Cerebrovascular Disease in Hodgkin Lymphoma Survivors
Cerebrovascular Disease in Hodgkin Lymphoma Survivors
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a retrospective cohort study among 2,201 five-year survivors of Hodgkin lymphoma, there was a two- to three-fold increased risk of stroke and TIA. Radiation to the mediastinum and neck were associated with the increased risk, but not the use of chemotherapy.
Source: De Bruin ML, et al. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst. 2009;101:928-937.
Oncologists are aware of risks associated with providing curative therapy for cancer and, perhaps, this is best exemplified by the assortment of long-term problems encountered by individuals treated and cured of Hodgkin lymphoma. Included among these would be the appearance of myelodysplastic syndrome, acute leukemia, and other second malignancies, as well as cardiovascular disease, hypothyroidism, and gonadal failure.1-4 Also included is an apparent increased incidence of cerebrovascular disease,5,6 although this has been less extensively evaluated.
To address the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma, De Bruin et al, from the Netherlands, performed a retrospective cohort study among 2,201 five-year survivors who were treated before age 51 and between the years 1965 and 1995. They compared incidence rates of clinically verified stroke and TIA with those in the general population.
After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio (SIR), comparing patients to the general population (age and sex matched) for stroke, was 2.2 (95% confidence interval [CI] = 1.7 to 2.8) and, for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5%-8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs. without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and obesity were not.
Commentary
Thus, patients with Hodgkin lymphoma experience a two- to three-fold increased risk of stroke and TIA for a prolonged period after treatment. Radiation to the neck and mediastinum is an important contributor to cerebrovascular late effects, and this may relate to the fact that both carotids and the heart are exposed in the typical upper mantle irradiation fields. It has been proposed that such exposure might accelerate atherosclerosis7 and, this alone, might be explanatory. It is curious that, despite a plethora of potential mechanisms for increased risk of cerebrovascular disease among recipients of chemotherapy, the rates of stroke or TIA were not observed to be excessive for those patients having received chemotherapy alone. These potential risks include hypercoaguability,8 cardiotoxicity, including cardiomyopathy,9 and gonadal failure.10
Oncologists planning initial therapy for patients with Hodgkin lymphoma need to be cognizant of these consequences. With the mounting evidence for the role of radiation therapy in the pathogenesis of these adverse long-term sequelae, and the understanding that chemotherapy alone provides comparable Hodgkin lymphoma cure rates,11 we need to design treatment strategies accordingly. The likelihood is that most patients will be cured of Hodgkin lymphoma, and the strategies to minimize long-term negative consequences should be strongly considered when planning initial therapy. For those patients who currently are five years or more after completion of radiation therapy, the risk-reduction strategy should be focused on removing other modifiable factors. To reduce the chance for stroke or TIA, this would include treatment of hypertension and advice regarding the avoidance of cerebrovascular-associated lifestyle risk factors.
References
1. Aleman BM, et al. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol. 2003;21:3431-3439.
2. Aleman BM, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:1878-1886.
3. Hodgson DC, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol. 2007;25:1489-1497.
4. Travis LB, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97:1428-1437.
5. Bowers DC, et al. Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2005;23: 6508-6815.
6. Hull MC, et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA. 2003;290:2831-2837.
7. Dorresteijn LD, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol. 2002;20:282-288.
8. Serrano-Castro PJ, et al. Ischemic stroke following cisplatin and 5-fluorouracil therapy: a transcranial Doppler study. Eur Neurol. 2000;44:63-64.
9. Simmons A, et al. Anthracycline-induced cardiomyopathy. Postgrad Med. 2008;120:67-72.
10. De Bruin ML, et al. Treatment-related risk factors for premature menopause following Hodgkin lymphoma. Blood. 2008;111:101-108.
11. Longo DL. Chemotherapy alone in the treatment of patients with early stage Hodgkin's disease. Ann Oncol. 1996;7:85-89.
In a retrospective cohort study among 2,201 five-year survivors of Hodgkin lymphoma, there was a two- to three-fold increased risk of stroke and TIA.Subscribe Now for Access
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