Increased risk of stroke and transient ischaemic attack in 5-year survivors of Hodgkin's lymphoma

Purpose/Objective(s)
The incidence of self-reported stroke in survivors of Hodgkin's lymphoma (HL) treated before the age of 21 has been stated to be increased compared to their siblings. Our aim was to evaluate whether the increased risk is also present when analyses are restricted to clinically verified strokes and transient ischaemic attacks (TIAs).

Materials/Methods
We performed a cohort study among 2196 5-year survivors treated for HL in the period 1965-1995 before age 51 (545 treated before age 21) in the Netherlands. Sixty-four percent of patients were treated with radiotherapy (RT) plus chemotherapy (CT), 28% with RT only, and 8% with CT only. Overall 63% of patients received full mantle field, 15% received treatment including neck RT, and only 17% had no radiation exposure of the neck. We compared the incidence of stroke and TIA with the general population and calculated standardized incidence ratios (SIRs) and absolute excess risks (AERs per 10,000 person years) for different age, treatment, and sex strata. Multivariable Cox regression was used to quantify treatment effects on risks of ischaemic cerebrovascular accidents (CVA consisting of TIA and ischaemic stroke).

Results
During follow-up (median, 17.8 years), we observed 61 strokes (SIR 1.9 [95% Confidence Interval (CI) 1.5-2.4]) and 47 TIAs (SIR 3.4 [95% CI 2.5-4.5]) in 98 patients. Seven patients died of stroke. The AERs for stroke and TIA were 10.5 (95% CI 5.7-16.3) and 10.8 (95% CI 6.7-15.8) per 10,000 person years, respectively. SIRs of stroke and TIA remained significantly increased even after more than 25 years of follow-up. SIRs were highly dependent on age at first treatment. SIRs of stroke were 4.0 (95% CI 1.8-7.6) for those treated before the age of 20 years and 1.1 (95% CI 0.5-1.9) for those treated between 41 and 50 years and SIRs of TIA were 10.0 (95% CI 4.0-20.6) for those treated before the age of 20 years and 2.1 (95% CI 1.2-3.6) for those treated between 41 and 50 years. Females experienced slightly higher risks than males, especially those treated before age 21. The multivariable analysis showed a 2.5-fold (95% CI 1.2-5.0) increased risk of ischaemic cerebrovascular accidents (CVA) after neck radiotherapy corrected for gender, age at diagnosis, and risk factors for cardiovascular diseases. Supraclavicular RT did not seem to increase the risk of ischaemic CVA; the number of patients at risk, however, was low. Chemotherapy was not a significant risk factor for CVA. Hypertension and hypercholesterolemia were associated with increased risk of CVA.

Conclusions
Survivors of HL are at increased risk for clinically verified stroke and TIA even after prolonged follow-up. The risks are RT and gender related and substantially higher for those first treated at younger age. Limiting exposure of the neck is important in preventing CVAs after HL treatment.