Hormone Deficiencies in Cancer Survivors MEMS Annual Congress (MAC) May 2013

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1 Hormone Deficiencies in Cancer Survivors MEMS Annual Congress (MAC) May 2013 Dr. Fuziah Md. Zain Paediatric Department

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3 Content Introduction Chronic health problems late effects Endocrine late effects Screening and monitoring Recommendation Conclusion

4 Introduction - 1 Effective treatment of childhood cancer / malignancy by paediatric oncologists. Increasing numbers of children become long-term cancer survivors. In British Columbia, 3,000 patients, > 17 yrs old, survivors of childhood cancer (1). Each year, >120 patients graduate to become adult survivors. USA : 1 of every 640 adults, years is a childhood cancer survivor (Oeffinger KC 2006). The 5-year cure rate for cancer is nearly 80% (2) Cure rates exceed 90% for ALL and Hodgkin s disease (3,4) 1) Lauren M, ) Bhatia S, ) Cohen LE, ) Marina N, 1997

5 Introduction - 2 Many survivors face long-term negative health. Many are unaware of the specific cancer therapy they received. They do not know that they may face significant long-term risks to their health & well-being (6) A need for evidence-based surveillance of the long-term effects of cancer therapy. Nearly 2/3 of all childhood cancer survivors will suffer some late effects. The endocrine system is commonly involved (5,6) 1) Lauren M, ) Sklar C ) Oeffinger KC 2006

6 Childhood Cancer Survivors 40% : may have endocrine disturbances related to underlying malignancy, surgery, radiation therapy or chemotherapy (4,6). These factors are modified by the age at which treatment was initiated, the length of time since treatment and gender (3,7) Late effects are more severe in children in comparison to survivors of adult cancers. Why? Cancer treatment is received during periods of growth & development (1). 1) Lauren M, ) Sklar C ) Gleeson HK ) Meacham L 2003

7 Childhood Cancer Survivors Acute lymphoblastic leukaemia (ALL) survivors reported more adverse general & mental health, functional impairment, & activity limitations compared with siblings (P < 0.001). Rates of marriage, college graduation, employment, and health insurance were all lower compared with sibling controls (P < 0.001). Long-term survivors of childhood ALL exhibit excess mortality & morbidity. Rajen M, Blood 2008

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9 Severity of overall & specific late effects according to risk factors JW Han, 2009

10 Late Effects Health Endocrine Cardiovascular (cardiac toxicity, coronary disease, vascular damage, CVA) Pulmonary Kidney Neurologic toxicity Neurocognitive dysfunction Recurrence of original disease Second neoplasms Post-traumatic stress disorder Late deafness Non health related Education poor educational outcome Social consequences Lauren M, BCMJ Vol 52, 2010; Rajen M et al, Blood 2008, JW Han 2009

11 JW Han, 2009

12 JW Han, 2009

13 Second Neoplasms Radiation exposure increases the risk for : Brain tumours Breast cancer Thyroid cancer Bone tumours Soft tissue sarcoma Exposure to alkylating agent & topoisomerase II inhibitors: Myeloid malignancy Myelodysplastic syndromes Benign meningiomas Lauren M 2010

14 Endocrine Late Effects Growth problems Hypothyroidism Hyperthyroidism Thyroid nodules Central adrenal insufficiency Precocious puberty Gonadotrophin deficiency Delayed puberty Premature menopause Infertility, obstetrical problems Hyperprolactinaemia Low bone mineral density Overweight / obese Metabolic syndrome, dyslipidaemia Lauren M 2010 Figure from Health Link, Children s Oncology Group

15 Studies Childhood Cancer Survivor Study (CCSS) - USA Pediatric Oncology AfterCare Program (Pediatric Oncology Group of Ontario) - Canada The Childhood, Adolescent, Young Adult Cancer Survivorship Research Program (CAYACS) British Columbia Long-term Follow-up Clinic (LTFUC) South Korea

16 Target Organ Irradiation Cranial irradiation includes cranial, orbital/eye, ear/infratemporal & nasopharyngeal Thyroid irradiation includes thyroid, neck, cervical spine, oropharyngeal, supraclavicular, mantle and mini mantle Gonadal radiation includes lumbosacral spine, abdomen and pelvis (females) and pelvis and testicular (males) Target organ irradiation has the most pronounced endocrine late effects

17 Cranial Radiation There is well-established association between the total radiation dose & development of pituitary hormone deficiencies. The GH axis is the most sensitive of the hypothalamic functions to radiation. Dose : >18 Gy Dose >40 Gy : gonadotropin, corticotropin, thyrotropin secretion may be compromised. Age of patient at the time of diagnosis and RT may affect degree of hypothalamic-pituitary damage sustained. Younger age : more deleterious effect on hypothalamaic-pituitary axis. Shalet SM 1976; Constine 1993; Brownstein CM 2004; Costin G 1988, Gleeson HK 2004, Radha N 2007.

18 Gonadal Radiation & Total Body Irradiation (TBI) TBI The effects of TBI parallel those of cranial & craniospinal RT TBI & haematopoietic cell transplantation are most often utilised as salvage therapy after primary cancer failure. Cumulative effect of aggressive use of multiagent cancer therapy - Endocrine dysfunction - Increased risk of metabolic syndrome (absence of overweight/ obesity) Ovarian TBI, abdominal, pelvic & lumbosacral irradiation especially in postpubertal female. can compromise ovarian function. Increased risk of premature menopause. High risk : Dose of radiation of >10 Gy and high dose alkylating agents. Sklar C 2005

19 Gonadal Radiation & Total Body Irradiation (TBI) Testes are particularly sensitive to irradiation. Germ cells suffer more damage compared to Leydig cells at lower levels of radiation. The efffect of testicular irradiation is highly dosedependent. Dose (Gy) Effects 1-3 Azoospermia may be reversible 3-6 Azoospermia is less likely reversible > 6 Permanent azoospermia >20 Leydig cell damage & affect testosterone production Howell SJ, 2001&2005 : Kenney LB, 2001;

20 Chemotherapy Effects of chemotherapeutic agents on the endocrine system are less extensive than radiation. Gonadal dysfunction, dyslipidaemia, osteopaenia / osteoporosis Alkylating agents, heavy metals, non-classical alkylators cause dose-related male & female gonadal dysfunction. Alkylating agents : busulfan, procarbazine, mechlorethamine, cyclophosphamide are gonadotoxic. Cumulative cyclophosphamide dose >7.5 mg/m2 : highest risk of gonadal toxicity. Combination of chemotherapy with testicular, pelvic or TBI significantly increases the gonadal dysfunction. Afify Z, 2000; Muller J 2002

21 Proposed screening & monitoring the potential late effects based on The Children s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFUG) Radha N, Caroline L, Daniel M, Melissa H, Lilian M Horm Res 2008;69:65-74, 2008

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23 Endocrine Late Effects Growth problems Hypothyroidism Hyperthyroidism Thyroid nodules Central adrenal insufficiency Precocious puberty Gonadotrophin deficiency Delayed puberty Premature menopause Infertility Hyperprolactinaemia Low bone mineral density Overweight / obese Metabolic syndrome, dyslipidaemia

24 Growth Problems History Assess nutritional status Physical frequency Every 6 months until growth complete Every 6 months until sexually mature History frequency Physical Every 6 months Height & weight BMI Tanner staging Further considerations when to refer If poorly growing: bone age & TFT Refer to endocrine: if height/weight <P3, drop >2 percentile channels, growth 4-5 cm/year Lack of pubertal growth spurt If GH deficiency, consider DEXA

25 Hypothyroidism: Central and Primary Radiation doses >10 Gy in the region of the thyroid à Hypothyroidism, rarely hyperthyroidism History & Frequency Fatigue, weight gain Cold intolerance Cobstipation Dry skin, brittle hair, depressed mood Repeat history yearly Lab studies Lab frequency Free T4 TSH Yearly Physical Height & weight Hair, skin Thyroid exam Further considerations when to refer Refer to endocrine for thyroid hormone replacement

26 Hyperthyroidism History Heat intolerance Tachycardia, palpitations Weight loss, emotional lability Muscle weakness Hyperphagia Lab studies Free T4 TSH History frequency Yearly Lab frequency Yearly Physical & frequency Eyes, skin Thyroid Cardiac Neurologic Yearly Further considerations when to refer Refer to endocrine for management of hyperthyroidism

27 Thyroid nodule Physical Physical frequency Thyroid exam Yearly Radiation doses >25 Gy --> thyroid nodules Radiation to the neck --> thyroid cancer Further considerations when to refer Ultrasound & FNA for nodule Refer to endocrine & surgery for biopsy & thyroidectomy Nuclear ablation for ablation Refer to endocrine for postop management

28 Central adrenal insufficiency Cranial RT At radiation dose >40Gy, ACTH axis may be affected to varying degrees. Lab studies 8.00 am cortisol History Failure to thrive, anorexia Dehydration, hypoglycaemia Lethargy unexplained Hypotension Lab frequency Yearly for 15 years until off therapy History frequency Yearly Further considerations When to refer If morning cortisol <10 ug/dl, refer to endocrine for further evaluation & treatment.

29 Precocious Puberty (PP) Cranial RT & Puberty Radiation dose >18 Gy à true PP, early puberty, normally-timed puberty Risk factor : female, younger age at treatment Lab studies Lab frequency LH, FSH Testosterone / oestradiol Prn signs of early puberty Physical Physical frequency Height & weight Tanner staging Testicular volume Yearly until sexually mature Further considerations When to refer If rapidly growing bone age Refer to endocrine if accelerated puberty in girls <8 yo, boys <9 yo

30 Gonadotropin deficiency, Delayed Puberty, Premature Menopause, Infertility - Females Cranial RT & Puberty Radiation dose >40 Gy Delay in puberty through gonadotropin deficiency Lab studies LH, FSH Oestradiol History Physical & frequency Pubertal (onset, tempo) Menstrual/pregnancy history Sexual function (vaginal dryness, libido) Medication use impacting sexual function Elicit history yearly Tanner stage Yearly until sexually mature Lab frequency Further considerations When to refer Begin at 13 yrs & prn Consider DEXA Refer to endocrine if delayed puberty Refer to reproductive endocrine for infertility

31 Fertility of female survivors of childhood cancer Childhood Cancer Survivor Study (CCSS) Review of 5,149 female participants in CCSS, 5-year survivors. 1,441 female siblings of CCSS participants age years. The relative risk for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90, p <0.001) compared with female siblings. Those who received hypothalamic/pituitary radiation dose >30 Gy or an ovarian/uterine radiation dose >5Gy were less likely to have ever been pregnant (RR 0.56 for 5-10 Gy, 95% CI, , RR 0.18 for >10 Gy 95% CI, ) Daniel M. Green et al, J Clin Oncol 27: , 2009

32 Gonadotropin deficiency, Delayed Puberty, Infertility - Males Cranial RT & Puberty At radiation dose >40 Gy à may delay through gonadotropin deficiency Lab studies LH, FSH Testosterone Semen analysis History Physical & frequency Pubertal (onset, tempo) Sexual function (erections, nocturnal emissions, libido) Medication use impacting sexual function Elicit history yearly Tanner stage Testicular volume Yearly until sexually mature Lab frequency Further considerations When to refer Begin at 14 yrs and prn Consider DEXA Refer to endocrine if delayed/arrested puberty Refer to reproductive endocrine for infertility Consider inhibin B

33 Hyperprolactinaemia Notes Radiation dose >40 Gy, mid-brain surgery or tumour in hypothalamic area à hyperprolactinaemia It interferes with pulsatile secretion of GnRH Lab studies Prolactin History Physical & frequency Galactorrhoea Decrease libido Menstrual history (females) To assess yearly Tanner stage Testicular volume Yearly until sexually mature Lab frequency Further considerations When to refer prn CT of sella Refer to endocrine if hyperprolactinaemia, galatorrhoea, amenorrhoea

34 Potential Late Effects Low bone mineral density Notes Lab Studies & frequency Further consideration when to refer Adverse effect from antimetabolite agents (methotrexate, corticosteroids) Altered bone metabolism (hinder acquisition of peak bone mass) Baseline Bone density evaluation DEXA or qualitative CT Refer to endocrine if osteoporosis T score >2.5 SD or history of multiple fractures Notes Lab studies & frequency Dyslipidaemia Heavy metals as carboplatin & cisplatin cause dyslipidaemia Fasting lipid profile Baseline (entry into a long term follow-up program)

35 Overweight and Obesity Cranial RT History Physical & frequency It leads to weight management issues Risk factors : - Females - children <4 yo - hypothalamic radiation dose >18 Gy Overweight : - Age 2-20 : BMI >P Age >21 : BMI Obese : - Age 2-20 : BMI >P95 - Age >21 : BMI >30 Height & weight, BMI BP Yearly Lab studies Lab frequency Further considerations When to refer FBS Fasting serum insulin Fasting lipid profile Every 2 yrs in overweight / obese patients Every 5 years in normal weight patients Refer to endocrine if insulin resistance / metabolic syndrome Nutrition, cardiology referrals

36 Care of Childhood Cancer Survivor (CCS) Comprehensive follow-up care strategy is needed. Many cancer centres have comprehensive, long-term follow-up clinics where interdisciplinary teams screen for late effects based on published guidelines (1) Source of referral to paediatric endocrinologists. Life long surveillance should be supported by an ongoing registry for adult survivors of childhood cancer Vital facts : diagnosis, treatment, risk category for late effects, monitor any subsequent health problems (2) 1) Landier W ) Lauren M 2010

37 Surveillance Monitoring All survivors should have a medical summary details of diagnosis & therapy. Counseling (by nurse practitioners, physicians) anticipated health risks. Survivors should consent to annual contact (directly or via GP) for F/U of their health. Provide risk-based guidelines to patients & health care professionals. Hewitt M, 2005; Lauren M 2010

38 General Recommendations - 1 Education on healthy lifestyle Minimize the added effects of obesity on CVD Minimize the risk of malignancy associated with obesity. Anthracyclines therapy ECHO to measure EF & fractional shortening ECG every 5 years. Chest radiation (female) Mammography or MRI breast screening starting at age 25. Kremer LC 2001, Steinherz LJ, 1992, Lalonde L 2005, Lee CH 2005

39 General Recommendations - 2 Radiation to the brain Screen for benign meningiomas MRI starting 10 yrs post-treatment Radiation to the thyroid Pelvic radiation Screen for thyroid nodules Perform US neck starting 5 yrs posttreatment TFT T4 & TSH Risk of infertility Premature menopause Early pregnancy loss & premature delivery (uterine insufficiency) Winther JF 2008, Reulen RC 2009, Lauren M 2010

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43 Conclusion The most common late effects were associated with the endocrine system. The timely & appropriate recognition of the endocrine sequelae can dramatically improve the QoL of these survivors. Many questions about the late endocrine effects of childhood cancer therapy remain unanswered. Cancer survivors must be continuously monitored after the completion of cancer treatment. A program is needed to provide life-long health surveillance, counseling and a registry for this population.

44 Thank you