Late effects
of treatment
for childhood cancer
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1950 – 1960 5 years EFS –
20%
>1990 70%
>200080%
Approximately 1 of every 640 individuals
in US between ages of 20 and 39 years
is survivor of childhood cancer
10 cancer survivors/100,000 healthy children/year
Children Cancer Survivor Study
(CCSS)
>20,000 survivors at least 5 years, treated from 1970 to
1986 (CCSS)
- standarized mortality rate (SMR)
=10,8
 SMR higher in women
 SMR higher in survivors treated <5years of age
 SMR highest in children treated for:
CNS tumors and acute leukemias
Causes of death
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Cancer recurrence/ second neoplasm
SMR =19.4
Pulmotoxicity
SMR = 9.2
Cardiotoxicity
SMR = 8.2
infections
Secondary malignancy
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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%
Risk factors:
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Primary neoplasm (retinoblastoma, HL, STS)
Younger age at the time of therapy
Female sex
Radiotherapy
Chemotherapy
(alkylating agents, topoizomerase inhibitors)
Genetic predisposition ( Li-Fraumeni syndrome, NF t.1,
Fanconi anemia, gene polimorphisme)
enviroment
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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
Management
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Patient education
Detailed history, including family history
Careful clinical examination
Advice on reduction risk behaviours,
especially smoking and sunbathing
Circulatory system
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Anthracyclines (doxorubicin, daunorubicin, idarubicin,
epirubicin, mitoxantrone) , cyclophosphamide
- myocytes damage due to free radicals generation
Thoracic radiation therapy
- affected fine vasculature of the heart
The risks to the heart are related to:
- Cumulative anthracycline dose:
>200-300mg/m2
>600mg/m2 > 30%
500- 600mg/m2 > 11%
- method of administration (bolus)
- younger age (<15years of age)
- female sex
- trisomy 21
and in addition:
-
hypothyroidism
- ovarian failure
obesity
- renal failure
hyperlipidemia
- pulmonary failure
pregnancy
- cong.heart disease
growth hormone therapy
sex steroid replacement therapy
Cardiomyopathy
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Early:
at the time of treatment to 1 year after the treatment
Late:
> 1 year after treatment
Thoracic radiation therapy >15Gy
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Delayed pericarditis
Pancarditis, which includes pericardial and myocardial
fibrosis, with or without endocardial fibroelastosis
Myopathy
Coronary artery disease (CAD)
Functional valve injury
Conduction defects
Signs and symptoms
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Cardiomyopathy (after chemotherapy):
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Valvular damage (after radiation therapy >40Gy):
fatigue, cough,dyspnea on exertion, peripheral edema,
hypertension, tachypnea/rales, tachycardia, cardiomegaly, syncope,
palpitations, arrhytmias
weakness,cough, dyspnea on exertion, new murmur
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Pericardial damage ( radiation >35 Gy) :
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Coronary artery disease (radiation > 30Gy):
fatigue, dyspnea on exertion, chest pain, cyanosis, ascites,
peripheral edema, hypotension, friction rub, muffled heart sounds,
venous distension, pulsus paradoxus
chest pain on exertion, dyspnea, diaphoresis, pallor, arrhytmias
Diagnosis
Electrocardiogram (ST-T changes voltage, decreased
voltage)
 Chest x-ray
 Holter monitoring
 Exercise testing baseline
 Echocardiogram
( lower % EF, shortening fraction <28%, higher afterload)
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Indications
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Abnormal clinical examination & abnormal
echocardiogram & planning sport & before pregnancy :
->cardiologist consultation
Treatment
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angiotensin converting enzyme inhibitors
cardiac transplantation
Respitatory system
Radiation therapy >15 Gy
(whole lungs, mediastinal, mantle, TBI):
 Pneumonitis acute (>40 Gy alone
- or lower dose + dactynomycin/ anthracyclines )
signs: fever, congestion, cough, dyspnea
 12 – 14 Gy – reduced total lung capacity and vital
capacity to about 70%
 Pulmonary fibrotic disease with permanent restrictive
disease
Chemotherapy:
- Bleomycine >200mg/m2
- busulphan
- Lomustine, carmustine, cyclophosphamide
Signs and symptoms
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Fatigue
Cough
dyspnea on exertion
reduced exercise tolerance
Orthopnea
Cyanosis
finger clubbing
Rale
cor pulmonare
Screening and diagnostic tests
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Baseline chest x-ray
O2 saturation
Pulmonary function test
Management and intervention
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Advice against smoking
Pneumococcal immunisation
Annual influenze immunisation in patients with
etablished lung disease
Urinary system
Renal failure due to:
 Disease: nephroblastoma, NHL, leukemia >
> renal infiltration
> blood vessels compression
> hypertension
Chemotherapy:
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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
Radiotherapy
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Doses > 25 Gy to both kidneys > renal failure at
delayed intervals of more than 6 months
Radiation 20 – 30 Gy or 10- 15 Gy with
chemotherapy >
- hypoplastic kidney/ renal arteriosclerosis:
*fatigue, poor linear growth, hypertension,
headache, edema, albuminuria
- nephrotic syndrome
* proteinuria, edema
- bladder: fibrosis or hypoplasia (reduced bladder
capacity)
*urgency, frequency, incontinence (nocturia), pelvic
hypoplasia
- bladder tenderness
*urinary tract infections, renal calculi
Management and intervention
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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
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
Adhesions due to:
 Radiation
 Surgery
-abdominal pain
- bilious vomiting
- hyperactive bowel sounds
Indications:
* abdominal radiograph
* adhesion lysis
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
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
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
Hepatic late effects
Fibrosis/ cirrhosis due to:
 Chemotherapy ( mtx, act D, 6-MP, 6-TG)
 Radiation >30 Gy
 Surgery
 Hepatitis B/C infection
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
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Compensated hypothyroidism- asymptomatic
Hyperthyroidism –nervousness, tremor, heat
intolerance, weight loss,increased apppetite, insomnia,
diarrhea, moist skin, goiter
Thyroid nodules – any dose radiation
hoarseness, fatigue, dry skin, cold intolerance, dry
brittle hair, alopecia, constipation, lethargy, poor linear
growth
Biopsy!
Neuroendocrine late effects
GH deficiency
- Radiation >24 Gy
- Surgery (tumor in region of H-P axis)
Adrenocorticotropic hormone deficiency
- Radiation >40 Gy/ surgery
Thyrotropin-releasing hormone deficiency
- Radiation > 40 Gy
Precocious puberty
- Radiation >20 Gy
Gonadotropin deficiency
- Radiation >40 Gy/ surgery
Hyperprolactinemia
- Radiation >40 Gy/surgery
Metabolic syndrome:
(insulin resistance, hyperglycemia, hyperinsulinemia,
hypertension, hyperlipidemia, obesity):
- steroids
- radiation ? >18 Gy
Musculoskeletal system
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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
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diminution of bone growth
> lenght discrepancy:
lower back pain, limp,hip pain, discrepancy in muscle
mass and length when compared with untreated
extremity, scoliosis
> pathological fracture
>osteonecrosis (steroids, radiation >40Gy):
pain in affected joint, limp
>osteopenia/ osteoporosis (steroids,radiation >18 Gy)
Obesity
Risk factors:
 Female survivors
 ALL
 CNS radiation
 Steroids
 Cranial irradiation
 Genetic predisposition
 Polimorphism in the leptin receptor gene
 Brain tumors (hypothalamic dysfunction)
Reproductive system
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Male gonadal function:
Germ cell damage (oligospermia/azoospermia)
 Chemotherapy: cyclophosphamide, lomustine,
carmustine, procarbazine, ifosfamide, busulfan,
melphalan,dacarbazine
 Radiation >1 Gy
 Surgery (orchiectomy or surgical manipulation)
* Symptoms: testicular atrophy
* Diagnosis: FSH, inhibin B, spermiogram
* Management: sperm banking prior to treatment
Leydig cell damage:
 Chemotherapy: cyclophosphamide, etoposide
 Radiation> 12 Gy to the testes or scattered from pelvis
 Surgery: orchiectomy
*Symptoms: delayed/arrested/absent pubertal
development, lack of penile and testicular enlargement,
voice change, body odor and acne, testicular atrophy
* Diagnosis: LH, testosterone
* Management: testosterone replacement regarding
testosterone deficiency
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
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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
Growth impairment
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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
Monitoring for growth problems
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Regular height measurement
Endocrinologist consultation
Treatment with growth hormone
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Craniopharyngioma
After cranial iradiation (acute leukemia)
– possibility of cancer recurrence???
- second cancers?
CNS late effects
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Neurocognitive deficits
(after radiation >18Gy, HD MTX)
-difficulty with: reading, language, memory, attention,
decreased IQ, poor school attendance, poor hand-eye
coordination
Leuko-encephalopathy
(MTX, Ara-C, radiation >18 Gy) -seizures, neurologic
impairment
Focal necrosis
(MTX,cisplatin, carmustine, radiation >50 Gy)
-headaches, seizures, papilledema, hemiparesis,
speech/learning/memory deficits
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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
Ear late effects
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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)
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
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Cataract
Secondary glaucoma
Iris neovascularization
Retina:
infarction, exudates, hemorrhage, teleangiectasia,
neovascularization, macular edema, optic neuropathy
Dental late effects
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Xerostomia (decreased salivary gland function)
radiation >40 gy
Abnormal tooth and root development due to
radiation >10 Gy and chemotherapy
due to