Endocrinopathies Associated with CNS Radiation Therapy

AAMD 44th Annual MeetingJune 16 – 20, 2019

6/20/2019

1

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.

1

2


6/20/2019

2

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

3

4


6/20/2019

3

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

5

6


6/20/2019

4

What cancers do kids get?

Li. Pediatrics. 2008

Trends in Outcomes for Pediatric Oncology

Smith MA, et al, JCO 28:2625-2634 2010

7

8


6/20/2019

5

Making Good Progress

Focusing on a few cancer types

9

10


6/20/2019

6

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

11

12


6/20/2019

7

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

13

14


6/20/2019

8

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

15

16


6/20/2019

9

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

17

18


6/20/2019

10

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

19

20


6/20/2019

11

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

21

22


6/20/2019

12

Neuroendocrine Late Effects from Radiation: Somewhat Age‐Dependent


Neuroendocrine Late Effects from Radiation


23

24


6/20/2019

13

Growth Hormone Late Effects from Radiation


Thyroid Hormone Late Effects from Radiation


25

26


6/20/2019

14

ACTH Late Effects from Radiation


Gonadotropin Late Effects from Radiation


27

28


6/20/2019

15

Neuroendocrine Late Effects from Radiation by Dose levels


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

29

30


6/20/2019

16

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

31

32


6/20/2019

17

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

33

34


6/20/2019

18

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)

35

36


6/20/2019

19

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

37

38


6/20/2019

20

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

39

40


6/20/2019

21

Craniospinal Irradiation: Reducing radiation dose to the thyroid

41

Acta Oncologica, 57:9, 1240‐1249

A cautionary article about craniospinalirradiation: tomotherapy versus 3d CRT

41

42


6/20/2019

22

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

43

44


6/20/2019

23

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

46

Acta Oncologica, 57:9, 1240‐1249

45

46


6/20/2019

24

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!

47

48

Documents

Endocrinopathies Associated with CNS Radiation Therapy