Download Jacek Wachowiak

Jacek Wachowiak
COMPLICATIONS
OF CHEMO- AND RADIOTHERAPY
IN CHILDREN WITH CANCER
STANDARDS OF CONTEMPORARY
CANCER TREATMENT
• Early diagnosis
• Start of treatment as soon as possible after diagnosis
• Complex interdisciplinary treatment :
> chemotherapy (CT)
> HSCT
> radiotherapy ( RT )
> immunotherapy
> surgery
> target therapy
• Treatment exclusively in properly experienced and
equiped centers
CANONS OF CONTEMPORARY
CHEMO- AND RADIOTHERAPY OF CANCER
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Mobilization and synchronization
Multiagent
Periodicity
Long duration
Use of maximal tolerated doses of cytostatics
and
irradiation
• Selective destroy of cancer tissue with minimal
and reversible damage of healthy tissues
• Prophylaxis of complications of chemotherapy
and radiotherapy
• Supportive care
TISSUE MOST ENDANGERED TO
GENERAL AND SELECTIVE TOXICITY
OF CHEMOTHERAPY AND RADIOTHERAPY
• GENERAL TOXICITY
> tissue demonstrating high proliferative activity
- hematopoietic tissue
- lymphopoietic tissue
- epithelial tissue
> germinal cells
• SELECTIVE TOXICITY
> cardiac toxicity
> hepatotoxicity
> renal toxicity
> pulmonary toxicity
> neurotoxicity
> epiphyseal cartilage
( anthracyklines )
( antimetabolities, RT )
( cisplatin, RT )
( busulfan, bleomycin, RT )
( vincristin, RT )
( RT )
CHEMOTHERAPY & RADIOTHERAPY
OF CANCER IN CHILDREN
1. early side effects and complications
2. delayed consequences
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
I. tissue and organ toxic injury
II. compromized cellular and humoral
immunity and alteration of mucosal
and skin barriers
EARLY COMPLICATIONS
OFCANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
I. TISSUE AND ORGAN TOXICITY
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myelosupression
immunosupression
oral mucositis and gastrointestinal mucosa damage
nausea, vomiting and anorexia
hepatic toxicity
skin toxicity
renal toxicity
bladder toxicity
peripheral and central neurotoxicity
ototoxicity
cardiac toxicity
pulmonary toxicity
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• MYELOSUPRESSION
> LABORATORY EXPOTENTS
- leuko-, neutro- and monocytopenia
- thrombocytopenia
- decreased number of retikulocytes
- decreased bone marrow cellularity
> CONSEQUENCES
- infections ( mainly bacterial and fungal )
- diathesis haemorrhagica and bleedings
- anemia
MONITORING, PROPHYLAXIS AND THERAPY OF
CONSEQUENCES OF MYELOSUPRESSION
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blood cell count control
therapy modification according to WBC,
and thrombocytes counts
• thromocytopenia
# platelets concentrate transfusions
( platelet count < 20 x 109 / L )
# rekombinated thrombopoetin
• anemia
# erythrocytes transfusions
( Hb < 7 g% )
# rekombinated erythropoetin
WARNING ! All blood products should be leukocyte depleted,
screened viral infection and irradiated (24-30 Gy)
• granulocytopenia (<0.5 x 109 / L )
# infections prophylaxis, monitoring and treatment
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• IMMUNOSUPRESSION
> LABORATORY EXPOTENTS
- lymphopenia;
- hipogammaglobulinemia;
> CONSEQUENCES
- increased risk of infections, especially viral, fungal and
protozoal;
> MONITORING, PROPHYLAXIS AND TREATMENT OF
CONSQUENCES OF IMMUNOSUPRESSION
- monitoring of electrophoresis and immunoelectrophoresis;
- prophylaxis and treatment (7S-polyvalent intravenous
immunoglobulins, anti-viral drugs, anti-fungal drugs, antiprotozoal drugs);
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
- INFECTIONS AND THEIR SPECTRUM IN RELATION
TO THE TYPE OF DEFICIT IN PATIENTS DEFENSES (PART A)
• neutropenia
- Gram - positive bacteria
- Gram - negative bacteria
- fungi (Candida spp., Aspergillus spp., Mucor spp.)
• lymphopenia
# lymphocytes T
- Herpes viruses (VZV, HSV, CMV, EBV)
- Pneumocystis carinii
# lymphocytes B
- encapsulated bacteria (Streptococcus
pneumoniae, Haemophilus influenzae, Neisseria
meningitidis)
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
- INFECTIONS AND THEIR SPECTRUM IN RELATION
TO THE TYPE OF DEFICIT IN PATIENTS DEFENSES (PART B)
• decreased number of monocytes and tissue macrophages
- monocytes presents antigens to lymphocytes and
create a main source of inflammatory cytokines;
therefore monocytes are important in the host’s
defence against viral, fungal and protozoal infections
- monocytes are especially important in responding to
bacteria (Salmonella, Mycobacteria, Brucella, Listeria)
and fungi (Candida spp., Histoplasma), which act as
intracellular parasites
• damaged mucosal and skin barriers
- endogenous bacteria
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• TOXIC INJURY OF ORAL AND GASTROINTESTINAL
MUCOSA
> CLINICAL SYMPTOMS
- stomatitis with ulceration and pain
- abdominal pain, watery stools not related to
infection, hemorrhagic stools
> CONSEQUENCES
- infections (mainly with opportunistic endogenous
microflora)
- bleedings
- perforation
- worsening of general status
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• NAUSEA AND VOMITING
> PATOGENESIS
- 5HT released under the influence of cytostatics from
enterochromafin cells of stomach and gut, activates
its receptors and initiates fibers depolarization of
vagus nerve (n. X)
> CONSEQUENCES
- difficulties with oral drugs administration and oral
feeding
- exacerbation toxic injury of the mucosa in oral cavity,
pharynx and esophagus
- releuctance to treatment continuation
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• NAUSEA AND VOMITING PROPHYLAXIS
> antagonists of 5HT receptor
(ondansetron - Zofran, tropisetron - Navoban,
granisetron - Kytril)
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• HEPATOTOXICITY
> HEPATOTOXIC FACTORS
- antimetabolities ( methotrexate, merkaptopurin,
thioguanin, cytarabine )
- actinomycin D
- radiotherapy
- other factors ( viral infections - HCV, HBV, CMV, EBV;
antiviral drugs, amphotericin, long period of
parenteral nutrition )
> CONSEQUENCES
- hepatic dysfunction with increased bilirubin level,
liver enzymes activity with subsequent liver fibrosis
and insufficiency
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• HEPATOTOXICITY
> SURVEILLANCE
- serum bilirubin, AlAt, AspAt, GGTP, NH3,
electrophoresis, PTT
- liver USG
- biopsy and immunohistopathology (if necessary)
> PROPHYLAXIS
- dose of cytostatics atapted to current liver function
- prevention measueres against infection with
hepatotropic viruses (HBV, HCV)
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• CARDIAC TOXICITY
> CARDIOTOXIC FACTORS
- anthracyclines (daunorubicin, adriamycin )
> CONSEQUENCES
- unspecific arrhythmias
(acute toxicity shortly after the administration)
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• CARDIAC TOXICITY
> SURVEILLANCE
- EKG, ECHO, CK, AspAt and LHD activity in serum
> PREVENTION
- cumulative dose of doxorubicin below 550 mg/m2,
- cumulative dose of daunorubicin below 600 mg/m2
- cumulative dose of adriamycin below 450 mg/m2
- correct way of administration (duration, concentration,
period betwen subsequent doses)
- administration of dexrazoxane ( Cardioxane )
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• BLADDER TOXICITY
> PATOGENESIS
- akrolein ( urotoxic metabolite of
cyclophosphamide, which induce
hemorrhagic cystitis)
> SYMPTOMS
- dysuria
- urgency
- erythrocytes and clots in urine
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
> PREVENTION OF HEMORHHAGIC CYSTITIS
- intensive i.v. hydratation ( 3000 ml /m2 )
- diuresis stimulation
- mesna ( Uromitexan ) at the dose of
160% the dose of cyclophospamide –
binds acrolein
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• RENAL TOXICITY
> ANTINEOPLASTIC AGENTS ASSOCIATED WITH
NEPHROTOXICITY
- cisplatin
- methotexate
> PATOGENESIS
- necrosis of proximal and distal renal tubules
> CONSEQUENCES
- renal insufficency
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• RENAL TOXICITY
> SURVEILLANCE
- concentration of urea and creatinin in serum and in urine
- ccreatinine clearance;
- cisplatin; beta 2-microglobuline in urine; GGTP
- GGTP, leucinaminopeptidse, alaninaminopeptidse and Mg
in serum ;
- metotrexate – monitoring of drug concentration in blood;
> PREVENTION
- cisplatin – administration of magnesium sulphate, mannitol
for diuresis induction and hyperhydratation;
- metotrexate – hyperhydratation, diuretics,urine alkalization;
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• TUMOR LYSIS SYNDROME (TLS)
> PATOGENESIS
- hyperuricemia, hyperphosphatemia, hyperkaliemia and
symptomatic hypocalcemia resulted from death of
numerous tumor cells and release of their contents into the
circulation;
- cristalization uremic acid in renal tubules;
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• TUMOR LYSIS SYNDROME (TLS)
> PREVENTION AND THERAPY
- hyperhydratation ( 3000 ml/m2 / 24 h )
- urine alkalization pH > 7,0 ( 8,4% Natrii
bicarbonici )
- diuretics
- uric acid reduction
(allopurinol or urate oxidase)
- correction of electrolyte disturbances
- dialysis when : volume overload, hyperkaliemia,
hyperphosphatemia, hyperuricaemia,
symptomatic hypocalcemia, renal failure
- recombinated uric oxydase (conversion of uric
acid to soluble allantoin) - Rasburicase
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• PERIPHERAL NERVOUS SYSTEM TOXICITY
- Vinca alkaloids( vincristin, vinblastin )
- symptoms :
# loos of deep tendon reflexes
# neuritic pain
# paresthesias
# wrist and foot drop
# urinary retention
# paralytic ileus – most dangerous !!!
EARLY COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN
• CENTRAL NERVOUS SYSTEM TOXICITY
> metotrexate ith. +/- CNS radiotherapy
- meningeal irritation or arachnoiditis
with severe headache, stiff neck,
vomiting, lethargy, trancient or permanent
paraplegia, fever, and inflammatory
pleocytosis in the CSF;
LATE COMPLICATIONS
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• impaired linear growth and development
• impaired gonadal development and reproductions
aberrations
• disruption of function in other organ systems:
- CNS (neurologic, intellectual and psychosocial
sequelaes)
- liver
- kidney
- heart
- lungs
- pancreas
- gastrointestinal tract
- skeleton
• genetic aberrations, oncogenesis, teratogenesis
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• impaired linear growth and development
> systemic causes
- growth hormone (GH) deficiency
- thyroid hypofunction
- corticosteroids administration
- malnutrition related to chronic disease and
treatment
> local factors
- radiotherapy (dose related impaired growth of
bones and joints due to growth plates injury and
deficient blood supply related to vessels sclerosis)
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• GONADAL FUNCTION IMPAIRMENT
> gonadotoxic factors
- alkylating agents, methotrexate, doxorubicin,
vincristin, vinblastin
- radiotherapy
> boys / men
- Leydig cell hypofunction
(low testosterone blood levels)
- azoospermia lub oligospermia
(infertility)
> girls / women
- premature menopause, infertility
> hormonal substitution
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• CENTRAL NERVOUS SYSTEM LESIONS
> radiotherapy, methotrexate ith., cytarabine ith.
> leucoencephalopathy
> intellectual regression
> psychological anomalies
> neurological local symptoms
> seizures
• LIVER
> antimetabolities (methotrexate, mercaptopurine)
+/- irradiation
> veno-occlusive disease with subsequent chronic
dysfunction and liver cirrhosis
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• HEART
> radiotherapy > 45 Gy
> anthracyclines (adriamycin > 450 mg/m2,
doxorubicin > 550 mg/m2, daunorubicin 600 mg/m2)
> congestive heart failure (CHF) with arrhytmia and
sudden death
• LUNGS
> bleomycin, alkylating agents and irradiation
> lung fibrosis with restrictive impairment of ventilation
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• URINARY TRACT
> irradiation > 15-20 Gy
hypertension +/- late renal failure
> cisplatin ;
persistent injury of renal tubules with renal failure
> cyclophosphamide, ifosfamide ;
fibrosis of bladder wall
DELAYED CONSEQUENCES
OF CANCER CHEMOTHERAPY & RADIOTHERAPY
IN CHILDREN
• SECONDARY MALIGNANCY
> in 0,95% of children with acute leukemias 15
years from treatment cessation
> in 5,1% of children with Hodgkin’s disease 20 years after
treatment cessation