Risk of Stroke Among 5 Year Survivors of Childhood Leukemia and Brain Tumors: A Report from the Chil

1
Risk of Stroke Among 5 Year Survivors of
Childhood Leukemia and Brain Tumors A Report
from the Childhood Cancer Survivor Study

• Daniel C. Bowers
• University of Texas
• Southwestern Medical Center at Dallas
• Supported by NCI U24 CA55727

2
Introduction

• Few reports of stroke among childhood cancer
  survivors
• Survivors of childhood brain tumors
• Survivors with adult head and neck cancer
• Survivors of adult and childhood Hodgkins
  disease
• Recognized association between treatment with
  radiation therapy and subsequent stroke

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Study Objectives

• Determine the incidence of stroke among survivors
  of childhood leukemia and brain tumors
• Identify risk factors for stroke among survivors
  of childhood leukemia and brain tumors

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Childhood Cancer Survivor Study

• Multi-institutional collaborative study
• 26 Centers in the USA and Canada
• Subject eligibility
• Diagnosis of leukemia or brain tumor
• Diagnosis date between 1970 1986
• Age
• Survival of 5 years

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Childhood Cancer Survivor Study

• Self administered questionnaire
• Leukemia survivors
• Brain tumor survivors
• Comparison group Siblings of childhood cancer
  survivors
• Subjects asked if and when they had a stroke
• Did not ask about ischemic or hemorrhagic strokes
• Did not ask about TIAs or RINDs
• Medical records reviewed, including details
  regarding cancer, treatment, and co-morbidities
• Radiation doses and treatment fields
• Chemotherapeutic agents and cumulative doses
• Relapse

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Methods Subjects

• 4828 Leukemia Survivors
• Acute lymphoblastic leukemia 4152
• Acute myeloid leukemia 356
• Other leukemia 320
• 1871 Brain Tumor Survivors
• Astrocytoma/Glioma 1229
• Medulloblastoma/PNET 395
• Ependymoma 147
• Other brain tumor 100
• 3846 Siblings of childhood cancer survivors

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Methods

• The incidence rates of stroke were calculated and
  compared
• Leukemia survivors
• Brain tumor survivors
• Siblings of cancer survivors
• Cox proportional hazards models, adjusted for
  age, gender, and race, were used to estimate
  hazard ratios, reported as relative risks (RR),
  of developing stroke

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Characteristics of participating leukemia and
brain tumor survivors and siblings of childhood
cancer survivors
Leukemia Brain Tumor Variable Siblings
Survivors Survivors Total number of
participants 3846 4828
1871 p Value p Value Sex,
female 2000 52 2277 47.2 44.8 (9.3) 24.3 (7.2) () 3366 87.5 3943 81.7 85.8 0.042 Black () 99 2.6 183
3.8 73 3.9 Hispanic/Latino ()
58 1.5 132 2.7 32
1.7 Other/Missing () 323 8.4 570
11.8 161 8.6
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Characteristics of participating leukemia and
brain tumor survivors and siblings of childhood
cancer survivors
Leukemia Brain Tumor Variable
Siblings Survivors Survivors Total
number of participants 3846 4828
1871 Co-Morbidities p
Value p Value Hypertension() 80
2.1 94 2.0 0.502 30 1.6
0.167 OCP use Females only () 890 44.5
967 42.5 0.001 Diabetes () 22 0.6 98
2.0 () 1289 33.5 843 17.5 16.6 9 0.2 2 0.1 0.008 39
2.1 10
Comparison Group

• Nine siblings reported a stroke
• Rate 8.0 per 100,000 person-years 95 CI 3.85
  14.43 per 100,000 PY
• Reported rate of stroke among adults in general
  population aged 18 - 44 years old 10 to 23 per
  100,000 PY

Kristensen B. Stroke, 28 1702-1709, 1997
Marini C. Stroke, 32 52-56, 2001 Naess H.
Stroke, 33 2105-2108, 2002 Jacobs BS. Stroke,
33 2789-2793, 2002.
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Results Leukemia Survivors

• 97 Strokes / 4828 Leukemia Survivors
• Mean interval from cancer diagnosis to stroke
  5.3 years (SD 5.7 years)
• Unknown 3
• Prior to diagnosis of leukemia 3
• Diagnosis 5 years after diagnosis 54
• 5 9.9 years 24
• 10 14.9 years 5
• 15 19.9 years 5
• 20 years 3

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Results Leukemia Survivors

• 97 Strokes / 4828 Leukemia Survivors
• Mean interval from cancer diagnosis to stroke
  5.3 years (SD 5.7 years)
• Unknown 3
• Prior to diagnosis of leukemia 3
• Diagnosis 5 years after diagnosis 54
• 5 9.9 years 24
• 10 14.9 years 5
• 15 19.9 years 5
• 20 years 3

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Results Leukemia Survivors

• 37 patients with stroke 5 years after
  diagnosis
• Incidence 58.0 per 100,000 PY
• 95 CI 41.3 78.7 per 100,000 PY
• Relative risk 6.4
• 95 CI 3.0 13.8 p

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Rate, Relative Risk and 95 CI of stroke among
survivors of childhood leukemia
Number Relative Number of Strokes
Rate Risk 95 CI Siblings 3846 9
8.0 1.0 Leukemia Survivors 4768
37 58.0 6.4 3.0 13.8 Leukemia without
RT 1363 6 35.6 4.0 1.4
11.5 Leukemia RT 2726 20 52.1
5.9 2.6 13.4 Leukemia Relapse 802
18 235.7 21.6 8.6 54.2
Rate per 100,000 person years
Adjusted for age, gender, and race
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5 Year Leukemia Survivors Incidence of Stroke
(log rank p 0.51 )
16
Results

• Among leukemia survivors, strokes were not
  associated with
• Hypertension
• Diabetes
• Smoking
• Neurofibromatosis type-1
• OCP use by females
• Treatment with specific chemotherapeutic agents

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Results Brain Tumor Survivors

• 117 Strokes / 1871 Brain Tumor Survivors
• Mean interval from cancer diagnosis to stroke
  9.4 years (SD 7.9 years)
• Unknown 6
• Prior to diagnosis of brain tumor 4
• Diagnosis 5 years after diagnosis 44
• 5 9.9 years 19
• 10 14.9 years 18
• 15 19.9 years 14
• 20 years 12

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Results Brain Tumor Survivors

• 117 Strokes / 1871 Brain Tumor Survivors
• Mean interval from cancer diagnosis to stroke
  9.4 years (SD 7.9 years)
• Unknown 6
• Prior to diagnosis of brain tumor 4
• Diagnosis 5 years after diagnosis 44
• 5 9.9 years 19
• 10 14.9 years 18
• 15 19.9 years 14
• 20 years 12

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Results Brain Tumor Survivors

• 63 patients with strokes 5 years after
  diagnosis
• Rate 267.6 per 100,000 PY
• 95 CI 206.8 339.2 per 100,000 PY
• Relative risk 29.0
• 95 CI 13.8 60.7 p

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Rate, Relative Risk and 95 CI of stroke among
survivors of childhood brain tumors
Number Relative Number of
Strokes Rate Risk 95 CI Siblings
3846 9 8.0 1.0 Brain Tumor
Survivors 1817 63 267.6 29.0 13.8
60.7 Brain Tumor without RT 488 8
117.9 12.9 4.8 34.5 Brain Tumor
RT 1044 45 339.5 37.5 17.6
79.9 Brain Tumor Relapse 328 18
707.3 64.5 27.3 152.7 Brain Tumor RT
Alkylating Agent 367 24 661.1
78.3 35.1 174.5
Rate per 100,000 person years
Adjusted for age, gender, and race
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5 Year Brain Tumor Survivors Incidence of
Stroke (log rank p 0.015)
Radiation Therapy
Cumulative Incidence
No Radiation Therapy
5
10
15
20
25
30
Years Since Diagnosis
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Leukemia and Brain Tumor Survivors Association
of Dose of Radiation Therapy and Frequency of
Stroke
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Results

• Among brain tumor survivors, strokes were not
  associated with
• Hypertension
• Diabetes
• Smoking
• Neurofibromatosis type-1
• OCP use by females
• Treatment with chemotherapy agents excluding
  alkylating agents

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Conclusions

• Survivors of childhood leukemia and brain tumors
  are at significantly increased risk of stroke.
• The incidence rate of stroke is low among
  survivors of childhood leukemia but relatively
  high among brain tumors.

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Conclusions

• Higher doses of cranial radiation exposure are
  strongly associated with risk of stroke in brain
  tumor survivors
• Proposed mechanisms
• Brain Tumor Survivors
• Radiation therapy
• Alkylating agent use may reflect more intensive
  therapy
• Leukemia Survivors
• Mechanism is unknown, but may reflect CNS
  leukemia prophylaxis
• More intensive therapy for relapsed leukemia

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Acknowledgements

• Kevin C. Oeffinger, MD
• Yan Liu, MS
• D. Elizabeth McNeil, MD
• Yutaka Yasui, PhD
• Marilyn Stovall, PhD
• James Gurney, PhD
• Leslie L. Robison, PhD
• Roger J. Packer, MD