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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Endocrinopathies Associated with CNS Radiation Therapy
Ralph Ermoian, MDAssociate Professor of Radiation Oncology
University of Washington
Disclosures
• I am employed by the University of Washington.
• My sites of practice include the University of Washington Medical Center, Seattle Children’s Hospital, and the Seattle Cancer Care Alliance Proton Therapy Center.
• I have no conflicts of interest to disclose.
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AAMD 44th Annual MeetingJune 16 – 20, 2019
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Learning Objectives
The medical dosimetrist will be able to:– Identify resources to reproducibly contour the hypothalamus
– Discuss recent advancements in research about late endocrine effects of radiation therapy
– List 4 strategies for reducing late endrocrineeffects in radiation therapy
Outline
• Background
• Hypothalamic‐Pituitary Axis
• Thyroid
• Ovaries
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AAMD 44th Annual MeetingJune 16 – 20, 2019
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Where do CNS cancers fit into overall picture
of Cancer in the United States? Incidence.
Pediatric cancers: 12,500 cases in patients up to 15 years old CA Cancer J Clin 2017; 67:7‐30
Deaths from Cancer
1,284 children (age 0‐14) died of cancer in 2008
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AAMD 44th Annual MeetingJune 16 – 20, 2019
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What cancers do kids get?
Li. Pediatrics. 2008
Trends in Outcomes for Pediatric Oncology
Smith MA, et al, JCO 28:2625-2634 2010
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Making Good Progress
Focusing on a few cancer types
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AAMD 44th Annual MeetingJune 16 – 20, 2019
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Long‐term Mortality of Medulloblastoma Treatment
• Treatment usually includes craniospinal irradiation with a boost
• Childhood Cancer Survivor Study report
• Solloum. JCO. 2019
• 1,311 medulloblastomapatients from 1970s through 1990s
Long‐term Morbidity: Endocrine, Hearing, Vision, Pulmonary, Cardiovascular, Neurologic
Solloum. JCO. 2019
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AAMD 44th Annual MeetingJune 16 – 20, 2019
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Hypothalamic Pituitary Axis
• How the body regulates most of its hormones– Reproduction
– Salt/fluid management
– Muscle and bone growth
– Adrenal gland
– Thyroid
– Lactation
Pituitary Gland and Hypothalamus
• Pituitary gland: the easy one. In the sella turcica
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Pituitary Gland and Hypothalamus• Hypothalamus: the
hard one.– Below line from
anterior commissure to posterior commissure
– Above pituitary stalk– Beside 3rd ventricle Elson. Front Onc. 2014
Pituitary Gland and Hypothalamus• Hypothalamus: the
hard one.– Below line from
anterior commissure to posterior commissure
– Above pituitary stalk– Beside 3rd ventricle
• Dr. Ladra also has a contouring training on the AAMD website
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Neuroendocrine Late Effects from Radiation
Late Effect Radiation
GH deficiency >18 Gy to hypothalamic‐pituitary (HP) axis
Adrenocorticotropic hormone deficiency >40 Gy to HP axis
Thyrotropin‐releasing Hormone Deficiency >40 Gy to HP axis
Precocious puberty (especially girls) >20 Gy to HP axis
Male gonadotropin deficiency >40 Gy to hypothalamic region
Female gonadotropin deficiency >40 Gy to hypothalamic region
Hyperprolactinemia >40 Gy to HP axis
Metabolic syndrome ?>18 Gy to HP axis
Friedman and Constine. Late Effects of Cancer Treatment. in Pediatric Radiation Oncology. 5th edition. Haperin, Constine, Tarbell, Kun eds. Lippincott williams and Wilkins. 2010.
Growth Hormone Deficiency
• Can affect child’s growth
• Also involved in adults regulation of muscle development and fat, among other functions
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Adrenocorticotropic hormone (ACTH) deficiency
• Weakness
• Hypoglycemia
• Weight loss
Treated with steroids
HyperprolactinemiaWomen•Loss of periods and reduced libido•Breast milk secretion•Infertility
Men•Progressive loss of libido•Impotency•Low sperm count•Breast enlargement
https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/pituitary_center/conditions/hyperprolactinemia.html
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6/20/2019
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Vatner, et al paper
• J Clin Oncol. 2018 Oct 1;36(28):2854‐2862
• 222 pediatric and young adult patients with brain tumors treated with protons
• Median follow up 4.4 years
Neuroendocrine Late Effects from Radiation: Dose Dependent
Vatner, et al. JCO. 2018
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Neuroendocrine Late Effects from Radiation: Somewhat Age‐Dependent
Vatner, et al. JCO. 2018
Neuroendocrine Late Effects from Radiation
Vatner, et al. JCO. 2018
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Growth Hormone Late Effects from Radiation
Vatner, et al. JCO. 2018
Thyroid Hormone Late Effects from Radiation
Vatner, et al. JCO. 2018
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ACTH Late Effects from Radiation
Vatner, et al. JCO. 2018
Gonadotropin Late Effects from Radiation
Vatner, et al. JCO. 2018
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Neuroendocrine Late Effects from Radiation by Dose levels
Vatner, et al. JCO. 2018
General Strategies for Avoiding Radiation Effects
• Don’t treat with radiation. Always happy to choose this one.
• Move the organ that would be effected. Not an option in most endocrine organs
• Minimize dose to the organ
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Reduce the dose to the Pituitary Gland and Hypothalamus: Neck extension
Fusia = Pituitary Light Blue = Hypohalamus Yellow = PTV
Strategies for Avoiding Radiation Effects: Modality of Radiation
• Limits side effects because almost no exit dose
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Infratentorial Ependymoma: MGH Series
MacDonald. Neuro-Oncology. 2013
Treat post-op resection bed to 54-59.4 Gy. Only 2 of 44 patients went on to require GH replacement
Endocrine Outcomes: Protons vs Photons
Eaton, et al. Neuro‐oncology. 2016
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Neuroendocrine Outcomes for Average Risk Medulloblastoma: Photons vs. Protons
Eaton. Neurooncology. 2016
Protons Cost Effective When Reduce Dose to Pituitary Gland (Mailhot Vega, et al, 2015)
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There are limits to how much protons can help
• One has to plan accounting for range uncertainties, set up error, etc
• Small organs at risk abutting the target often cannot be spared– The pituitary function can be protected when treating an infratentorial ependymoma
– The pituitary function cannot be protected when a pituitary adenoma is being treated
Hypothyroidism Craniospinal Irradiation
Chow. Ped Blood and Cancer. 2009
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Thyroid Dysfunction Outcomes for Average Risk Medulloblastoma: Photons vs. Protons
Eaton. Neurooncology. 2016
Challenges to Reducing Dose to Thyroid in Craniospinal Irradiation
• In skeletally immature patients, one reduces asymmetric grow by delivering (most) of the dose to all of the vertebral body, almost abutting the thyroid
• IMRT can provide more conformal radiation but at the expense of higher integral dose
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Craniospinal Irradiation: Reducing radiation dose to the thyroid
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Acta Oncologica, 57:9, 1240‐1249
A cautionary article about craniospinalirradiation: tomotherapy versus 3d CRT
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Reproductive Late Effects from Radiation
Late Effect Radiation
Ovarian Failure 4‐12 Gy with tolerance decreasing with age
Temporary azospermia 0.1‐0.3 Gy to testicles
Permanent azospermia 3‐4 Gy to testicles
Permanent azospermia and reduced testicular volume with elevated FSH and LH
12 Gy to testicles
Permanent azospermia and reduced testicular volume with elevated FSH and LH (more severe)
24 Gy to testicles
Friedman and Constine. Late Effects of Cancer Treatment. in Pediatric Radiation Oncology. 5th edition. Haperin, Constine, Tarbell, Kun eds. Lippincott williams and Wilkins. 2010.
Ovarian Function Effects from Craniospinal Irradiation
• Balachandar, et al. Pediatric Blood Cancer. 2015
• 26 girls treated with craniospinal irradiation
• 3 had long term ovarian failure requiring hormone replacement
– Rate was less than in more intensive chemotherapy that allows patients to avoid craniospinal irradiation
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Practically‐speaking one does not transpose the ovaries for this risk
• Risks of surgery
• Urgent to start radiation
• Transposed ovaries may preserve endocrine function but fertility is more complicated
Craniospinal Irradiation: Reducing radiation dose to the thyroid
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Acta Oncologica, 57:9, 1240‐1249
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AAMD 44th Annual MeetingJune 16 – 20, 2019
6/20/2019
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Strategies to reduce ovarian dose
• Contour it as an organ at risk and limit dose to 4 Gy or less• Have the gynecologists transpose it superior and laterally
• Not a reasonable option in this context, but an option when treating to higher doses in pelvic tumors
• Consider treating with empty bladder when uterus is anteverted; consider how bladder filling will affect calculated dose
Thank you!
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