Hodgkin's Therapy Raises Long-Term MI Risk

SUTTON, England, Feb. 7 -- Survivors of Hodgkin's disease have about a 2.5-fold greater risk of dying from a myocardial infarction than the general population for up to 25 years.

That's the conclusion of Anthony J. Swerdlow, D.Sc., of the Institute of Cancer Research here, and colleagues, on the basis of a follow-up of a cohort of more than 7,033 patients treated for Hodgkin's from 1967 through 2000.

Independent risk factors for cardiovascular death included treatment with supradiaphragmatic radiotherapy and anthracyclines, and possibly Oncovin (vincristine), they reported in the Feb. 7 issue of the Journal of the National Cancer Institute.

"Overall, our data suggest, but do not give conclusive evidence, that treatment with vincristine may increase the long-term risk of death from myocardial infarction," the authors wrote. "The findings point to the need to re-examine the relationship between vincristine and MI mortality in other cohorts and for a more detailed examination of this relationship, which we plan to do by a nested case-control study."

Patients who had received combination chemotherapy with the ABVD regimen -- Adriamycin (doxorubicin), Blenoxane (bleomycin), Oncovin, and dacarbazine -- regimen were at particularly high risk for death from myocardial infarction, the investigators found.

"The goal of keeping these patients alive has been achieved; the next challenge is to continue to reduce the toxicity of curative treatments and to make long-term survival as disease free as possible, breaking as few hearts as possible along the way," wrote John D. Boice Jr., Sc.D., of the International Epidemiology Institute in Rockville, Md., in an accompanying editorial.

To determine which components or combinations of treatment regimens conferred the great risk for MI, the authors compared the 7,033 patients' risk for death from MI against mortality figures from the general population of England and Wales, using statistical two-sided tests.

They identified a total of 166 deaths from MI in the cohort, which was significantly higher than expected. The standardized mortality ratio (SMR), compared with that of the general public, was 2.5 (95% confidence interval, 2.1 to 2.9).

The absolute excess risk of death from myocardial infarction was 125.8 per 100,000 person-years, and was three times higher among men than women.

The relative risk for death from MI for the entire cohort remained unchanged after censoring follow-up at the occurrence of a second malignancy.

"The relative risk of death from myocardial infarction decreased sharply with older age at first treatment and was only slightly and non-statistically significantly increased in the oldest age-at-first-treatment group (i.e., cohort members who were 65 years or older) compared with the general population," the investigators wrote. "However, the absolute excess risks of death from myocardial infarction increased steadily with older age at first treatment except beyond age 65 years at first treatment."

When they looked at the risk of MI death by treatment, they found that it was significantly higher for patients who had received total nodal irradiation (SMR 8.9, 95% CI, 5.4 to 13.8), mantle radiotherapy (SMR. 3.2, 95% CI, 2.3 to 4.2), other supradiaphragmatic radiotherapy (SMR. 1.9, 95% CI. 1.2 to 2.9), or radiotherapy to unknown fields (SMR, 2.3, 95% CI, 1.4 to 3.6).

There was no significantly elevated risk, however, for patients who had received infradiaphragmatic radiotherapy alone (SMR, 1.2, 95% CI, 0.4 to 2.8).

The risk of death from MI was also significantly higher for patients who had received anthracyclines (SMR 2.9, 95% CI, 1.9 to 4.3), and particularly so for those who were treated with the ABVD regimen (SMR 9.5, 95% CI, 3.5 to 20.6).

"Some striking case reports have described myocardial infarction occurring in close temporal proximity to vincristine therapy, but there are no published data, to our knowledge, on the long-term risk of myocardial infarction after vincristine therapy," the investigators noted. "Vincristine has been associated with autonomic cardio neuropathy and this association distinguishes it from vinblastine, for which raised myocardial infarction mortality risk was not seen in our data."

The authors acknowledged that they did not take into account potential differences in non-therapeutic risk factors for MI between members of the cohort or specific treatment groups and the general population. They also noted that because of variations in the recipes for chemotherapy combinations, they could not accurately estimate the risks associated with specific chemotherapy agents.

"Long-term studies that follow lymphoma survivors for many years, such as the one conducted by Swerdlow et al, are needed to help better understand the processes and factors that worsen heart function, especially now that patients in remission are living to older ages when cardiac disease is common," Dr. Boice wrote in his editorial.

"The possible interaction between radiotherapy and anthracyclines in the development of heart disease should be investigated, as well as the concomitant influence of other known cardiac risk factors such as cigarette smoking and hyperlipidemia," he advocated.