Clinical Investigation
Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries

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Background and Purpose

The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer.

Methods

We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT.

Results

Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients.

Conclusion

The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.

Introduction

It is well established that exposure to radiation increases the risk of stroke, and the dose response to radiation has been investigated in several studies (1). Nevertheless, present knowledge is insufficient to predict the long-term risk of stroke after radiation therapy (RT) because the dose response to fractionated high doses of radiation to the brain is not known. This lack of knowledge is of special concern for RT to children because of the greater radiation sensitivity of children. Although the spinal cord, optic nerves, and chiasma are considered organs at risk (OARs) under national guidelines for RT, the cerebral arteries are not 2, 3.

Mortality due to cerebrovascular diseases has been studied in large cohorts of childhood cancer survivors 4, 5, 6, and stroke risk has been studied in long-term survivors of Hodgkin disease (7), leukemia, and brain tumors (8).

The role of the maximal radiation dose received during cranial irradiation in the risk of stroke (9) and in the risk of recurrent stroke in survivors who have experienced a first stroke (10) has been investigated in the large United States Childhood Cancer Survival Study (CCSS). Nevertheless, the same maximal radiation dose received during cranial irradiation could recover very different dose distributions and therefore very different radiation doses to the OARs to be considered when the relation between irradiation and stroke risk is investigated. Additionally, new RT modalities and treatment techniques, which include intensity modulated RT (IMRT) and proton therapies, result in different organ dose distributions.

To be able to anticipate the stroke risk in former patients, and to predict the stroke risk of current treatments, it is necessary to identify such OARs and to investigate the role of radiation dose received by these organs and its potential dose-response modifiers in the risk of stroke. The aim of this study was to evaluate these risk factors in a cohort of 3172 5-year survivors of solid childhood cancer.

Section snippets

Patients

Euro2K is a retrospective cohort of children treated from 1942 to 1985 in 8 centers in France and the United Kingdom. It was constituted from 1985 to 1995, and the children have been prospectively followed up since. To be included in the cohort, the patients had to be alive 2 years (France) or 3 years (UK) after a first cancer diagnosis before the age of 16 years (before 15 in UK centers). The constitution of the cohort was first described in 1995 (11). In this publication, the cohort included

Radiation dose pattern: Circle of Willis

The average radiation dose received to the WC arteries was 22 Gy for brain tumors, 13 Gy for non-Hodgkin lymphoma (NHL), and 9 Gy for retinoblastoma (Fig. E2; available online at www.redjournal.org). The high radiation dose to the WC (13 Gy) for the NHL is due to the fact that prophylactic irradiation of the brain was quasisystematic in France for NHL before 1974 and for high-grade NHL afterward.

Stroke risk

During a median follow-up time of 26 years, 54 patients experienced a permanent stroke that could be

Discussion

To our knowledge, this is the first study to investigate in detail the relation between the radiation dose to the WC arteries, rather than the maximal radiation dose received to the brain, and the risk of late-occurring strokes after childhood cancer. It included medical validation and a complete description of the type and location of each stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median of 26 years. It indicated that the main risk factor for

Acknowledgment

The authors thank Martine Labbé, MSc, and Catherine Paoletti, MSc for their help in data management, and the physicians and physicists who participated in the elaboration of the study or data collection at the Gustave Roussy (Villejuif), Thames Cancer Registry (London), Institut Godinot (Reims), Institut Curie (Paris), Centre Regaud (Toulouse), and Centre Lacassagne (Nice).

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    Supported by the Ligue Nationale Contre le Cancer, CerebRad FP7 project (Grant Agreement No. 295552), Institut de Recherche en Santé Publique, Programme Hospitalier de Recherche Clinique, Electricité de France, the Fondation Force, the Wyeth Foundation for Childhood and Adolescent Health, National Institute of Cancer, and the Agence Nationale Pour la Recherche.

    Conflict of interest: none.

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