Late effects Late effects of treatment of treatment

for childhood cancerfor childhood cancer

1950 – 1960 5 years EFS – 20%1950 – 1960 5 years EFS – 20% >1990 - 70%>1990 - 70% >2000- 80%>2000- 80% Approximately 1 of every 640 individuals Approximately 1 of every 640 individuals

in US between ages of 20 and in US between ages of 20 and 39 years is 39 years is survivor of childhood cancersurvivor of childhood cancer

10 cancer survivors/100,000 healthy 10 cancer survivors/100,000 healthy children/yearchildren/year

Children Cancer Survivor Children Cancer Survivor Study (CCSS)Study (CCSS)

>20,000 survivors at least 5 years, treated from >20,000 survivors at least 5 years, treated from 1970 to 1986 (CCSS) 1970 to 1986 (CCSS)

- - standarized mortality rate (SMR)standarized mortality rate (SMR) =10,8 =10,8 SMR higher in womenSMR higher in women SMR higher in survivors treated <5years of ageSMR higher in survivors treated <5years of age SMR highest in children treated for: SMR highest in children treated for:

CNS tumors and acute leukemias CNS tumors and acute leukemias

Causes of deathCauses of death

Cancer recurrence/ second neoplasm Cancer recurrence/ second neoplasm SMR =19.4 SMR =19.4

Pulmotoxicity Pulmotoxicity SMR = 9.2 SMR = 9.2

Cardiotoxicity Cardiotoxicity SMR = 8.2 SMR = 8.2

infectionsinfections

Secondary malignancySecondary malignancy

Standarized incidence ratio (SIR) is 6.38 Standarized incidence ratio (SIR) is 6.38 for the largest observed for the largest observed excesses for bone excesses for bone (SIR=19.1) and breast cancer (SIR=16.2) (SIR=19.1) and breast cancer (SIR=16.2) a 10-fold - for a 10-fold - for subsequent CNS cancer and thyroid cancersubsequent CNS cancer and thyroid cancer

The cumulative incidence of SMN 20 years from The cumulative incidence of SMN 20 years from the time of original cancer diagnosis is 3.2% the time of original cancer diagnosis is 3.2% overall and varied by diagnostic subgroups: overall and varied by diagnostic subgroups:

- Hodgkin lymphoma - 7.6% - Hodgkin lymphoma - 7.6% - soft-tissue sarcoma - 4.0%- soft-tissue sarcoma - 4.0% - bone sarcoma - 3.3%- bone sarcoma - 3.3%

Risk factors:Risk factors:

Primary neoplasm (retinoblastoma, HL, STS)Primary neoplasm (retinoblastoma, HL, STS) Younger age at the time of therapyYounger age at the time of therapy Female sexFemale sex RadiotherapyRadiotherapy Chemotherapy Chemotherapy

(alkylating agents, topoizomerase inhibitors) (alkylating agents, topoizomerase inhibitors) Genetic predisposition ( Li-Fraumeni syndrome, Genetic predisposition ( Li-Fraumeni syndrome,

NF t.1, Fanconi anemia, gene polimorphisme)NF t.1, Fanconi anemia, gene polimorphisme) enviromentenviroment

Hodgkin lymphoma >ALL, ANLL, CML, Hodgkin lymphoma >ALL, ANLL, CML, bone tumors, thyroid cancer, breast/ skin bone tumors, thyroid cancer, breast/ skin cancercancer

Retinoblastoma > osteosarcomaRetinoblastoma > osteosarcoma Nephroblastoma (genetic form) Nephroblastoma (genetic form)

>osteochondroma, adenocarcinoma>osteochondroma, adenocarcinoma T-ALL > ANLLT-ALL > ANLL Radiotherapy > osteosarcoma, STS, skin cancerRadiotherapy > osteosarcoma, STS, skin cancer Radiotherapy of neck > thyroid cancerRadiotherapy of neck > thyroid cancer

ManagementManagement

Patient educationPatient education Detailed history, including family historyDetailed history, including family history Careful clinical examinationCareful clinical examination Advice on reduction risk behaviours, Advice on reduction risk behaviours,

especially smoking and especially smoking and sunbathingsunbathing

Circulatory systemCirculatory system

AnthracyclinesAnthracyclines (doxorubicin, daunorubicin, (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone) , idarubicin, epirubicin, mitoxantrone) , cyclophosphamide cyclophosphamide - myocytes damage due to free radicals - myocytes damage due to free radicals generationgeneration

Thoracic Thoracic radiationradiation therapy therapy - affected fine vasculature of the - affected fine vasculature of the heartheart

The risks to the heart are The risks to the heart are related to:related to:

-- Cumulative Cumulative anthracycline dose: anthracycline dose:

>200-300mg/m>200-300mg/m22 >600mg/m >600mg/m22 > 30% > 30% 500- 600mg/m 500- 600mg/m22 > > 11% 11%

- method of administration (bolus) - method of administration (bolus) - younger age (<15years of - younger age (<15years of age) age) - female sex - female sex - trisomy 21 - trisomy 21

and in addition:and in addition:

- hypothyroidism - ovarian - hypothyroidism - ovarian failurefailure

- obesity - renal failure- obesity - renal failure

- hyperlipidemia - pulmonary - hyperlipidemia - pulmonary failurefailure

- pregnancy - cong.heart - pregnancy - cong.heart diseasedisease

- growth hormone therapy- growth hormone therapy

- sex steroid replacement therapy - sex steroid replacement therapy

CardiomyopathyCardiomyopathy

Early: Early: at the time of treatment to 1 at the time of treatment to 1 year after the treatmentyear after the treatment

Late: Late: > 1 year after treatment > 1 year after treatment

Thoracic radiation therapy >15GyThoracic radiation therapy >15Gy

Delayed pericarditisDelayed pericarditis Pancarditis, which includes pericardial and Pancarditis, which includes pericardial and

myocardial fibrosis, with or without endocardial myocardial fibrosis, with or without endocardial fibroelastosisfibroelastosis

MyopathyMyopathy Coronary artery disease (CAD)Coronary artery disease (CAD) Functional valve injuryFunctional valve injury Conduction defectsConduction defects

Signs and symptomsSigns and symptoms

CardiomyopathyCardiomyopathy (after chemotherapy): (after chemotherapy): fatigue, cough,dyspnea on fatigue, cough,dyspnea on exertion, peripheral edema, hypertension, tachypnea/rales, exertion, peripheral edema, hypertension, tachypnea/rales, tachycardia, cardiomegaly, syncope, palpitations, arrhytmiastachycardia, cardiomegaly, syncope, palpitations, arrhytmias

Valvular damage Valvular damage (after radiation therapy >40Gy): (after radiation therapy >40Gy): weakness,cough, dyspnea on exertion, new weakness,cough, dyspnea on exertion, new murmurmurmur

Pericardial damage Pericardial damage ( radiation >35 Gy) : ( radiation >35 Gy) : fatigue, dyspnea on exertion, chest pain, cyanosis, ascites, fatigue, dyspnea on exertion, chest pain, cyanosis, ascites, peripheral edema, hypotension, friction rub, muffled heart sounds, peripheral edema, hypotension, friction rub, muffled heart sounds, venous distension, pulsus paradoxus venous distension, pulsus paradoxus

Coronary artery disease Coronary artery disease (radiation > 30Gy):(radiation > 30Gy): chest pain on exertion, dyspnea, diaphoresis, pallor, arrhytmias chest pain on exertion, dyspnea, diaphoresis, pallor, arrhytmias

DiagnosisDiagnosis

Electrocardiogram (ST-T changes voltage, Electrocardiogram (ST-T changes voltage, decreased voltage)decreased voltage)

Chest x-rayChest x-ray Holter monitoringHolter monitoring Exercise testing baselineExercise testing baseline EchocardiogramEchocardiogram

( lower % EF, shortening fraction <28%, higher ( lower % EF, shortening fraction <28%, higher afterload)afterload)

IndicationsIndications

Abnormal clinical examination & abnormal Abnormal clinical examination & abnormal echocardiogram & planning sport & before echocardiogram & planning sport & before pregnancy :pregnancy :

->cardiologist consultation ->cardiologist consultation

TreatmentTreatment- angiotensin converting enzyme inhibitorsangiotensin converting enzyme inhibitors- cardiac transplantation cardiac transplantation

Respitatory systemRespitatory system

Radiation therapy Radiation therapy >15 Gy >15 Gy (whole lungs, mediastinal, mantle, (whole lungs, mediastinal, mantle, TBI):TBI):

Pneumonitis acute (>40 Gy alone Pneumonitis acute (>40 Gy alone - or lower dose + dactynomycin/ - or lower dose + dactynomycin/ anthracyclines ) anthracyclines ) signs: fever, congestion, cough, dyspneasigns: fever, congestion, cough, dyspnea

12 – 14 Gy – reduced total lung capacity and vital 12 – 14 Gy – reduced total lung capacity and vital capacity to about 70%capacity to about 70%

Pulmonary Pulmonary fibrotic disease fibrotic disease with permanent with permanent restrictive diseaserestrictive disease

Chemotherapy:Chemotherapy:- Bleomycine >200mg/mBleomycine >200mg/m22

- busulphanbusulphan- Lomustine, carmustine, cyclophosphamideLomustine, carmustine, cyclophosphamide

Signs and symptomsSigns and symptoms

Fatigue Fatigue CoughCough dyspnea on exertiondyspnea on exertion reduced exercise tolerancereduced exercise tolerance OrthopneaOrthopnea CyanosisCyanosis finger clubbingfinger clubbing RaleRale cor pulmonarecor pulmonare

Screening and diagnostic testsScreening and diagnostic tests

Baseline chest x-rayBaseline chest x-ray O2 saturationO2 saturation Pulmonary function test Pulmonary function test

Management and interventionManagement and intervention

Advice against smokingAdvice against smoking Pneumococcal immunisation Pneumococcal immunisation Annual influenze immunisation in patients with Annual influenze immunisation in patients with

etablished lung diseaseetablished lung disease

Urinary systemUrinary system

Renal failure due to:Renal failure due to: Disease: nephroblastoma, NHL, leukemia >Disease: nephroblastoma, NHL, leukemia >

> renal infiltration> renal infiltration

> blood vessels compression> blood vessels compression

> hypertension> hypertension

Chemotherapy:Chemotherapy:

Cisplatin ,carboplatinCisplatin ,carboplatin -> glomerular dysfunction -> glomerular dysfunction

- Asymptomatic or fatigue, anemia, oliguria- Asymptomatic or fatigue, anemia, oliguria cisplatin, carbo, ifosfamidecisplatin, carbo, ifosfamide -> tubular dysfunction -> tubular dysfunction

- seizures (- seizures (low Magnesiumlow Magnesium!), weakness (low PO4), !), weakness (low PO4), glikozuria, poor linear growthglikozuria, poor linear growth

ifosfamideifosfamide -> glomerular and tubular toxicity with -> glomerular and tubular toxicity with renal acidosis and Fanconi’s syndromerenal acidosis and Fanconi’s syndrome

cyclophosphamide, ifosfamidcyclophosphamide, ifosfamid ->hemorrhagic ->hemorrhagic cystitiscystitis

- Hematuria, dysuria- Hematuria, dysuria

RadiotherapyRadiotherapy

Doses > 25 Gy to both kidneys > renal failure at delayed Doses > 25 Gy to both kidneys > renal failure at delayed intervals of more than 6 monthsintervals of more than 6 months

Radiation 20 – 30 Gy or 10- 15 Gy with chemotherapy > Radiation 20 – 30 Gy or 10- 15 Gy with chemotherapy > - hypoplastic kidney/ renal - hypoplastic kidney/ renal arteriosclerosis: *fatigue, poor arteriosclerosis: *fatigue, poor linear growth, hypertension, headache, edema, linear growth, hypertension, headache, edema, albuminuria albuminuria - nephrotic syndrome - nephrotic syndrome * proteinuria, edema * proteinuria, edema - bladder: fibrosis or hypoplasia (reduced - bladder: fibrosis or hypoplasia (reduced bladder capacity) bladder capacity) *urgency, frequency, incontinence (nocturia), pelvic *urgency, frequency, incontinence (nocturia), pelvic hypoplasia hypoplasia - bladder tenderness - bladder tenderness *urinary tract infections, renal calculi *urinary tract infections, renal calculi

Management and interventionManagement and intervention

In dependence of late effect:In dependence of late effect: Glomerular dysfunction, hypoplastic kidney Glomerular dysfunction, hypoplastic kidney

- low-protein diet, dialysis, renal - low-protein diet, dialysis, renal transplanttransplant

Tubular dysfunction Tubular dysfunction - Mg supplement, PO4 supplement - Mg supplement, PO4 supplement

Nephrotic syndrome Nephrotic syndrome - low salt diet, diuretics - low salt diet, diuretics

Gastrointestinal tractGastrointestinal tract

Enteritis due to:Enteritis due to: Chemotherapy (actinomycin D, doxorubicin)Chemotherapy (actinomycin D, doxorubicin) Radiation >40GyRadiation >40Gy Surgery (abdominal surgery enchance RT effect) Surgery (abdominal surgery enchance RT effect)

- abdominal pain - abdominal pain - diarrhea, - diarrhea, decreased stool bulk decreased stool bulk - emesis - emesis - weigth loss, poor linear growth - weigth loss, poor linear growth

Adhesions due to:Adhesions due to:

Radiation Radiation Surgery Surgery

-abdominal pain -abdominal pain - bilious vomiting - bilious vomiting - - hyperactive bowel sounds hyperactive bowel sounds Indications: Indications:

* abdominal radiograph* abdominal radiograph

* adhesion lysis* adhesion lysis

Fibrosis esophagus (stricture) due to:Fibrosis esophagus (stricture) due to: Chemotherapy (actinomycine D, doxorubicine) Chemotherapy (actinomycine D, doxorubicine)

Radiation >50 –50 GyRadiation >50 –50 Gy Abdominal surgery Abdominal surgery

- weight loss - weight loss - dysphagia - dysphagia

- poor linear growth- poor linear growthIndications:Indications:* esophagus dilatation* esophagus dilatation* Antireflux therapy* Antireflux therapy

Fibrosis small intestine due to:Fibrosis small intestine due to: Radiation > 40 GyRadiation > 40 Gy Abdominal surgery Abdominal surgery

- diarrhea - diarrhea - weight loss - weight loss

- obstruction- obstruction - abdominal pain - abdominal pain

- constipation - constipationIndications:Indications:*high –fiber diet*high –fiber diet*decompression, resection, balloon dilatation*decompression, resection, balloon dilatation

Large intestine/ colon fibrosis due to:Large intestine/ colon fibrosis due to: Radiation >40 GyRadiation >40 Gy Abdominal surgery Abdominal surgery

Signs: Signs: - abdominal colic - abdominal colic

- rectal pain - rectal pain - constipation- constipation - melena- melena - weight loss- weight loss - obstruction- obstruction Indications:Indications:* stool softeners, high-fiber diet* stool softeners, high-fiber diet

Hepatic late effectsHepatic late effects

Fibrosis/ cirrhosis due to:Fibrosis/ cirrhosis due to: Chemotherapy ( mtx, act D, 6-MP, 6-TG)Chemotherapy ( mtx, act D, 6-MP, 6-TG) Radiation >30 GyRadiation >30 Gy SurgerySurgery Hepatitis B/C infectionHepatitis B/C infection

Endocrine systemEndocrine system

Thyroid late effectsThyroid late effects Overt hypothyroidismOvert hypothyroidism - radiation >20 Gy to the neck, cervical spine- radiation >20 Gy to the neck, cervical spine - TBI- TBI - partial or total thyroidectomy- partial or total thyroidectomySymptoms: Symptoms:

hoarseness, fatigue, weight gain, cold hoarseness, fatigue, weight gain, cold intolerance, dry brittle hairs, alopecia, intolerance, dry brittle hairs, alopecia, constipation, lethargy, pubertal delay, constipation, lethargy, pubertal delay, bradycardia, hypotensionbradycardia, hypotension

Diagnosis: T4, TSHDiagnosis: T4, TSH

Compensated hypothyroidismCompensated hypothyroidism- asymptomatic- asymptomatic Hyperthyroidism –Hyperthyroidism –nervousness, tremor, heat nervousness, tremor, heat

intolerance, weight loss,increased apppetite, intolerance, weight loss,increased apppetite, insomnia, diarrhea, moist skin, goiterinsomnia, diarrhea, moist skin, goiter

Thyroid nodulesThyroid nodules – any dose radiation – any dose radiation

hoarseness, fatigue, dry skin, cold intolerance, hoarseness, fatigue, dry skin, cold intolerance, dry brittle hair, alopecia, constipation, lethargy, dry brittle hair, alopecia, constipation, lethargy, poor linear growthpoor linear growth

Biopsy!Biopsy!

Neuroendocrine late effectsNeuroendocrine late effects

GH deficiencyGH deficiency

- Radiation >24 Gy- Radiation >24 Gy

- Surgery (tumor in region of H-P axis)- Surgery (tumor in region of H-P axis)

Adrenocorticotropic hormone deficiencyAdrenocorticotropic hormone deficiency

- Radiation >40 Gy/ surgery- Radiation >40 Gy/ surgery

Thyrotropin-releasing hormone deficiencyThyrotropin-releasing hormone deficiency

- Radiation > 40 Gy- Radiation > 40 Gy

Precocious pubertyPrecocious puberty

- Radiation >20 Gy- Radiation >20 Gy

Gonadotropin deficiencyGonadotropin deficiency - Radiation >40 Gy/ surgery- Radiation >40 Gy/ surgeryHyperprolactinemiaHyperprolactinemia - Radiation >40 Gy/surgery- Radiation >40 Gy/surgery

Metabolic syndromeMetabolic syndrome: : (insulin resistance, hyperglycemia, (insulin resistance, hyperglycemia, hyperinsulinemia, hypertension, hyperlipidemia, hyperinsulinemia, hypertension, hyperlipidemia, obesity):obesity):

- steroids- steroids - radiation ? >18 Gy- radiation ? >18 Gy

Musculoskeletal systemMusculoskeletal system

Radiation therapy> 20 Gy : Radiation therapy> 20 Gy : > soft tissue hypoplasia> soft tissue hypoplasia > > assymmetry of muscle mass when compared with assymmetry of muscle mass when compared with untreated area,decreased range of motion, stiffness untreated area,decreased range of motion, stiffness and pain in affected area and pain in affected area > spinal abnormalities : > spinal abnormalities : scoliosis, kyfosis, lordosis, decreased sitting height scoliosis, kyfosis, lordosis, decreased sitting height > back > back pain, hip pain, uneven shoulder height, rib humps or pain, hip pain, uneven shoulder height, rib humps or flares, deviation from vertical curve, gait flares, deviation from vertical curve, gait abnormalitiesabnormalities

diminution of bone growthdiminution of bone growth

> lenght discrepancy: > lenght discrepancy: lower back pain, limp,hip pain, lower back pain, limp,hip pain, discrepancy in muscle mass and length when discrepancy in muscle mass and length when compared with untreated extremity, scoliosiscompared with untreated extremity, scoliosis

> pathological fracture> pathological fracture

>osteonecrosis (steroids, radiation >40Gy): >osteonecrosis (steroids, radiation >40Gy): pain in affected joint, limp pain in affected joint, limp

>osteopenia/ osteoporosis (steroids,radiation >osteopenia/ osteoporosis (steroids,radiation >18 Gy)>18 Gy)

ObesityObesity

Risk factors:Risk factors: Female survivorsFemale survivors ALLALL CNS radiationCNS radiation SteroidsSteroids Cranial irradiationCranial irradiation Genetic predispositionGenetic predisposition Polimorphism in the leptin receptor gene Polimorphism in the leptin receptor gene Brain tumors (hypothalamic dysfunction)Brain tumors (hypothalamic dysfunction)

Reproductive systemReproductive system

Male gonadal functionMale gonadal function::Germ cell damage (oligospermia/azoospermiaGerm cell damage (oligospermia/azoospermia)) Chemotherapy: cyclophosphamide, lomustine, Chemotherapy: cyclophosphamide, lomustine,

carmustine, procarbazine, ifosfamide, busulfan, carmustine, procarbazine, ifosfamide, busulfan, melphalan,dacarbazinemelphalan,dacarbazine

Radiation >1 GyRadiation >1 Gy Surgery (orchiectomy or surgical manipulation)Surgery (orchiectomy or surgical manipulation)

* * SymptomsSymptoms: testicular atrophy: testicular atrophy

* * Diagnosis: Diagnosis: FSH, inhibin B, spermiogramFSH, inhibin B, spermiogram

* * Management: Management: sperm banking prior to treatmentsperm banking prior to treatment

Leydig cell damage:Leydig cell damage: Chemotherapy: cyclophosphamide, etoposideChemotherapy: cyclophosphamide, etoposide Radiation> 12 Gy to the testes or scattered from Radiation> 12 Gy to the testes or scattered from

pelvispelvis Surgery: orchiectomySurgery: orchiectomy**SymptomsSymptoms: delayed/arrested/absent pubertal : delayed/arrested/absent pubertal

development, lack of penile and testicular development, lack of penile and testicular enlargement, voice change, body odor and acne, enlargement, voice change, body odor and acne, testicular atrophytesticular atrophy

* * DiagnosisDiagnosis: LH, testosterone: LH, testosterone* * ManagementManagement: testosterone replacement regarding : testosterone replacement regarding

testosterone deficiencytestosterone deficiency

Female gonadal late effectsFemale gonadal late effects

Ovarian failure:Ovarian failure: Chemotherapy (cyclophosphamide,procarbazine, Chemotherapy (cyclophosphamide,procarbazine,

busulfan,melphalan, dacarbazine, carmustine, busulfan,melphalan, dacarbazine, carmustine, ifosfamide)ifosfamide)

Radiation >4 GyRadiation >4 Gy Surgery: oophorectomy or oophoropexySurgery: oophorectomy or oophoropexy **Symptoms: Symptoms: delayed/arrested pubertal development delayed/arrested pubertal development

(breasts, female habitus, menses, estrogen (breasts, female habitus, menses, estrogen deficiency, infertility), osteoporosis, atherosclerosisdeficiency, infertility), osteoporosis, atherosclerosis

*Diagnosis*Diagnosis: LH,FSH, inhibin B, anti-mullerian hormone: LH,FSH, inhibin B, anti-mullerian hormone **ManagementManagement: hormone replacement: hormone replacement

Vagina: Vagina: fibrosis/diminished growthfibrosis/diminished growth Chemo: act D, doxo – enhance radiation therapy Chemo: act D, doxo – enhance radiation therapy

effecteffect Radiation >40GyRadiation >40Gy

Uterus:Uterus: Radiation >20 Gy (prepubertal), >40 Gy Radiation >20 Gy (prepubertal), >40 Gy

(pubertal)(pubertal)

*Symptoms: *Symptoms: spontaneous abortions, low birth-spontaneous abortions, low birth-weight infants, small uterusweight infants, small uterus

**Diagnosis: Diagnosis: usgusg

Growth impairmentGrowth impairment

Brain tumors (craniopharyngioma)Brain tumors (craniopharyngioma) Cranial radiotherapy > GH deficiency (>24 Gy) Cranial radiotherapy > GH deficiency (>24 Gy)

LH/ FSH/ ACTH/ TSH deficiency LH/ FSH/ ACTH/ TSH deficiency (>40 Gy)(>40 Gy)

Spinal irradiation > spinal growth is affected > Spinal irradiation > spinal growth is affected > skeletal disproportionskeletal disproportion

Radiation directed on the gonadsRadiation directed on the gonads TBITBI Precocious puberty after cranial irradiationPrecocious puberty after cranial irradiation Chemotherapy, steroidsChemotherapy, steroids

Monitoring for growth problemsMonitoring for growth problems

Regular height measurementRegular height measurement Endocrinologist consultationEndocrinologist consultation

Treatment with growth hormoneTreatment with growth hormone- CraniopharyngiomaCraniopharyngioma- After cranial iradiation (acute leukemia) After cranial iradiation (acute leukemia)

– possibility of cancer – possibility of cancer recurrence???recurrence???

- - - second cancers?second cancers?

CNS late effectsCNS late effects

Neurocognitive deficitsNeurocognitive deficits (after radiation >18Gy, HD MTX) (after radiation >18Gy, HD MTX) -difficulty with: -difficulty with: reading, language, memory, attention, decreased IQ, reading, language, memory, attention, decreased IQ, poor school attendance, poor hand-eye coordinationpoor school attendance, poor hand-eye coordination

Leuko-encephalopathyLeuko-encephalopathy (MTX, Ara-C, radiation >18 Gy) -seizures, (MTX, Ara-C, radiation >18 Gy) -seizures, neurologic impairmentneurologic impairment

Focal necrosisFocal necrosis (MTX,cisplatin, carmustine, radiation >50 Gy) (MTX,cisplatin, carmustine, radiation >50 Gy) -headaches, seizures, papilledema, -headaches, seizures, papilledema, hemiparesis, speech/learning/memory deficitshemiparesis, speech/learning/memory deficits

Large vessel strokeLarge vessel stroke (radiation >50 Gy) (radiation >50 Gy) -headache, seizures, hemiparesis, -headache, seizures, hemiparesis, aphasia, focal neurologic findingsaphasia, focal neurologic findings

Vision lossVision loss (cisplatin, radiation >50 Gy, surgery) (cisplatin, radiation >50 Gy, surgery) -progressive visual loss -progressive visual loss

OtotoxicityOtotoxicity (cisplatin, carboplatin, radiation >35 (cisplatin, carboplatin, radiation >35 Gy, surgery) Gy, surgery) - abnormal speech development, - abnormal speech development, hearninghearning

Myelitis Myelitis (radiation >45 Gy, surgery) (radiation >45 Gy, surgery) -paresis, spasticity, altered -paresis, spasticity, altered sensation, loss of sphincter controlsensation, loss of sphincter control

Ear late effectsEar late effects

Chronic otitis (radiation >35 Gy)Chronic otitis (radiation >35 Gy) Sensorineural hearing loss (cisplatin, carboplatin, Sensorineural hearing loss (cisplatin, carboplatin,

radiation >40 Gy) radiation >40 Gy) Decreased production of cerumen (radiation >30 Decreased production of cerumen (radiation >30

Gy)Gy) Chondritis ( radiation 50 Gy)Chondritis ( radiation 50 Gy) Chondronecrosis (radiation 60 Gy)Chondronecrosis (radiation 60 Gy)

Eye late effectsEye late effects

Radiation >50 Gy:Radiation >50 Gy: Decreased tear production Decreased tear production Lacrimal duct fibrosisLacrimal duct fibrosis Ulceration of eyelidsUlceration of eyelids Conjunctiva: necrosis, scarring Conjunctiva: necrosis, scarring Thinning of acleraThinning of aclera Cornea ulcerationCornea ulceration NeovascularizationNeovascularization keratinizationkeratinization

CataractCataract Secondary glaucomaSecondary glaucoma Iris neovascularizationIris neovascularization Retina: Retina:

infarction, exudates, hemorrhage, infarction, exudates, hemorrhage, teleangiectasia, neovascularization, macular teleangiectasia, neovascularization, macular edema, optic neuropathyedema, optic neuropathy

Dental late effectsDental late effects

Xerostomia (decreased salivary gland function) Xerostomia (decreased salivary gland function) due to radiation >40 gydue to radiation >40 gy

Abnormal tooth and root development due to Abnormal tooth and root development due to radiation >10 Gy and chemotherapy radiation >10 Gy and chemotherapy