can facilitate access. If treatment information is unavailable, discussion with a specialist in late effects at a nearby cancer center can be helpful to estimate risk based on specific cancer diagnosis and knowledge of era-specific, standardized treatment regimens. If information about risk factors used in the algorithm are not available, assessment of left ventricular ejection fraction may be reasonable in treating any woman with a history of cancer who is pregnant or contemplating pregnancy but particularly in survivors of malignancies known to require treatment with high-dose anthracyclines such as acute myeloid leukemia or bone and soft tissue sarcomas.
The algorithm advises referral for high-risk obstetrical care and cardiology consultation for all women with a history of cancer therapy-related cardiac dysfunction commensurate with their marked excess risk of peripartum cardiac decompensation. For women who are pregnant or contemplating pregnancy who do not already have a pattern of normal left ventricular systolic function established by participation in guideline-recommended cardiomyopathy surveillance (5), echocardiographic assessment with consideration of factors reported in the extant medical literature to contribute to risk represents an evidence-based approach to identify those who would most likely benefit from high-risk obstetrical care. Limitations in the evidence currently available underscore the need for future research to better characterize patient and treatment factors contributing to risk of peripartum cardiomyopathy in cancer survivors and to guide risk-stratified obstetrical care. Considering the relative rarity of this outcome, international collaboration is encouraged to track cardiomyopathy events among clinically well-characterized survivor cohorts to advance understanding about management that will optimize maternal and fetal outcomes.
↵∗ Editorials published in JACC: CardioOncology reflect the views of the authors and do not necessarily represent the views of JACC: CardioOncology or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: CardioOncology author instructions page.
- 2020 The Authors
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