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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

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Jacek Wachowiak

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  1. Jacek Wachowiak COMPLICATIONS OF CHEMO- AND RADIOTHERAPY IN CHILDREN WITH CANCER

  2. STANDARDS OF CONTEMPORARYCANCER 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

  3. CANONS OF CONTEMPORARY CHEMO- AND RADIOTHERAPY OF CANCER • 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

  4. 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 ( anthracyklines ) > hepatotoxicity ( antimetabolities, RT ) > renal toxicity ( cisplatin, RT ) > pulmonary toxicity ( busulfan, bleomycin, RT ) > neurotoxicity ( vincristin, RT ) > epiphyseal cartilage ( RT )

  5. CHEMOTHERAPY & RADIOTHERAPYOF CANCER IN CHILDREN 1. early side effects and complications 2. delayed consequences

  6. EARLY COMPLICATIONSOF CANCER CHEMOTHERAPY & RADIOTHERAPYIN CHILDREN

  7. EARLY COMPLICATIONSOF CANCER CHEMOTHERAPY & RADIOTHERAPYIN CHILDREN I. tissue and organ toxic injury II. compromized cellular and humoral immunity and alteration of mucosal and skin barriers

  8. EARLY COMPLICATIONS OFCANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN I. TISSUE AND ORGAN TOXICITY • 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

  9. 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

  10. MONITORING, PROPHYLAXIS AND THERAPY OF CONSEQUENCES OF MYELOSUPRESSION • 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

  11. 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, anti- protozoal drugs);

  12. 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)

  13. 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

  14. 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

  15. 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

  16. EARLY COMPLICATIONS OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN • NAUSEA AND VOMITING PROPHYLAXIS > antagonists of 5HT receptor (ondansetron - Zofran, tropisetron - Navoban, granisetron - Kytril)

  17. 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

  18. 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)

  19. EARLY COMPLICATIONS OF CANCER CHEMOTHERAPY & RADIOTHERAPY IN CHILDREN • CARDIAC TOXICITY > CARDIOTOXIC FACTORS - anthracyclines (daunorubicin, adriamycin ) > CONSEQUENCES - unspecific arrhythmias (acute toxicity shortly after the administration)

  20. 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 )

  21. 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

  22. 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

  23. 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

  24. 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;

  25. 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;

  26. 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

  27. 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 !!!

  28. 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;

  29. LATE COMPLICATIONSOF CANCER CHEMOTHERAPY & RADIOTHERAPYIN CHILDREN

  30. 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

  31. 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)

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

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