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DR. J.A.

DOGBE
COSULTANT PAEDIATRICIAN/PUBLIC HEALTH SPECIALIST SMS-KNUST/KATH

OUTLINE OF THE VARIOUS PAEDIATRIC CANCERS THE CELL LIFE CYCLE GENERAL PRINCIPLES OF DIAGNOSIS MAIN INDIVIDUAL FEATURES PRINCIPLES OF CHEMOTHERPY SOPPORTIVE CARE

HODGKIN DISEASE NON-HODGKIN LYMPHOMAS CNS MALIGNANCIES NEUROBLASTOMA WILMS TOMOUR

RHABDOMYOSARCOMA & OTHER SOFT TISSUE SARCOMAS MALIGNANT BONE TUMOURS HISTIOCYTOSIS SYNDROME RETINOLASTOMA MISCELLNEOUS TUMOURS

The process of cell division by normal and malignant cells There are 5 phases to the process Phase 1:Gap 0(G0) Phase 2:Gap 1(G1) Phase 3:S-phase Phase 4:Gap 2(G2) Phase 5:M-phase

G0 phase Cell rests and receives nourishment Rapidly dividing cells may rest for a short time or bypass to next phase G1 phase Lasts hours to days RNA and proteins needed for DNA synthesis are produced

Synthesis phase; S (8-12hrs) RNA, Protein, DNA synthesis occur and DNA replicates Chemical reactions occur between various amino acids resulting in a double stranded DNA helix DNA helix serves as the genetic template of the cell

G2 phase Lasts 2-4Hrs More RNA and protein synthesis takes place in prep for mitosis

Phase 5:M-phase has sub-phases Prophase Metaphase Anaphase Telophase

M phase The cell progresses through sub-phases Cytoplasm and nucleus divide with replication of cells and birth to 2 daughter cells

Not clearly understood how body maintains cellular homeostasis Postulated that body has a feedback system that signals a cell to multiply in response to cell death Principles of cellular growth (inhibition, adhesion and differentiation)

Cancer cells defy these principles

Most cancers have Proliferating and Resting cells


Number of cells in cycle are called the growth fraction of the tumor

HISTORY PHYSICAL EXAMINATION INVESTIGATIONS DIAGNOSIS STAGING INVESTIGATION*

FOR DIAGNOSIS FOR SAFE TREATMENT

DISCUSS Hematological studies FNA Biopsy Biochemical studies Immunological evaluation Radiologic studies: x-rays, US, CT, MRI

Discussion
CNS MALIGNANCIES HISTOLOGY HISTORY PHYSICAL EXAM INVESTIGATIONS

SURGERY RADIATION CHEMOTHERAPY BIOLOGIC RESPONSE MODIFIERS (BRMS) COMBINATION

Introduction to cancer chemotherapy Chemotherapy and cell life cycle Treatment strategies Classification of chemo agents Biologic Response Modifiers (BRMs)*

Use of chemotherapeutic agents to destroy cancer cells Goals: cure, control, palliation Primary treatment and adjunct

Two main categories of drugs

Cell-cycle specific
Cell-cycle non-specific

GOALS OF CELL-CYCLE SPECIFIC CHEMO

Administered in divided doses or continuous infusion


These drugs reduce the growth fraction

GOALS OF CELL-CYCLE NON-SPECIFIC

Cause death independent of proliferating state of the cell Given in bolus Reduce the tumor burden (no. of cells in tumor)

GOALS OF COMBINATION CHEMO

To achieve maximum tumor cell kill Cycle-specific and cycle-nonspecific drugs are given in combination to reduce growth fraction and burden Given in courses (cycles) Number of cycles vary depending on cancer type, chemo agent and patient response

GOALS OF COMBINATION CHEMO


Drugs used in combination should have:

Demonstrated anti-tumor activity Diff mechanisms of action Produce synergy

Similar side effects at diff points in time

Chemo agents are used in the following strategies:

Adjuvant: short course of high dose, usually combination drugs given after rad. or surg.
Neoadjuvant: adjuvant drugs used pre- or perioperative period

Induction: usually in Haematologic malignancies. A combination of high dose drugs to induce complete response when initiating a curative regimen Consolidation: given after induction has achieved a complete remission. Repeated to increase cure rate or prolong survival

Intensification: after complete remission is achieved, same agents used in induction or diff agents are given at high doses to effect better cure rate or longer remission Maintenance: single or combination, low dose given on long term basis in remission to delay re-growth of residual cancer cells

Palliative: given to prolong life or control symptoms if cure is not possible Salvage: curative high dose given when symptoms have recurred or treatment has failed with another regimen

Cell-cycle specific agents:

Plant alkaloids: arrest metaphase in M-phase VINCRISTINE, VINBLASTINE Antimetabolites: (anti-folate) arrest S-phase METHOTREXATE, CYTOSINE ARABINOCIDE

Cell-cycle nonspecific agents:

Alkylating agents: destroy DNA genetic template leading to cell lysis. e.g. CYCLOPHOSPHAMIDE
Antitumor antibiotics: prevent cell division by interfering with RNA and DNA synthesis. E.g. DOXORUBICIN, DACTINOMYCIN

Cell-cycle nonspecific agents:

Hormones: blocks naturally occurring substances that stimulate tumor growth


Glucocorticoids e.g. prednisolone Estrogenes e.g. diethylstilbestrol Androgenes e.g. testosterone

CUTANEOUS TOXICITY Most devastating and constant reminder of cancer is Alopecia Erythema Hyperpigmentation Nail changes Photosesitivity Mucositis

GI TOXICITY Nausea and vomiting Anorexia Mucositis Diarrhoea or constipation

Hepatotoxicity
(methotrexate; fibrosis, cirrhosis)

HAEMATOLOGIC TOXICITY Myelosuppresion


Aneamia (survival time 120days) Infection (wbc, 6-8hrs circulating, 2-3days in tissue) Thrombocytopaenia (<75,000mm3 ) (5-10 days)

Fatigue

NEPHROTOXICITY (Cyclophosphamide, Methotrexate)


Haemorrhagic cyctitis(Cyclophosphamide) Oliguria, dysuria, suprapubic discomort Low back pain Abnormal renal function Hyperuricaemia (high-dose methotrexate) Renal failure

PULMONARY TOXICITY (Bleomycin, Busulfan) Intestitial Pneumonitis, Alveolitis Fibrosis

CARDIOTOXICITY (Doxorubicin) Arrthymias, ischaemia, CHF

SEXUALITY AND FERTILITY

Gonadal dysfunction Perimenopause (Failing ovaries) Premature menopause (failed ovaries)

Infertility Testicular dysfunction Azospermia or Oligospermia


Teratogenicity or Mutagenicity

Cancer therapy requires care in the following areas:


Mx of infectious complications Blood component therapy Pain management Management of nausea and vomiting Nutritional support Psychosocial support

Arise from:

Metabolic or Endocrine disturbances from malignancy or therapy Space-occupying lesions that can press or obstruct vital organs Pancytopaenia due to bone marrow replacement or chemotherapy

TUMOUR LYSIS SYNDROME SIADHS HYPERLEUKOCYTOSIS

Hyperuricaemia Hyperkalaemia Hyperphosphataemia Hypocalcaemia Hypercalcaemia Renal Failure

Metabolic Complications Management of Hyperuricaemia Allopurinol Hydration Alkalinization of urine

Metabolic Complications Management of Hyperkalaemia Potassium should not be administered Sodium Bicarbonate Insulin and Glucose Calcium Chloride Sodium polystyrene sulfonate (Kayexalate) Dialysis

Metabolic Complications
Management of Hyperphosphataemia

Aluminum hydroxide Maintain high urine output


Management of Hypocalcaemia Calcium gluconate Dialysis if hyperphosphataemia persists

Metabolic Complications of Hypercalcaemia Causes: osteolytic bone lesions, bone demineralization, immobilization

Management of Hypercalcaemia Correct dehydration Increase renal calcium excretion by inducing forced diuresis (normal saline/furosemide) Decrease demineralization(prednisone, calcitonin, biphosphonates

Management of Renal failure Haemodialysis or Haemofiltration


Mechanism of renal failure: Precipitation of urates in acid environment of urine Increase in hypoxanthine levels with allopurinol Precipitation of calcium phosphates in renal microvasculature and tubules

Indications for dialysis Congestive heart failure Auria Symptomatic hypocalcaemia with hyperphos Hyperkalaemia High creatinine with poor urine output BP >150/90 and low urine output at 10hrs from start of treatment

CAUSES: Pain Infections Lymphomas and leukaemias Pulmonary and CNS lesions Drugs: vincritine, cyclo,

Treatment: Fluid restriction Hydrate with hypertonic saline 3% Furosemide to force diuresis

White cell count>100,000/mm3 Seen in ALL, AML, CML Leads to Hyperviscosity of blood and Embolization Clinical Features: CNS: blurred vision, confusion, delirium, papilledema Polmonary: tachypnoea, dyspnoea, hypoxia Genitourinary: oliguria, anuria, priapism

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MANAGEMENT Hydration and alkalinization Diuresis Uric acid reduction Leukocyte reduction Transfusion Chemotherapy Dialysis Monitor

Follow-up evaluation Relapse disease Prognostic factors Biologic Response Modifiers (BRMs) Preparation, administration and handling of chemo agents Management of late effects of childhood cancer

DISCUSSION