Radiation Dose and Use of Anthracyclines Increase Risk of Heart Failure in Hodgkin Lymphoma Survivors

Previous studies have linked mediastinal radiotherapy (RT) and/or anthracycline-containing chemotherapy with increased risk of coronary heart disease, valvular heart disease, and heart failure (HF) in survivors of Hodgkin lymphoma (HL). A case-control study published in Blood confirmed these findings, as well as a dose-response relationship between radiation dose and HF rate.

“Our analyses showed that the only factors significantly associated with HF rate were radiation dose and whether anthracyclines were used, with no significant multiplicative interaction between the two,” wrote the authors, led by Frederika A. van Nimwegen, PhD, from the Department of Epidemiology at the Netherlands Cancer Institute in Amsterdam. “While there is little increase in HF risk for lower doses, HF rates increase rapidly at higher doses.”

The authors also found that treatment with anthracyclines increased HF risk threefold, independent of radiation dose.

The study was conducted within an existing multicenter, hospital-based cohort of 2,617 HL survivors treated in the Netherlands between 1965 and 1995. Patients were included if:

  • they were treated before age 51
  • they survived ≥5 years after diagnosis
  • HL was the first primary malignancy (except for non-melanoma skin cancer or carcinoma in situ of the cervix uteri or the breast)
  • RT was administered to the neck or trunk prior to the cutoff date (October 2013)

The authors identified 91 patients (median age = 28.3 years; range = 21.9-37.7 years) who developed HF, defined as either symptomatic congestive HF or cardiomyopathy with an ejection fraction of <50 percent (and/or a ≥10% drop from baseline). Outcomes were compared with an age- and sex-matched control cohort of 278 HL patients (median age = 28.2 years; range = 22.9-37.7 years) who were free of any cardiac disease at the cutoff date.

In the 91 cases, HF occurred a median of 20.6 years (range = 13.7-25.5 years) after the HL diagnosis; the majority of HF diagnoses were for grade 2 (44%) or 3 (43%) disease. More than half of the patients (57%) died by the end of follow-up, with a median time from HF to death of 3.6 years (range = 0.2-5.6 years).

“The cumulative risks of heart failure were substantial for this patient population. Therefore patients should be counselled regarding these risks before treatment and during follow-up,” co-author Berthe M. P. Aleman, MD, PhD, from the Department of Radiation Oncology at the Netherlands Cancer Institute, told ASH Clinical News.

Most patients received RT (90.1 percent of cases, 82.3 percent of controls) at an average prescribed dose of 30.5 Gy (32.7 Gy for cases, 29.8 Gy for controls). Specifically, mean heart dose (MHD) was 20.9 Gy (23.2 Gy for cases, 20.1 Gy for controls), and mean left ventricular dose (MLVD) was 14.5 Gy (16.7 Gy for cases, 13.8 Gy for controls).

For all three dose measures (total, MHD, and MLVD), the HF rate increased as the dose increased (ptrend=0.027; ptrend=0.002; ptrend<0.001, respectively). “For MHD, the dose-response relationship was non-linear, with little evidence of an increase for MHDs [at] 1 Gy to 25 Gy, but increasing steeply with MHDs ≥25 Gy,” the authors reported (TABLE).

Treatment with anthracycline-containing chemotherapy was also associated with an increased HF rate (rate ratio [RR] = 2.83; 95% CI 1.43-5.59; p value not reported); however, chemotherapy without anthracyclines was not associated with an increased risk (RR=0.93; 95% CI 0.63-1.37; p value not reported).

Unlike with RT, there was no dose-response relationship observed for cumulative doses of anthracyclines.

Notably, though, treatment with anthracyclines appeared to increase HF rate, irrespective of cardiac radiation exposure (RR=2.92 for MHD 0-25 Gy, 7.09 for MHD 26-30 Gy, 10.71 for MHD ≥31 Gy). In addition, the 25-year cumulative risk of HF was higher in patients treated with anthracyclines and appeared to increase with greater MLVD:

  • MLVD 0-15 Gy: 11.2 % (with anthracyclines) and 4.4% (without)
  • MLVD 16-20 Gy: 15.9% and 6.2%
  • MLVD ≥21 Gy: 32.9% and 13.3%

Though the data indicate that “salvage therapy with anthracyclines following primary treatment with mediastinal RT would be more harmful than primary treatment with mediastinal RT and anthracyclines,” the authors noted that “the small number of patients treated with anthracyclines makes it impossible to draw any firm conclusions regarding the possible effect of the time elapsed between exposure of the heart to anthracyclines and to radiation.”

“This study supports the possible need for long-term cardiological surveillance to detect and hopefully modify the course of cardiac dysfunction,” said Dr. Aleman.

Additional research may indicate whether treatment sequence could influence HF risk, they added. This information could contribute to risk-prediction models of cardiovascular disease in HL survivors who have been treated in the past.

The study is limited by the small number of patients who received both anthracyclines and mediastinal RT. The authors noted that current anthracycline doses and MHDs and MLVDs are usually well below the average values reported in this study “due to reductions in both treatment volumes and prescribed doses,” which may limit the results’ generalizability. They suggested that future studies examine larger populations of HL survivors treated more recently to help characterize the risk of more modern treatments.


Reference

van Nimwegen FA, Ntentas G, Darby SC, et al. Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines. Blood. 2017 January 21. [Epub ahead of print]

TABLE. Associations Between Radiation Dose and HF Risk
Cases (n=91) Controls (n=278) Rate Ratio (95% CI) p Value
n % n %
Prescribed Mediastinal Dose
Average (SD) 32.7 (12.2) 29.8 (14.6) 0.027
0 Gy 9 9.9 49 17.6 1.00 (0.45-2.23)
20-34 Gy 15 16.5 45 16.2 2.35 (0.85-6.46)
35-39 Gy 34 37.4 113 40.7 2.10 (0.86-5.13)
≥40 Gy 33 36.3 71 25.5 3.02 (1.23-7.40)
Mean Heart Dose
Average (SD) 23.2 (9.6) 20.1 (10) 0.002
0 Gy 7 7.7 29 10.4 1.00 (0.39-2.55)
1-20 Gy 21 22.2 70 24.4 1.43 (0.83-2.50)
21-25 Gy 20 22.2 102 37.1 1.03 (0.63-1.67)
26-30 Gy 27 30.0 57 20.7 2.78 (1.69-4.59)
≥31 Gy 16 17.8 20 7.3 4.16 (2.14-8.10)
Mean Left Ventricular Dose
Average (SD) 16.7 8.8 13.8 7.9 <0.001
0 Gy 7 7.7 29 10.4 1.00 (0.39-2.55)
1-15 Gy 36 39.5 144 51.8 1.27 (0.86-1.89)
16-20 Gy 20 22 68 24.5 1.65 (0.98-2.77)
21-25 Gy 16 17.6 23 8.3 3.84 (1.97-7.47)
≥26 Gy 12 13.2 14 5.1 4.39 (2.00-9.65)
HF = heart failure; SD = standard deviation
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