Post-radiotherapy Endocrine Effects

Endocrine Morbidity of Cancer Therapy Dr Kate Lissett Department of Diabetes & Endocrinology Torbay

Why do I need to know?• Increasing cure rates• Endocrine abnormalities are a common late effect• Pre-treatment counselling• Post-treatment screening• Knowledge of side effects may allow creation of better tolerated regimens

Which endocrine glands areinvolved?• Hypothalamo-pituitary dysfunction• Thyroid dysfunction• Thyroid carcinoma and nodules• Parathyroid dysfunction• Gonadal dysfunction

Hypothalamo-Pituitary AxisMain insult is radiotherapy used in Rx of:• Pituitary adenomas• Craniopharyngiomas• Intracranial tumours• Nasopharyngeal carcinoma• ALL• TBI for BMT

Generally GH LH/FSH ACTH TSH However ACTH may be lost before LH/FSH Hypothalamus more sensitive than pituitary

Hypothalamo-Pituitary Axis Incidence, extent and onset of deficiencies determined by: • irradiation dose • fractionation • age • pre-treatment status

GH status Age @ n Time XRT IGF-I Change in XRT since dose (ng / l) height (yrs) XRT (yrs) (24/18 SDS post Gy) XRT GH 3.9 9 20 9/0 199 -2.1 deficiency GH 5.6 11 19 9/3 205 -0.4 insufficiency ‘normal’ 12.9 12 12 3/8 314 -0.2Reassessment of GH status in survivors of childhood ALL whoreceived cranial irradiation (Brennan et al 1998. Clin Endo;48;777 - 783)

Hypothalamo-Pituitary AxisManagement: • Screen for at least 10 years • Screen growth rate and pubertal development in children • Regular biochemical screening in adults and children receiving high doses • Basal and stimulation tests • Rx is replacement

Precocious puberty50 Gy to HP axis ⇒ gonadotrophin deficiency< 50 Gy ⇒ early puberty • Males have higher threshold • Reduces time available for GH therapy • Significant psychological sequlea • Regular assessment of pubertal stage • +/- Bone age • +/- GnRH test • Rx: GnRH analogues to delay puberty

Thyroid • Hypothyroidism • Graves disease • Euthyroid Graves ophthalmopathy • Atypical thyroiditis • Thyroid cysts • Nodules (single / multiple) • Thyroid carcinoma

Hypothyroidism• XRT for treatment of lymphomas, head & neck cancer, craniospinal irradiation and TBI• Usually 30 - 50 Gy, multiple fractions• May be transient + resolve• Half of cumulative risk in first 5 years

Hypothyroidism• 27 years after irradiation for Hodgkin’s Disease 47% were hypothyroid 2% of the control population (Hancock et al 1991, NEJM, 325; 595-605)• 10 - 45% following XRT for head and neck cancers• 23 - 73% following TBI (single fraction)• 10 - 28% following TBI (multiple fractions)

HypothyroidismIncidence of hypothyroidism dependant on • dose and fractionation • prior hemithyroidectomy and cervical surgery • age < 20 years • time after XRT

HypothyroidismManagement:• Screen with twice yearly TFT initially and yearly thereafter • More frequent screening if symptomatic • Treat both definite and compensated hypothyroidism • Treatment is thyroxine

Hyperthyroidisma) Graves disease • 1677 pts treated with XRT for Hodgkin’s • 34 developed Graves disease • Predicted 7.2 - 20.4 Hancock et al 1991, NEJM 325; 595-605.b) Radiation induced thyroiditis - transient and frequently asymptomatic • Identification and treatment as for the unirradiated patient

Thyroid dysfunction and medicaltherapyInterferon & IL2 ∀ ⇑ Incidence autoimmune hypothyroidism, hyperthyroidism and thyroiditis5 flurouracil ∀ ⇑ tT3 / tT4 as a result of ⇑ TBGL- asparaginase ∀ ⇓ tT3 / tT4 as a result of ⇓ TBG, also ? ⇓ TSH secretion from pituitary

Thyroid Carcinoma• Association followed an observation that 9/28 children with thyroid Ca had received irradiation for thymic enlargement (Duffy & Fitzgerald 1950,Cancer, 3; 1018-32)• Confirmed on further epidemiological studies

Meta-analysis of 58,000 patients, XRTfield involving thyroid, predominantlychildhood therapy • Correlation between XRT dose and risk of thyroid Ca (RR 7.7/Gy, absolute risk 4.4/Gy/10,000 pt yrs) • No significant increased excess risk above 10 Gy • Little risk if XRT exposure after 20 yrs of age (Ron et al 1995, Radiation Research, 141; 259-77)

Thyroid Carcinoma• Increased risk observed in adults treated with XRT for Hodgkin’s Disease• Peak incidence of thyroid carcinoma 15-19 yrs post XRT, rare before 5 yrs• Histological types similar to that occurring in unirradiated patients• Increased frequency multicentric lesions, local invasion, distant metastasis but similar rate of progression

Thyroid nodules• Pathology: focal hyperplasia single or multiple adenomas chronic lymphocytic thyroiditis colloid nodules and fibrosis• Prevalence of palpable nodules: 1-5% in general population 20-30% in irradiated population

Thyroid nodules• Management: • T4 to suppress TSH reduces incidence of recurrent benign radiation induced nodules• In clinic Regular thyroid palpation FNA of palpable lesions Further Mx on histology

Parathyroid dysfunction• Increased risk hyperparathyroidisnm following XRT of neck - retrospective studies only• Long latency period (25-47 years)• ? many cases subclinical in both irradiated and unirradiated population• Dose response relationship supports hypothesis• Clinically: monitor Ca levels regularly

Gonadal Dysfunction-XRTTESTIS• Germinal epithelium > sensitivity than Leydig cells• Immature cells are most sensitive• < 0.8 Gy oligospermia• > 0.8 Gy azospermia• < 3 Gy spermatozoa counts fall at 60-70 days

Gonadal Dysfunction-XRT• Quicker fall with > 4 Gy as spermatids damaged• Spontaneous recovery from remaining stem cells Complete recovery at 9-18 months with < 1 Gy, 30 months with 2-3 Gy, 5 years with 4 Gy• TBI and chemotherapy for BMT results in azospermia, ?recovery

Gonadal Dysfunction-XRTLeydig cells• More resistant to XRT• Significant LH rise with > 0.75 Gy single 2.0 Gy fractionated No change in testosterone “compensated Leydig cell dysfunction”• LH normalises over 30 months

Gonadal Dysfunction-XRT• > doses result in more marked insufficiency• 10-20 Gy permanent testosterone deficiency• Replacement therapy with testosterone, especially important for puberty

Gonadal Dysfunction-ChemotherapyTESTIS• Complex• Damage and recovery dependant on drug and dosage• Germ cells more sensitive than Leydig cells

Table of cytotoxic agents known to be gonadotoxic Cytotoxic Drug Generic Drug Name Group Alkylating Agents Cyclophosphamide Chlorambucil Mustine Melphalan Busulphan Carmustine Lomustine Antimetabolites Cytarabine Vinca Alkaloids Vinblastine Others Procarbazine Cisplatin

Gonadal Dysfunction-ChemotherapyCyclophosphamide monotherapy 52/116 (45%) testicular dysfunction Correlation with dose 80% post-pubertal patients receiving a dose > 300 mg/kg had gonadal dysfunction

Gonadal Dysfunction-ChemotherapyLymphomas • MVPP for Hodgkins > 90% azospermia, ⇑ LH, normal testosterone • ABVD less gonadotoxic • NHL regimens less toxic ? Related to ⇓ dose alkylating agents or absence of procarbazine

Gonadal Dysfunction-ChemotherapyTesticular Cancer • 170 patients with germ cell carcinoma cis/carboplatin based regimens • 24% azospermia, 24% oligospermia pre-treatment

Gonadal Dysfunction-Chemotherapy• Of those normospermic recovery over long period: 48% & 80% spermatogenesis at 2 & 5 years respectively• Similar results from lung/osteosarcoma pts treated with cisplatin

Gonadal Dysfunction-Chemotherapy? Transmissible genetic damage • Demonstrated to occur in animals • Humans ⇑ abnormal spermatozoa • No ⇑ frequency of birth defects • No alteration in sex ratio or birth weights • ? Selection bias against abnormal sperm

Gonadal Dysfunction-XRTOVARY• Effects are age and dose dependent• Ovarian dose < 4 Gy infrequently associated with permanent premature ovarian failure (POF)• 97% POF from ovarian dose of 5 -10.5 Gy but 91% > 40 years, 20% > 50 years (Doll & Smith 1968. Br J Radiol, 41; 362-8)

Gonadal Dysfunction-XRT• < 40 years of age, estimated dose for POF = 20 Gy• > 40 years of age, estimated dose for POF = 6 Gy (Lushbaugh et al 1976. Cancer, 37; 1111-25)• Also loss of ovarian steroidogenesis with symptomatic of oestrogen deficiency

Gonadal Dysfunction-XRTUTERUS• XRT involving uterus during childhood can result in failure to carry a child ⇒ term• 20-30 Gy to abdomen reduced uterine length and loss of response to physiological dose exogenous E2• ? Vascular aetiology• Implications for IVF +/- donor oocytes

Gonadal Dysfunction-ChemotherapyOVARY - Hodgkin’s disease• MVPP, COPD, ChlVPP ⇒ 38-57% POF• Age > 35 yrs at Rx; POF inevitable• Retrospective study • > 1000 women, chemotherapy in childhood, menstruating at 21 years • 42% menopausal at age 31, 5% controls (Byrne et al 1992. Am J Obs Gyn 166; 788-93)

Gonadal Dysfunction-Chemotherapy• Newer regimes – ABVD• Results vary depending on age of patients treated• 0 - 44% of patients develop POF• One study (mean age 25) revealed no reduction in fertility followiABVng D Hematol Oncol 2007; 25: 11–15

Gonadal Dysfunction-Chemotherapy• Damage dose and age dependent• With ⇑ age ⇒ permanent amenorrhoea at smaller doses• Oligomenorrhoea post-therapy can ⇒ POF or resolve spontaneously• Evolution of ovarian dysfunction consistent with destruction of a fixed no. of oocytes

Gonadal Dysfunction-Chemotherapy• Older women smaller pool of oocytes ⇑ premature ovarian failure• Younger women frequently have normal ovarian function but premature menopause• < 50 yrs therapy HRT (osteoporosis, IHD, symptoms)• No evidence of ⇑ birth defects

Gonadal Dysfunction-ChemotherapyProtection of Gonadal FunctionTestis: Cryostorage of semen • ? prepubertal, ⇓ testicular function in malignant disease • ? suppression of testicular function (pre / post Rx) • ? harvest stem cells & re-implant

Gonadal Dysfunction-ChemotherapyOvary: • Cryopreservation of oocytes • Cryopreservation of strips of ovarian tissue • Protection of ovary with GnRH analogues

•From Anderson R., and Wallace H. Clinical Endocrinology “Accepted Article”

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Post-radiotherapy Endocrine Effects

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