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Late effects of treatment for childhood cancer

Late effects of treatment for childhood cancer. 1950 – 1960 5 years EFS – 20% >1990 - 70% >2000- 80%

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Late effects of treatment for childhood cancer

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  1. Late effects of treatment for childhood cancer

  2. 1950 – 1960 5 years EFS – 20% • >1990 - 70% • >2000- 80% • Approximately 1 of every 640 individualsin US betweenages of 20 and 39 yearsissurvivor of childhoodcancer • 10 cancersurvivors/100,000 healthychildren/year

  3. Children Cancer Survivor Study (CCSS) >20,000 survivorsatleast 5 years, treatedfrom 1970 to 1986 (CCSS) - standarizedmortalityrate (SMR) =10,8 • SMR higherinwomen • SMR higherinsurvivorstreated <5years of age • SMR highestinchildrentreated for: CNS tumors and acuteleukemias

  4. Causes of death • Cancer recurrence/ second neoplasm SMR =19.4 • Pulmotoxicity SMR = 9.2 • Cardiotoxicity SMR = 8.2 • infections

  5. Secondary malignancy • Standarized incidence ratio (SIR) is 6.38 for the largest observed excesses for bone (SIR=19.1) and breast cancer (SIR=16.2) a 10-fold - for subsequent CNS cancer and thyroid cancer • The cumulative incidence of SMN 20 years from the time of original cancer diagnosis is 3.2% overall and varied by diagnostic subgroups: - Hodgkin lymphoma - 7.6% - soft-tissue sarcoma - 4.0% - bone sarcoma - 3.3%

  6. Risk factors: • Primaryneoplasm (retinoblastoma, HL, STS) • Youngerageatthe time of therapy • Female sex • Radiotherapy • Chemotherapy (alkylatingagents, topoizomeraseinhibitors) • Geneticpredisposition ( Li-Fraumenisyndrome, NF t.1, Fanconi anemia, genepolimorphisme) • enviroment

  7. Hodgkin lymphoma >ALL, ANLL, CML, bone tumors, thyroid cancer, breast/ skin cancer • Retinoblastoma > osteosarcoma • Nephroblastoma (genetic form) >osteochondroma, adenocarcinoma • T-ALL > ANLL • Radiotherapy > osteosarcoma, STS, skin cancer • Radiotherapy of neck > thyroid cancer

  8. Management • Patient education • Detailed history, including family history • Careful clinical examination • Advice on reduction risk behaviours, especially smoking and sunbathing

  9. Circulatory system • Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone) , cyclophosphamide - myocytes damage due to free radicals generation • Thoracic radiation therapy - affected fine vasculature of the heart

  10. The risks to the heart are related to: -Cumulativeanthracyclinedose: >200-300mg/m2 >600mg/m2 > 30% 500- 600mg/m2 > 11% - method of administration (bolus) - youngerage (<15years of age) - female sex - trisomy 21

  11. and in addition: - hypothyroidism - ovarian failure - obesity - renal failure - hyperlipidemia - pulmonary failure - pregnancy - cong.heart disease - growth hormone therapy - sex steroid replacement therapy

  12. Cardiomyopathy • Early: at the time of treatment to 1 year after the treatment • Late: > 1 year after treatment

  13. Thoracic radiation therapy >15Gy • Delayed pericarditis • Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis • Myopathy • Coronary artery disease (CAD) • Functional valve injury • Conduction defects

  14. Signs and symptoms • Cardiomyopathy (after chemotherapy): fatigue, cough,dyspnea on exertion, peripheral edema, hypertension, tachypnea/rales, tachycardia, cardiomegaly, syncope, palpitations, arrhytmias • Valvular damage (after radiation therapy >40Gy): weakness,cough, dyspnea on exertion, new murmur • Pericardial damage ( radiation >35 Gy) : fatigue, dyspnea on exertion, chest pain, cyanosis, ascites, peripheral edema, hypotension, friction rub, muffled heart sounds, venous distension, pulsus paradoxus • Coronary artery disease (radiation > 30Gy): chest pain on exertion, dyspnea, diaphoresis, pallor, arrhytmias

  15. Diagnosis • Electrocardiogram (ST-Tchangesvoltage, decreasedvoltage) • Chestx-ray • Holter monitoring • Exercisetestingbaseline • Echocardiogram ( lower % EF, shorteningfraction <28%, higherafterload)

  16. Indications • Abnormal clinical examination & abnormal echocardiogram & planning sport & before pregnancy : ->cardiologist consultation Treatment • angiotensin converting enzyme inhibitors • cardiac transplantation

  17. Respitatory system Radiationtherapy>15 Gy (wholelungs, mediastinal, mantle, TBI): • Pneumonitisacute (>40 Gyalone - orlowerdose + dactynomycin/ anthracyclines ) signs: fever, congestion, cough, dyspnea • 12 – 14 Gy – reducedtotallungcapacity and vitalcapacity to about 70% • Pulmonaryfibroticdiseasewith permanent restrictivedisease

  18. Chemotherapy: • Bleomycine >200mg/m2 • busulphan • Lomustine, carmustine, cyclophosphamide

  19. Signs and symptoms • Fatigue • Cough • dyspnea on exertion • reduced exercise tolerance • Orthopnea • Cyanosis • finger clubbing • Rale • cor pulmonare

  20. Screening and diagnostic tests • Baseline chest x-ray • O2 saturation • Pulmonary function test

  21. Management and intervention • Advice against smoking • Pneumococcal immunisation • Annual influenze immunisation in patients with etablished lung disease

  22. Urinary system Renal failure due to: • Disease: nephroblastoma, NHL, leukemia > > renal infiltration > blood vessels compression > hypertension

  23. Chemotherapy: • Cisplatin ,carboplatin -> glomerular dysfunction - Asymptomatic or fatigue, anemia, oliguria • cisplatin, carbo, ifosfamide -> tubular dysfunction - seizures (low Magnesium!), weakness (low PO4), glikozuria, poor linear growth ifosfamide -> glomerular and tubular toxicity with renal acidosis and Fanconi’s syndrome • cyclophosphamide, ifosfamid ->hemorrhagic cystitis - Hematuria, dysuria

  24. Radiotherapy • Doses > 25 Gy to bothkidneys > renalfailureatdelayedintervals of morethan 6 months • Radiation 20 – 30 Gyor 10- 15 Gywithchemotherapy > - hypoplastickidney/ renalarteriosclerosis: *fatigue, poorlinear growth, hypertension, headache, edema, albuminuria - nephroticsyndrome * proteinuria, edema - bladder: fibrosisorhypoplasia (reducedbladdercapacity) *urgency, frequency, incontinence (nocturia), pelvichypoplasia - bladdertenderness *urinarytractinfections, renalcalculi

  25. Management and intervention • In dependence of late effect: • Glomerular dysfunction, hypoplastic kidney - low-protein diet, dialysis, renal transplant • Tubular dysfunction - Mg supplement, PO4 supplement • Nephrotic syndrome - low salt diet, diuretics

  26. Gastrointestinal tract Enteritis due to: • Chemotherapy (actinomycin D, doxorubicin) • Radiation >40Gy • Surgery (abdominal surgery enchance RT effect) - abdominal pain - diarrhea, decreased stool bulk - emesis - weigth loss, poor linear growth

  27. Adhesions due to: • Radiation • Surgery -abdominal pain - bilious vomiting - hyperactive bowel sounds Indications: * abdominal radiograph * adhesion lysis

  28. Fibrosis esophagus (stricture) due to: • Chemotherapy (actinomycine D, doxorubicine) • Radiation >50 –50 Gy • Abdominal surgery - weight loss - dysphagia - poor linear growth Indications: * esophagus dilatation * Antireflux therapy

  29. Fibrosis small intestine due to: • Radiation > 40 Gy • Abdominal surgery - diarrhea - weight loss - obstruction - abdominal pain - constipation Indications: *high –fiber diet *decompression, resection, balloon dilatation

  30. Large intestine/ colon fibrosis due to: • Radiation >40 Gy • Abdominal surgery Signs: - abdominal colic - rectal pain - constipation - melena - weight loss - obstruction Indications: * stool softeners, high-fiber diet

  31. Hepatic late effects Fibrosis/ cirrhosis due to: • Chemotherapy ( mtx, act D, 6-MP, 6-TG) • Radiation >30 Gy • Surgery • Hepatitis B/C infection

  32. Endocrine system Thyroid late effects • Overt hypothyroidism - radiation >20 Gy to the neck, cervical spine - TBI - partial or total thyroidectomy Symptoms: hoarseness, fatigue, weight gain, cold intolerance, dry brittle hairs, alopecia, constipation, lethargy, pubertal delay, bradycardia, hypotension Diagnosis: T4, TSH

  33. Compensatedhypothyroidism- asymptomatic • Hyperthyroidism –nervousness, tremor, heatintolerance, weightloss,increasedapppetite, insomnia, diarrhea, moist skin, goiter • Thyroidnodules – anydoseradiation hoarseness, fatigue, dry skin, coldintolerance, drybrittlehair, alopecia, constipation, lethargy, poorlinear growth Biopsy!

  34. Neuroendocrine late effects GH deficiency - Radiation >24 Gy - Surgery (tumor in region of H-Paxis) Adrenocorticotropichormonedeficiency - Radiation >40 Gy/ surgery Thyrotropin-releasinghormonedeficiency - Radiation > 40 Gy Precociouspuberty - Radiation >20 Gy

  35. Gonadotropindeficiency - Radiation >40 Gy/ surgery Hyperprolactinemia - Radiation >40 Gy/surgery Metabolicsyndrome: (insulin resistance, hyperglycemia, hyperinsulinemia, hypertension, hyperlipidemia, obesity): - steroids - radiation ? >18 Gy

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

  37. diminution of bone growth > lenghtdiscrepancy: lower back pain, limp,hippain, discrepancyinmuscle mass and lengthwhencomparedwithuntreatedextremity, scoliosis > pathologicalfracture >osteonecrosis (steroids, radiation >40Gy): paininaffected joint, limp >osteopenia/ osteoporosis (steroids,radiation >18 Gy)

  38. Obesity Risk factors: • Female survivors • ALL • CNS radiation • Steroids • Cranial irradiation • Genetic predisposition • Polimorphism in the leptin receptor gene • Brain tumors (hypothalamic dysfunction)

  39. Reproductive system • Male gonadalfunction: Germcelldamage (oligospermia/azoospermia) • Chemotherapy: cyclophosphamide, lomustine, carmustine, procarbazine, ifosfamide, busulfan, melphalan,dacarbazine • Radiation >1 Gy • Surgery (orchiectomyorsurgicalmanipulation) * Symptoms: testicularatrophy * Diagnosis: FSH, inhibin B, spermiogram * Management: sperm banking prior to treatment

  40. Leydigcelldamage: • Chemotherapy: cyclophosphamide, etoposide • Radiation> 12 Gy to thetestesorscatteredfrompelvis • Surgery: orchiectomy *Symptoms: delayed/arrested/absentpubertal development, lack of penile and testicularenlargement, voicechange, body odor and acne, testicularatrophy * Diagnosis: LH, testosterone * Management: testosteronereplacementregardingtestosteronedeficiency

  41. Female gonadal late effects • Ovarian failure: • Chemotherapy (cyclophosphamide,procarbazine, busulfan,melphalan, dacarbazine, carmustine, ifosfamide) • Radiation >4 Gy • Surgery: oophorectomy or oophoropexy *Symptoms: delayed/arrested pubertal development (breasts, female habitus, menses, estrogen deficiency, infertility), osteoporosis, atherosclerosis *Diagnosis: LH,FSH, inhibin B, anti-mullerian hormone *Management: hormone replacement

  42. Vagina: fibrosis/diminished growth • Chemo: act D, doxo – enhance radiation therapy effect • Radiation >40Gy Uterus: • Radiation >20 Gy (prepubertal), >40 Gy (pubertal) *Symptoms: spontaneous abortions, low birth-weight infants, small uterus *Diagnosis: usg

  43. Growth impairment • Brain tumors (craniopharyngioma) • Cranial radiotherapy > GH deficiency (>24 Gy) LH/ FSH/ ACTH/ TSH deficiency (>40 Gy) • Spinal irradiation > spinal growth is affected > skeletal disproportion • Radiation directed on the gonads • TBI • Precocious puberty after cranial irradiation • Chemotherapy, steroids

  44. Monitoring for growth problems • Regular height measurement • Endocrinologist consultation Treatment with growth hormone • Craniopharyngioma • After cranial iradiation (acute leukemia) – possibility of cancer recurrence??? • - second cancers?

  45. CNS late effects • Neurocognitivedeficits (afterradiation >18Gy, HD MTX) -difficultywith: reading, language, memory, attention, decreased IQ, poorschoolattendance, poorhand-eyecoordination • Leuko-encephalopathy (MTX, Ara-C, radiation >18 Gy) -seizures, neurologicimpairment • Focalnecrosis (MTX,cisplatin, carmustine, radiation >50 Gy) -headaches, seizures, papilledema, hemiparesis, speech/learning/memorydeficits

  46. Large vessel stroke (radiation >50 Gy) -headache, seizures, hemiparesis, aphasia, focal neurologic findings • Vision loss (cisplatin, radiation >50 Gy, surgery) -progressive visual loss • Ototoxicity (cisplatin, carboplatin, radiation >35 Gy, surgery) - abnormal speech development, hearning • Myelitis (radiation >45 Gy, surgery) -paresis, spasticity, altered sensation, loss of sphincter control

  47. Ear late effects • Chronic otitis (radiation >35 Gy) • Sensorineural hearing loss (cisplatin, carboplatin, radiation >40 Gy) • Decreased production of cerumen (radiation >30 Gy) • Chondritis ( radiation 50 Gy) • Chondronecrosis (radiation 60 Gy)

  48. Eye late effects Radiation >50 Gy: • Decreased tear production • Lacrimal duct fibrosis • Ulceration of eyelids • Conjunctiva: necrosis, scarring • Thinning of aclera • Cornea ulceration • Neovascularization • keratinization

  49. Cataract • Secondary glaucoma • Iris neovascularization • Retina: infarction, exudates, hemorrhage, teleangiectasia, neovascularization, macular edema, optic neuropathy

  50. Dental late effects • Xerostomia (decreased salivary gland function) due to radiation >40 gy • Abnormal tooth and root development due to radiation >10 Gy and chemotherapy

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