Phase IIA Lecture

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PEDIATRIC ONCOLOGY

• Phase IIA Lecture
• Dr. Mariana Silva, M.D., F.R.C.P.C.
• April 2009

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Pediatric Oncology Patients Diagnosed at the Five
Pediatric Oncology Treatment Programs in Ontario
by Year of Diagnosis and Residence
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Total Caseload of Malignant Neoplasms in
Children Diagnosed lt18 Years Followed at Kingston

• Average Annual
• YEAR CASELOAD
• 1997 - 2000 114
• 2003 - 2006 112

Does not include Camp Trillium or Limited
Registry Patients
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Age Profile of New Cases of Malignant Neoplasms
in Children (0-17), Resident in Ontario and Newly
Diagnosed at the Five Pediatric Oncology
Treatment Programs in Ontario 2000-2007
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Average Annual Number and Percent Distribution of
Malignant Diagnoses in Children (0-17 years),
Resident in Ontario and Newly Diagnosed at the
Five Pediatric Oncology Treatment Programs in
Ontario 2000-2007
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DISTRIBUTION OF ACTIVE CASES BY TYPE OF THERAPY,
()
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LEUKAEMIA IN CHILDHOOD

• Acute lymphoblastic leukaemia
• (80 cases )
• Acute leukaemias
  (lymphocytic)
• (95 of cases)
• Acute myeloid leukaemia
• (15 cases)
• Chronic leukaemias Chronic myeloid leukaemia
• (5 of cases)

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RISK FACTORS

• Constitutional genetic defects, e.g.
• Downs syndrome Trisomy 21
• Fanconis anaemia
• High rate of concordance in monozygotic twins (1
  year of life) ? Intrauterine genetic event
• Treatment related

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ACUTE LYMPHOBLASTIC LEUKAEMIA

• B Lineage T Lineage
• (85 of cases) (15 of cases)

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SUBTYPES OF B LINEAGE ALL

• Early precursor -B Cell ALL
• Precursor -B Cell ALL
• B Cell ALL

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CLINICAL PRESENTATION

• SYMPTOMS
• Fatigue/malaise, e.g. lack of energy
• Fever/infection, e.g. persistent sore throat,
  fever
• Extremity, joint or bone pain, e.g. limp
• Bleeding manifestations
• CNS symptoms, e.g. nausea and vomiting, headache,
  cranial nerve palsy
• Weight loss/failure to thrive

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CLINICAL PRESENTATION (2)

• SIGNS
• Pallor - reflects anaemia
• Hepatosplenomegaly
• Lymphadenopathy
• Petechiae and bruising - reflect low platelet
  count
• Testicular enlargement - rare

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DIAGNOSIS OF ALL (1)

• 1. Peripheral Blood
• Haemoglobin usually decreased
• WC may be high or normal or low
• lt10 x 109/L in 50
• gt50 x 109/L in 25
• T cell ALL is associated with a high WBC
• Neutropenia
• Thrombocytopenia usually present
• BLASTS present

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DIAGNOSIS OF ALL (2)

• 2. Bone Marrow gt 20 blast cells in marrow
• (normal lt 5)
• gt Morphology of Blasts
• 3. Flow Studies (Immunophenotyping )
• gt Lineage of Blasts
• gt B or T Lymphoid
• gt Subtype of B Lymphoid
• gt CD 10 positive or negative
• in B Lineage ALL

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DIAGNOSIS - ALL (3)

• Chromosomal Analysis (Karyotyping)
• Clonal chromosomal abnormalities can be
  demonstrated in up to 90 of childhood ALL
• ? Translocations (45)
• e.g. t(1221) 25 children (only 3 adults)
• e.g. t(922) 4 children (25 adults)
• ? Changes in ploidy
• e.g. Hyperdiploid gt 50 chromosomes
• e.g. Hypodiploid lt 45 chromosomes
• 5. DNA STUDIES

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SPECIAL FEATURES OF T-ALL

• Older boys
• High WBC
• Mediastinal mass
• Chest x-ray helpful in diagnosis

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TREATMENT OF ACUTE LYMPHOBLASTIC LEUKAEMIA

• BASED ON RISK STRATIFICATION
• FACTORS TO BE CONSIDERED
• T or B lineage
• Subtype of B lineage
• Patients age lt 1 1-9 gt 9 years
• Sex. Boys worse than girls
• WBC gt 50,000 or lt 50,000
• CD10 positive or negative in B lineage
• Cytogenetic and molecular studies

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IMPORTANT CONCEPTS IN THETREATMENT OF ALL

• Treatment is the most important prognostic factor
  in ALL
• Treatment is based on risk stratification at
  diagnosis
• Treatment stratification allows less toxic
  treatment for lower risk. Aggressive
  chemotherapy for very high risk.
• Treatment must include sanctuary sites, e.g. CNS

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TREATMENT OF ALL

• Intensive systemic multiagent chemotherapy
• Intrathecal chemotherapy
• Cranial irradiation when absolutely necessary in
  older children
• Bone marrow transplantation in special
  circumstances
• Chemotherapy treatment continued for 2 years
• Supportive care

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PROGNOSIS

• Improving
• Overall approximately 80 (range 55-92)

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TREATMENT RELATED MORBIDITY

• Immediate
• e.g. nausea
• vomiting
• diarrhea
• mucositis
• infection
• alopecia
• psychosocial morbidity

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TREATMENT RELATED MORBIDITY (contd)

• Delayed
• e.g. endocrinopathy obesity,
  short stature,osteoporosis
• second neoplasms, e.g. brain tumours
• neuropsychological deficits
• cardiac damage anthracyclines
• psychosocial damage
• sterility in certain circumstances

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FACTS YOU MUST TAKE AWAY

• Acute leukaemia most common malignancy in
  childhood
• Usually ALL B lineage
• Intensive multimodality treatment for
  approximately 2 years
• Currently 70 - 80 survival overall
• Supportive care involves whole family

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PEDIATRIC ONCOLOGY PART 2
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SUPPORTIVE CARE

• ANTIEMETICS
• Ondansetron
• Dexamethasone
• PAIN CONTROL - Mostly an issue in palliative care
• Oral
• Intravenous
• Subcutaneous pumps
• Intrathecal
• TRANSFUSIONS
• PRBC
• Platelets

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SUPPORTIVE CARE (contd)

• GROWTH FACTORS
• G-CSF (granuloctye colony stimulating factor)
• GM-CSF
• Epo (Erythropoietin)
• CENTRAL LINES
• Port-a-cath
• Hickman lines - single or double lumen
• PICC lines

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PSYCHOSOCIAL

• SHOCK AT DIAGNOSIS
• DENIAL - GUILT
• INFORMATION OVERLOAD
• PROCEDURES
• CARE OF SIBLINGS
• FINANCES, JOB LOSS
• UNCERTAIN FUTURE
• SHORT VERSUS LONG TERM

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SIDE EFFECTS OF TREATMENT

• SHORT TERM
• Vomiting
• Alopecia
• Fatigue
• Weight loss
• Infections
• Pancytopenia
• LONG TERM
• Vincristine - peripheral neuropathy
• Anthracycline - cardiotoxity
• Prednisone - osteoporosis, striae
• Radiation - CNS sequelae
• growth retardation

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INFORMATION TO OBTAIN DURING FOLLOW-UP CLINIC
VISITS BY SURVIVORS OF CHILDHOOD CANCER

• History of any intercurrent illnesses
• Review of systems
• Development of any benign tumors or other cancers
• Medications prophylactic antibiotics
• Educational status
• Grade completed special education classes?
• Grade point average results of IQ tests
• Areas of weakness

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INFORMATION TO OBTAIN DURING FOLLOW-UP CLINIC
VISITS BY SURVIVORS OF CHILDHOOD CANCER (contd)

• Employment status
• Insurance
• Individual policy, or coverage through parents?
• Difficulties getting insured
• Marital history
• Menses, libido, sexual activity
• Pregnancy outcome (patient or spouse)

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WRITE A SIMPLE DEFINITION FOR

• THROMBOCYTOPENIA
• ANEMIA
• LOW WBC COUNT
• EXPLAIN TO A FAMILY THE POSSIBLE SYMPTOMS OF
  THESE CONDITIONS AND SOME COPING STRATEGIES
• (THINGS TO AVOID, WHEN TO GET HELP ETC.)

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LOW PLATELET COUNT FAMILY INSTRUCTIONS

• I. Introduction
• Platelets are the small cells in the blood that
  are partially responsible for the clotting of the
  blood. A low platelet count (less than 100,000)
  sometimes called thrombocytopenia, can be caused
  by drugs or radiation or bone marrow disease.
• II. Possible symptoms
• a. Bleeding from the gums
• b. Nosebleeds
• c. Bruising
• d. Dark, loose stools
• e. Blood in the urine (red or brown color)
• f. Red spots in the skin called petechiae
• g. Increased amount of menstrual flow
• h. Severe headache or vomiting or changed level
  of consciousness

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LOW PLATELET COUNT FAMILY INSTRUCTIONS (contd)

• Patient-Family Teaching
• A. Use only an electric razor to shave
• B. Avoid the use of drugs, such as aspirin
  or aspirin-containing
• medications. Consult your
  physician before giving any drugs to
• your child
• C. Avoid straining during bowel movements.
  Encourage the use of
• stool softeners, bulk in the
  diet and adequate fluids
• D. Avoid lifting heavy objects
• E. Avoid rectal temperatures, examinations,
  suppositories, enemas
• and intramuscular injections
• F. Avoid contact sports, and activities such
  as biking, skateboarding
• and skating
• G. Use protective helmets as indicated
  (especially for toddlers)
• H. Pad the side rails of beds
• I. Use soft toothbrushes or sponges to
  maintain good oral hygiene

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ANEMIA - FAMILY INSTRUCTIONS

• I. Introduction
• Anemia is low red blood cell count (Hb lt 8.0)
  which can be reflected by measuring the pigment
  (hemoglobin) inside the red blood cells. It can
  be the result of cancer treatment with drugs or
  radiation.
• II. Possible symptoms
• a. Tire easily
• b. Feeling weak or lack of energy
• c. Pale-looking (especially around the lips and
  nail beds)
• d. Dizziness
• e. Shortness of breath in severe cases
• f. Confusion in severe cases

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ANEMIA - FAMILY INSTRUCTIONS (contd)

• III. Patient-Family Teaching
• A. During cancer treatments be alert to
  symptoms of anemia and report them to the
  physician or outpatient clinic.
• B. Periodic complete blood counts should be
  checked as
• recommended by the physician in
  OPD or by family
• doctor.
• C. Although this anemia is not usually related
  to dietary
• habits, it is always in the best
  interest of the child to encourage
  well-balanced meals.
• D. Vitamins or vitamins with iron will not
  resolve this
• anemia.
• E. In some children, a blood transfusion may
  be necessary.

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LOW WHITE BLOOD CELL COUNTFAMILY INSTRUCTIONS

• I. Introduction
• A low white blood cell count (called
  neutropenia) can be caused by cancer treatment.
  During times of a low white blood cell count, the
  patient is more prone to infections since the
  white blood cells help the body fight off
  infections.
• II. Possible symptoms
• a. Significant fever - temperature of 38.5C
  (by mouth)
• b. Irritability and vomiting
• c. Break in the skin which does not heal
• d. Cough
• e. Pain with bowel movements
• f. Sores in the mouth and/or throat
• g. Change in conscious states.

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LOW WHITE BLOOD CELL COUNTFAMILY INSTRUCTIONS
(contd)

• III. Patient-Family Teaching
• A. Periodic complete blood count should be
  checked during cancer treatment either in
  the OPD or by your family
• physician.
• B. Good hygiene - hand washing, brushing
  teeth and
• cleanliness.
• C. Check with the physician with regard to
  sending the child
• back to school and resuming other
  daily activities. If the
• white blood cell count is low (ANC
  lt 1000) check childs
• temperature every 4 hours. Avoid
  rectal temperatures.
• 1. Stay out of school at the recommendation
  of the
• physician.
• 2. Stay away from large crowds (church,
  shopping centres).
• 3. Keep people with infections away from
  child. 45

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LOW WHITE BLOOD CELL COUNTFAMILY
INSTRUCTIONS (contd)

• Seek medical attention for any fever gt 38C
  axillary.
• E. Avoid Tylenol as can mask fever

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PEDIATRIC ONCOLOGY PART 3
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Treatment Tumour associated problems that
present as emergencies - large mediastinal mass,
uric acid nephropathy Surgery for biopsy
only Radiation very rarely lymphoblastic
leukemia - type Tx for 1 to 3 years,
multiple drugs Chemotherapy SNCC alkylating
agent as Cyclophosphamide, short TX - 6
months Large cell Doxo VCR Pred regimen
is used Relapse Autologous or allogenic Bone
Marrow Transplant
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WILMS TUMOUR

• INCIDENCE
• most common abdominal tumour in childhood
• 1/15000 live births
• EPIDEMIOLOGY
• lack of geographic or racial variations
• age gt6 mo.. and lt 10 yr.
• mean age unilateral disease - 3.5 yr.
• bilateral disease - 2.5 yr.
• associated with aniridia
• hemihypertrophy
• genitourinary anomalies
• Beckwith Wiedmann Syndrome

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WILMS TUMOUR (contd)

• CLINICAL PRESENTATION
• asymptomatic abdominal mass
• increased abdominal girth
• 25 microscopic/gross hematuria
• 33 abdominal pain - exacerbated by falls or
  trauma
• polycythemia
• 25 hypertension - renin secreting tumour
• renovascular hypertension
• left variocele - compression of left renal vein
• ruptured Wilms secondary to trauma
• fever, malaise - bleeding into tumour

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WILMS TUMOUR (contd)

• TREATMENT
• (1) SURGICAL EXCISION
• - removal of involved kidney
• - biopsy of contralateral kidney
• - evaluation of possible tumour extension
• - inspect for lymph node involvement
• - inspect liver
• (2) CHEMOTHERAPY
• - stage I-II - Vincristine, Actinomycin D
• - stage III-IV - Vincristine, Actinomycin D,
  Doxorubicin
• (3) RADIATION
• - used in stage III and IV

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WILMS TUMOUR (contd)

• PROGNOSIS
• 2 YEAR SURVIVAL stage I - 98
• stage II - 95
• stage III - 90
• stage IV - 80
• 80 IF UNFAVOURABLE HISTOLOGY

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NEUROBLASTOMA

• Epidemiology
• Most common extracranial solid tumour in
  children
• Incidence 1 - in 7000 live births
• 10 of all childhood cancer, 15 of all cancer
  deaths
• Median age 22 months

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Pathology

• Small, round, blue cell tumour also Ewings
  sarcoma family, non-Hodgkins lymphoma, undiff
  soft tissue sarcomas (rhabdo)
• Derived from primordial neural crest cells
• Three patterns spectrum of differentiation
  Neuroblastoma, Ganglioneuroblastoma,
  Ganglioneuroma
• Neuroblastic nodules present at 17-20 wks.
  Gestation
• Normally regress - ? Remnants as nidus for tumour
• Estimated that half of all clinically detectable
  neuroblastomas (by screening) regress without
  therapy
• Cytogenetics 1p chromosomal deletions

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Genetics

• Associations with Neurofibromatosis type 1,
  Hirschsprungs dis.
• Autosomal dominant subset - two hit hypothesis
• Familial - median 9 months, 20 bilateral. or
  multifocal
• Monozygotic twins concordant as infants,
  discordant as older children

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Presentation - Most (65) primaries in abdomen
also thoracic cervical - Metastasis by
lymphatic or hematogenous spread to marrow, bone,
liver, skin Signs and Symptoms reflect
location of disease primary, regional,
metastatic - Abdominal fullness, discomfort,
fixed mass - Cervical Horners syndrome
(ptosis, miosis, anhidrosis) - Thoracic
Superior vena Cava syndrome - Scrotal lower
extremity edema compromised return
Metastasis proptosis - never ocular primary -
liver resp. compromise (infants) - bone
pain, marrow replacement - spinal cord
compression by extension through foramina
Paraneoplastic opsomyoclonus, diarrhea
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Diagnosis 1) Unequivocal pathology OR 2)
Marrow evidence elevated urinary
catecholamines Staging CT (chest and abdomen)
MRI, MIBG Bilateral bone marrow aspirates and
biopsies Bone scan VMA/HVA in urine to confirm
diagnosis and follow disease Prognosis Age,
stage, site Good Hyperdiploid,TRK
amplification, infant Bad 1p deletion, N-myc
amplification, older children
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Staging International Neuroblastoma Staging
System (INSS) 1 Localized, complete
excision /- microscopic residual, negative
nodes 2A Unilateral, incomplete excision,
negative nodes 2B Unilateral, complete or
incomplete excision, ipsilateral nodes 3
Crossing midline /- regional nodes OR
unilateral contralateral nodes OR midline
with bilateral nodes 4 Disseminated to
distant nodes, bone, marrow, liver, other
organs 4S Localized (1 or 2), dissemination
to liver, skin, marrow
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Treatment Surgery, Chemo, XRT

• Surgery Pathology for diagnosis, staging,or
  resection
• Ultimately gross total resection
  BUT may delay for chemotherapy
  consolidation
• Chemo Mainstay of management
• Many options cyclophosphamide,
  cisplatin, doxorubicin, VP16

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Treatment (contd)

• Radiation Residual disease, unresectable
  tumour, disseminated metastases
• Risk based strategies are the current trend
• LOW Infants Children
  Stages 1, 2A
• Infants Stages 2B, 3,
  4S
• Stages 1 - Surgery
  alone 90 cure
• Surgery minimal
  post-op chemo 80-90
• INTERMEDIATE Children Stages 2B, 3
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  Infants Stages 4
• Aggressive chemo 30
  
  irradiation 60
• HIGH Children St.4 lt15
  survival
• Marrow-ablative chemotherapy
  autologous Bone Marrow Transplant

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BONE TUMOURS

• OSTEOSARCOMA
• BACKGROUND
• Primary malignant bone tumour
• Most common malignant bone tumour of childhood
• 4/million people lt 20 yr.
• 5th most common extracranial solid tumour of
  childhood
• Peaks at 15-25 yr., but may occur at any age.
• Risk factors
• M F (before adolescence), M gt F
  (after adolescence)
• Exposure to ionizing radiation
• Bilateral Retinoblastoma (1
  of surviving patients)
• Li-Fraumeni Syndrome

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• SIGNS AND SYMPTOMS
• PAIN
• LOCAL HYPERTHERMIA
• VISIBLE MASS
• TENDERNESS
• LOCAL ERYTHEMA
• DECREASED RANGE OF MOTION
• PATHOLOGICAL FRACTURES

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• SITES
• Usually the metaphyses of long bones
• Most commonly distal femur
• proximal tibia
• proximal humerus
• 80 around the knee
• Other sites pelvis, jaw, fibula, ribs
• May occur in any bone of the body

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• STAGE
• LOCALIZED
• limited to the bone of origin
• may have skip lesions
• METASTATIC
• systemic signs suggest that metastases have
  occurred
• 20of patients have metastatic disease at time
  of presentation
• almost all patients have microscopic metastatic
  disease
• 85 of metastatic disease is in the lungs
• may present as pleural effusion, pneumothorax
• next most common sites is other bones
• other sites lymph nodes, bone marrow,
  pericardium, brain

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• INVESTIGATIONS
• Plain film of primary site
• lytic/destructive lesions
• may have calcifications
• extensive periosteal reaction adjacent to
  tumour (Codmans Triangle)
• MRI of local site
• Biopsy local site
• Bone scan
• CT chest
• Bone Marrow (biopsy and aspirate)

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TREATMENT - Not radiosensitive - 90
recurrence rate if surgery ALONE -
Chemotherapy Pre- operative - Induce
necrosis of tumour and destroy
micro metastases Not effective for
controlling clinically
detectable disease Agents high dose Mtx,
Bleomycin, VP -16
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• SURGERY
• Limb-sparing (70-90) vs amputation
• The amount of tumour necrosis observed is
  highly predictive of disease-free survival.

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• PROGNOSIS
• Poor
• metastases
• primary tumour is on axial skeleton
• high LDH/alk phos
• BEST predictor of good outcome is positive
  response to
• neoadjuvant chemotherapy
• No mets 66 survival
• mets lt 20 survival

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• EWINGS SARCOMA
• BACKGROUND
• Second most common malignant bone tumour of
  childhood
• 2/1 million white children lt 15 years of age.
• Most often 10-20 years of age, but may occur at
  any age.
• M gt F
• White gt Blacks
• SIGNS and SYMPTOMS
• Pain
• Fever, weight loss
• Tenderness
• Soft tissue mass

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• PATHOLOGY
• Small round blue cell tumour
• Arises from neural crest cells
• Diagnosis of exclusion, as no widely available
  markers yet
• SITES
• PRIMARY
• Axial skeleton (pelvis,ribs) or diaphyses of
  long bones (femur,
• humerus,proximal tibia)
• May occur in any bone
• CYTOGENETICS
• Balanced translocation, resulting in the joining
  of the EWS gene on
• chromosome 22 to a member of the Ets
  family of oncogenes
• Most common t (1122)

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• INVESTIGATIONS
• same as osteosarcoma
• Plain film destructive bony changes,
  diaphyses of long bones or flat bones,
  reactive bone formation (onion skin)
• Bone marrow if other metastatic disease
  present
• STAGE
• LOCALIZED
• Tumour not detectable beyond primary sit by
  clinical imaging technique
• Most (90) actually have microscopic mets at
  time of diagnosis
• METASTATIC
• - 25 present with overt metastases
• - Lung - Lymph nodes
• - Bone - CNS
• - Bone Marrow

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• TREATMENT
• CHEMOTHERAPY
• Neoadjuvant to decrease tumour size prior to
  surgery and
• to control or prevent micrometastic disease
• Vincristine Dactinomycin
• Doxorubicin Ifosfamide
• Cyclophosphamide VP-16
• RADIATION
• Use if wide surgical margins cannot be obtained
  or poor
• surgical sites
• Controls 90 of small lesions and 60-80of large
  lesions

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• PROGNOSIS
• POOR
• proximal extremity
• pelvic/sacral tumours
• metastases
• large tumours
• more neural differentiation
• GOOD
• distal extremity
• jaw/skull/face/vertebrae/clavicle/scapula
• good response to initial chemotherapy
• Non-metastatic 70 5 yr disease- free survival
• Metastatic 30-50 disease-free survival

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PROBLEM 1

• Mary is 4-years-old and has Acute Lymphoblastic
  Leukemia.
• She has been on chemotherapy for 2 months. Her
  mother calls you on a Friday evening to tell you
  that her 3-year-old son has chickenpox.
• What do you tell the mother?
• A. Suggest that she move her son to his
  grandparents until he no longer is
• contagious.
• B. Tell her not to worry.
• C. Ask her to make an appointment with for your
  Monday clinic.
• D. Ask her to call you back if Mary develops
  chickenpox.
• E. Tell her not to send her children to school
  so they dont infect other children.
• F. Tell her to bring Mary to the ER tonight.

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PROBLEM 2
Tom is 8-years-old and presents to the E.R. with
a temperature of 39C. He looks reasonable well
and has no complaints.He is on chemotherapy for
ALL. What do you do? A. Careful
history and physical exam. B. Blood, throat
and urine cultures. Lumbar puncture. C. Start
broad spectrum antibiotics. D. If not
neutropenic, send him home. E. G-CSF
(Granulocyte Colony Stimulating Factor. F. Stop
chemotherapy.
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PROBLEM 3
John is 14-years-old and is on chemotherapy for
osteogenic sarcoma. His mother calls you and
explains that he has a temperature of 38.6C but
doesnt want to come to the hospital as he has a
school party tonight. What do you do? A.
Tell John to come to the clinic tomorrow. B.
Ask his parents to bring him to the hospital
immediately using all means at their
disposal. C. Call the Childrens Aid Society
and explain the problem to them. D. Talk to
John over the phone then start him on oral
antibiotics. E. Compromise. What do you
really need to do?