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Researchers quantify risk for cardiovascular disease after Hodgkin's lymphoma treatment
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Researchers have quantified specific doses of radiation and anthracycline exposure associated with increased cardiovascular risk among patients with Hodgkin’s lymphoma based on an analysis of data from nine trials.
These data may help clinicians balance the harms and benefits of therapy for each individual patient with Hodgkin’s lymphoma, according to the researchers.
“For the individual patient with this disease, this approach enables treatment-specific risk counselling and follow-up programs tailored to the individual,” Maja V. Maraldo, MD, a resident in clinical oncology at Rigshospitalet in Copenhagen, Denmark and colleagues wrote. “… Use of the quantitative risk estimates from the present study will allow the optimal combination of systemic therapy and modern, individualized radiotherapy to be estimated for each individual patient with respect to cardiovascular risk.”
The investigators distributed a Life Situation Questionnaire to 1,919 patients (median age at treatment start, 29 years; 51% women) with Hodgkin’s lymphoma enrolled on nine successive EORTC or Group d’Etude des Lymphomes de l’Adulte (now LYSA) randomized trials conducted between 1964 and 2004. Median follow-up of the entire cohort from these studies (n = 6,039) was 9 years.
Overall, 703 patients (36.6%) reported 1,238 cardiovascular events. The most common events included ischemic heart disease (19%), arrhythmia (16%), congestive heart failure (12%) and valvular disease (11%).
Significant predictors of cardiovascular disease included mean radiation dose to the heart (HR per 1 Gy increase = 1.02; 95% CI, 1.01-1.02) and the dose of anthracyclines (HR per 50 mg/m² = 1.08; 95% CI, 1.02-1.14).
However, cumulative dose of vinblastine, cumulative dose of vincristine and mean radiation dose to the left or right internal carotid artery did not appear to predict risk for cardiovascular events.
Maraldo and colleagues noted that a limitation of their study was that other risk factors — such as smoking, hypertension, diabetes and being overweight — were not analyzed due to a lack of information; however, further analysis for these factors is planned.
“The radiation doses to all cardiac substructures correlated with mean heart radiation dose because all patients were treated with old-fashioned techniques and standardized fields; hence, we could now show the independent significance of these doses,” Maraldo and colleagues wrote. “With modern, highly conformal and individualized radiotherapy, the doses to cardiac substructures will vary substantially with less correlation to the mean heart radiation dose. … Clearly, to minimize the risk [for] cardiovascular disease, doses of both radiation to the heart and anthracyclines should be kept as low as possible without jeopardizing the patient’s chance of cure.”
Additional studies evaluating the risk for CVD with modern regimens are needed, Serhan Küpeli, MD, professor of medicine in the department of pediatric oncology and pediatric bone marrow transplantation at Cukurova University in Adana, Turkey, wrote in an accompanying editorial.
“For more accurate risk counselling, the effect of cyclophosphamide should be included in future studies investigating [CVD] burden in survivors of Hodgkin’s lymphoma who are treated with regimens containing cyclophosphamide,” Küpeli wrote. “Additionally, as Maraldo and colleagues state, the reported excess risks of [CVD] should be interpreted with caution and cannot be used in risk counselling because of data from the regimens that are currently outdated.” – by Anthony SanFilippo
Disclosure: The researchers and Küpeli report no relevant financial disclosures.
Perspective
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Gagan Sahni, MD, FACC, FACP
PERSPECTIVE
This meta-analysis of cardiovascular events in patients across nine successive European Hodgkin’s Lymphoma trials acknowledges that it encompasses patients from 1964 onwards, since which time the monitoring and detection of chemotherapy cardiotoxicity has evolved, and methods and dose of mediastinal radiation delivery have vastly improved. Moreover, this was a retrospective questionnaire that was not validated by the study patients’ physicians or actual patient medical records; therefore, the true incidence of cardiovascular disease (CVD) cannot be validated. The trial included exclusively European patients with no ethnicity data available and no correction for baseline cardiovascular risk factors others than chemotherapy and radiation.
However, despite those limitations, what sets this study apart is that it studies the incidence of CVD in a special cohort of young adult patients that had no significant other cardiovascular risk factors, thereby reaffirming similar data seen in studies of childhood cancer survivors exposed to anthracyclines and radiation who presented early CVD.
Secondly, it studies the combined cardiovascular effect of radiation and cardiotoxic chemotherapy, data for which has been lacking so far. Further, the early onset of cardiovascular events occurred on over a median follow-up of just 9 years, with median age of patients being just 30 years, which is earlier than that reported in studies with radiation alone or anthracyclines alone.
Lastly, late cardiotoxicity of anthracyclines can occur at even very low cumulative doses (< 200 mg/m2 average in this patient cohort) especially when combined with radiation. The doses of anthracyclines and the total radiation exposure with which late cardiovascular effects were seen, are much lower than those traditionally described, thereby demonstrating that combined cardiotoxicity can occur at much lower doses of both and have an incremental cardiovascular effect with minimal increase in dosage (ie, > 1 Gy radiation and > 50 mg/m2 anthracyclines).
This study raises appropriate questions for future research into the prospective incidence of cardiotoxicity with current stringent surveillance methods, more targeted and calculated radiation delivery, heightened cognizance of the increased cardiovascular effects with higher doses and when radiation and chemotherapy are combined. It also lays the foundation for assessing the impact of early cardiovascular screening and intervention in patients exposed to combined anthracyclines and radiation.
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