Late effects of treatment for childhood cancer

1
Late effects
of treatment for childhood cancer
2

• 1950 1960 5 years EFS 20
• gt1990 - 70
• gt2000- 80
• 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

3
Children Cancer Survivor Study (CCSS)

• gt20,000 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 lt5years of age
• SMR highest in children treated for
  CNS tumors
  and acute leukemias

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 (SIR19.1) and
  breast cancer (SIR16.2)
  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

• 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

7

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

• - Cumulative anthracycline dose
• gt200-300mg/m2
  gt600mg/m2 gt
  30
  500- 600mg/m2 gt 11
  
• - method of administration (bolus)
  - younger age
  (lt15years 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
  
  gt 1 year after treatment

13
Thoracic radiation therapy gt15Gy

• 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 gt40Gy)
  weakness,cough,
  dyspnea on exertion, new murmur
• Pericardial damage ( radiation gt35 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 gt 30Gy)
• chest pain on exertion, dyspnea,
  diaphoresis, pallor, arrhytmias
  

15
Diagnosis

• Electrocardiogram (ST-T changes voltage,
  decreased voltage)
• Chest x-ray
• Holter monitoring
• Exercise testing baseline
• Echocardiogram
• ( lower EF, shortening fraction lt28, higher
  afterload)

16
Indications

• Abnormal clinical examination abnormal
  echocardiogram planning sport before
  pregnancy
• -gtcardiologist consultation
  
  
• Treatment
• angiotensin converting enzyme inhibitors
• cardiac transplantation
  

17
Respitatory system

• Radiation therapy gt15 Gy
  (whole
  lungs, mediastinal, mantle, TBI)
• Pneumonitis acute (gt40 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

18

• Chemotherapy
• Bleomycine gt200mg/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 gt
• gt renal infiltration
• gt blood vessels compression
• gt hypertension

23
Chemotherapy

• Cisplatin ,carboplatin -gt glomerular
  dysfunction
• - Asymptomatic or fatigue, anemia, oliguria
• cisplatin, carbo, ifosfamide -gt tubular
  dysfunction
• - seizures (low Magnesium!), weakness (low
  PO4), glikozuria, poor linear growth
• ifosfamide -gt glomerular and tubular toxicity
  with renal acidosis and Fanconis syndrome
• cyclophosphamide, ifosfamid -gthemorrhagic
  cystitis
• - Hematuria, dysuria

24
Radiotherapy

• Doses gt 25 Gy to both kidneys gt renal failure at
  delayed intervals of more than 6 months
• Radiation 20 30 Gy or 10- 15 Gy with
  chemotherapy gt
  - 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

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 gt40Gy
• 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 gt50 50 Gy
• Abdominal surgery
  - weight loss
  
  - dysphagia
• - poor linear growth
• Indications
• esophagus dilatation
• Antireflux therapy

29

• Fibrosis small intestine due to
• Radiation gt 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 gt40 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 gt30 Gy
• Surgery
• Hepatitis B/C infection

32
Endocrine system

• Thyroid late effects
• Overt hypothyroidism
• - radiation gt20 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

• 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!

34
Neuroendocrine late effects

• GH deficiency
• - Radiation gt24 Gy
• - Surgery (tumor in region of H-P axis)
• Adrenocorticotropic hormone deficiency
• - Radiation gt40 Gy/ surgery
• Thyrotropin-releasing hormone deficiency
• - Radiation gt 40 Gy
• Precocious puberty
• - Radiation gt20 Gy

35

• Gonadotropin deficiency
• - Radiation gt40 Gy/ surgery
• Hyperprolactinemia
• - Radiation gt40 Gy/surgery
• Metabolic syndrome
  (insulin
  resistance, hyperglycemia, hyperinsulinemia,
  hypertension, hyperlipidemia, obesity)
• - steroids
• - radiation ? gt18 Gy

36
Musculoskeletal system

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

37

• diminution of bone growth
• gt lenght discrepancy
  
  lower back pain, limp,hip pain, discrepancy in
  muscle mass and length when compared with
  untreated extremity, scoliosis
• gt pathological fracture
• gtosteonecrosis (steroids, radiation gt40Gy)
  pain in affected
  joint, limp
• gtosteopenia/ osteoporosis (steroids,radiation
  gt18 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 gonadal function
• Germ cell damage (oligospermia/azoospermia)
• Chemotherapy cyclophosphamide, lomustine,
  carmustine, procarbazine, ifosfamide, busulfan,
  melphalan,dacarbazine
• Radiation gt1 Gy
• Surgery (orchiectomy or surgical manipulation)
• Symptoms testicular atrophy
• Diagnosis FSH, inhibin B, spermiogram
• Management sperm banking prior to treatment

40

• Leydig cell damage
• Chemotherapy cyclophosphamide, etoposide
• Radiationgt 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

41
Female gonadal late effects

• Ovarian failure
• Chemotherapy (cyclophosphamide,procarbazine,
  busulfan,melphalan, dacarbazine, carmustine,
  ifosfamide)
• Radiation gt4 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 gt40Gy
• Uterus
• Radiation gt20 Gy (prepubertal), gt40 Gy (pubertal)
• Symptoms spontaneous abortions, low
  birth-weight infants, small uterus
• Diagnosis usg

43
Growth impairment

• Brain tumors (craniopharyngioma)
• Cranial radiotherapy gt GH deficiency (gt24 Gy)
  LH/ FSH/ ACTH/ TSH
  deficiency (gt40 Gy)
• Spinal irradiation gt spinal growth is affected gt
  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

• Neurocognitive deficits
  (after
  radiation gt18Gy, HD MTX)
  -difficulty with
  reading, language, memory, attention, decreased
  IQ, poor school attendance, poor hand-eye
  coordination
• Leuko-encephalopathy
  (MTX, Ara-C,
  radiation gt18 Gy) -seizures, neurologic
  impairment
• Focal necrosis
  (MTX,cisplatin,
  carmustine, radiation gt50 Gy)
  -headaches, seizures, papilledema,
  hemiparesis, speech/learning/memory deficits

46

• Large vessel stroke (radiation gt50 Gy)
  -headache, seizures,
  hemiparesis, aphasia, focal neurologic findings
• Vision loss (cisplatin, radiation gt50 Gy,
  surgery) -progressive
  visual loss
• Ototoxicity (cisplatin, carboplatin, radiation
  gt35 Gy, surgery)
  
  - abnormal speech development, hearning
• Myelitis (radiation gt45 Gy, surgery)
  -paresis, spasticity,
  altered sensation, loss of sphincter control

47
Ear late effects

• Chronic otitis (radiation gt35 Gy)
• Sensorineural hearing loss (cisplatin,
  carboplatin, radiation gt40 Gy)
• Decreased production of cerumen (radiation gt30
  Gy)
• Chondritis ( radiation 50 Gy)
• Chondronecrosis (radiation 60 Gy)

48
Eye late effects

• Radiation gt50 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 gt40 gy
• Abnormal tooth and root development due to
  radiation gt10 Gy and chemotherapy