Cerebrovascular disease

Radiation-induced vascular damage is a complex process that involves both arterial and capillary damage, with veins being less sensitive.

The spectrum of abnormalities includes lacunar lesions, vascular malformations, telangiectasias, intracranial hemorrhage, moyamoya, microbleeds, and cavernomas, each with potential symptomatic consequences.[54,55]

While brain tumor survivors have traditionally had the greatest risk, other survivors exposed to cranial irradiation (≥18 Gy) and neck irradiation (≥40 Gy), such as leukemia and lymphoma survivors, have also been reported to be at increased risk.[56-59]

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

Of 3,898 pediatric patients analyzed in five reports, 101 experienced at least one cerebrovascular toxicity (e.g., transient ischemic attack [TIA], stroke, moyamoya, or arteriopathy).

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

The risk of any cerebrovascular toxicity was 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy (D50, 75.6 Gy; 68.4–89.4 Gy).

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

At an attained age of 35 years, the predicted stroke incidence at d doses was 0.9% to 1.3% at 30 Gy, 1.8% to 2.7% at 45 Gy, and 2.8% to 4.1% at 54 Gy (population baseline risk, 0.2%–0.3%).

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

At an attained age of 45 years, the predicted stroke incidence was 2.1% to 4.2% at 30 Gy, 4.5% to 8.6% at 45 Gy, and 6.7% to 13.0% at 54 Gy (population baseline risk, 0.5%–1.0%).

In a PENTEC analysis, risk of cerebrovascular toxicity and future risk of stroke were analyzed and modeled (COX proportional hazards and baseline cumulative incidences of stroke in nonradiation therapy exposed, age-matched cancer patients and the general population).[60]

Thus, the risk of future cerebrovascular toxicity continues to rise as follow-up duration increases. Additionally, because the stroke hazard was based on prescribed tumor bed dose rather than circle-of-Willis dose, the reported stroke risk was likely underestimated.

In lymphoma survivors who received only chest and/or neck radiation therapy, cerebrovascular disease is thought to be caused by large-vessel atherosclerosis and cardiac embolism.[57]

The risk increases with cumulative dose received. One study (N = 325) reported that the stroke hazard increased by 5% (HR, 1.05; 95% CI, 1.01–1.09; P = .02), with each 1 Gy increase in the radiation dose, leading to a cumulative incidence of 2% for the first stroke after 5 years and 4% after 10 years.[61]

Survivors who experienced a stroke were at much greater risk of recurrent strokes.[62]

The population-based British Childhood Cancer Survivor Study (n = 13,457) used Hospital Episode Statistics data for England to assess the risk of cerebrovascular-related hospitalizations (e.g., nontraumatic intracranial hemorrhage, cerebral infarction, or cerebral artery occlusion), particularly in patients older than 50 years.[59]

The population-based British Childhood Cancer Survivor Study (n = 13,457) used Hospital Episode Statistics data for England to assess the risk of cerebrovascular-related hospitalizations (e.g., nontraumatic intracranial hemorrhage, cerebral infarction, or cerebral artery occlusion), particularly in patients older than 50 years.[59]

They found that 2.3% of the survivors had been hospitalized at least once for cerebrovascular disease, with a fourfold risk compared with the expected rate.

The population-based British Childhood Cancer Survivor Study (n = 13,457) used Hospital Episode Statistics data for England to assess the risk of cerebrovascular-related hospitalizations (e.g., nontraumatic intracranial hemorrhage, cerebral infarction, or cerebral artery occlusion), particularly in patients older than 50 years.[59]

Survivors of central nervous system (CNS) tumors or leukemia who received cranial irradiation were at greatest risk of cerebrovascular disease (CNS tumor standardized hospitalization ratio [SHR], 15.6; 95% CI, 14.0–17.4 and leukemia SHR, 5.4; 95% CI, 4.5–6.4).

The population-based British Childhood Cancer Survivor Study (n = 13,457) used Hospital Episode Statistics data for England to assess the risk of cerebrovascular-related hospitalizations (e.g., nontraumatic intracranial hemorrhage, cerebral infarction, or cerebral artery occlusion), particularly in patients older than 50 years.[59]

Beyond age 60 years, on average, 3.1% of CNS tumor survivors treated with cranial irradiation were hospitalized annually for cerebrovascular disease. By age 65 years, as many as 26% of these patients will have been hospitalized for a cerebrovascular event.

CCSS investigators observed that 295 of 13,060 participants (35% treated with cranial radiation therapy) reported having a stroke (6.3%; 95% CI, 5.1%–7.5%) by age 50 years (median follow-up, 19 years). For survivors considered to be high risk, the cumulative incidence of cerebrovascular disease up to age 50 was 19.9%.[63]

A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was formed from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[64]

A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was formed from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[64]

Patients who received radiation therapy had an 8.5-fold increased risk (95% CI, 6.3–11.0) of stroke in contrast to a nonelevated risk for patients who did not receive radiation therapy.

A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was formed from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[64]

The relative risk was 15.7 (95% CI, 4.9–50.2) for doses of 40 Gy or higher.

A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was formed from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[64]

At age 45 years, the cumulative incidence was 11.3% (95% CI, 7.1%–17.7%) in patients who received 10 Gy or higher to the circle of Willis, compared with 1% in the general population.

Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[65]

Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[65]

The investigators found that survivors of adolescent and young adult cancers had a 40% increased risk of hospitalization for cerebrovascular event compared with the general population.

Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[65]

Survivors of CNS tumors (SHR, 4.6), head and neck tumors (SHR, 2.6), and leukemia (SHR, 2.5) had the highest risk of hospitalization for a cerebrovascular complication.

Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[65]

Males had significantly higher absolute excess risks than did females, especially among head and neck tumor survivors. By age 60 years, 9% of CNS tumor survivors, 6% of head and neck tumor survivors, and 5% of leukemia survivors had been hospitalized for a cerebrovascular event.

Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[65]

The risk of hospitalization for a cerebral infarction was particularly increased among survivors of a CNS tumor older than 60 years, whereas this risk was increased across all ages in survivors of head and neck tumors.

CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[62]

CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[62]

Among responding participants (329 of 443), 271 confirmed a first stroke (at median age, 19 years) and 70 reported a second stroke (at median age, 32 years).

CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[62]

Independent predictors of recurrent stroke included treatment with a cranial radiation therapy dose of 50 Gy or higher (vs. no cranial radiation therapy), history of hypertension, and age 40 years or older at first stroke (vs. age 0–17 years).

CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[62]

The 10-year cumulative incidence of late recurrent stroke was 21% overall and 33% for those treated with 50 Gy or higher of cranial radiation therapy.

CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[62]

A follow-up study of 224 CCSS participants who experienced stroke demonstrated an increased risk of all-cause and health-related mortality and a negative impact on social attainment, neurocognitive function, emotional distress, and other health-related quality-of-life measures.[66]

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

Most ischemic events were from large-artery atherosclerosis (36%) or cardiac embolism (24%).

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

The cumulative incidence of ischemic CVA or TIA 30 years after lymphoma treatment was 7%.

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

The overall standardized incidence ratio (SIR) was 2.2 for CVA and 3.1 for TIA. However, SIR estimates appeared to be greater among childhood cancer survivors, with SIRs of 3.8 for CVA and 7.6 for TIA.

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

Irradiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR, 2.5; 95% CI, 1.1–5.6) versus no radiation therapy. Treatment with chemotherapy was not associated with increased risk.

A multicenter retrospective Dutch study evaluated 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients) who were followed for a median of 18 years. Among 2,201 survivors, 96 developed cerebrovascular disease (CVA and TIA).[57]

Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease.