Pediatrics Flashcards
ALL background and incidence -5
Most common pediatric cancer by far
2400 new cases/year in US
80% ALL and 20% AML
Peak incidence for ALL is 2-3 years of age
Cause is unknown
ALL signs and symptoms -8
common misdiagnosis is rheumatoid arthritis
WBC is normal or low in 59% of kids
Normochromic, normocytic anemia
Thrombocytopenia
Fever
Bleeding
Bone pain (limping, want to be carried)
Lymphadenopathy
Hepatosplenomegaly
ALL dx -3
Bone marrow aspirate and biopsy
If at least 25% of lymphoid cells in BM are blasts, the patient has ALL
MRD = MINIMAL RESIDUAL DISEASE is tested during induction
ALL tx - TLS -5
First, deal with tumor lysis issues
Hydrate (maintenance fluids = 1500ml/m2/day), give 1.5-2 times this rate
Alkalinization has fallen out of favor. Thought it kept uric acid in solution, but not shown to be helpful. however some places use it.
Allopurinol
Rasburicase if uric acid is >10mg/dl or Creatinine is elevated or WBC is greater than 100,000/mm3
ALL tx - TLS - At a glance method for evaluating creatinine: -3
Creatinine is normally 0.2mg/dl up to 2 years of age
Then you add 0.1mg/dl per year until they reach 8 years of age,
Then their creatinine values are the same as adults
ALL - Induction - key concepts -3
DOES RISK STRATIFICATION MATTER?
Lasts 4 weeks
Standard risk: 3 drugs (besides IT chemo)
High risk: 4 drugs (besides IT chemo)
ALL - Induction - high risk definition -4
kids less than 1 year of age or greater than 9 years of age,
presenting WBC > 50,000,
T-cell ALL,
certain translocations
ALL - Induction - 3 drug regimen -6
DEX INC RISK OF AVASCULAR NECROSIS IF PT >9YR
DOSING DURING INDUCTION IS NOT BASED ON BLOOD COUNTS
Prednisone 40mg/m2/day or dexamethasone 6mg/m2/day for 28 days
ALL - IT methotrexate -2
Dose is based on age with a max of 15mg for kids greater than or equal to 9 years of age
Example is MTX
1-1.99 years get 8mg
2-2.99 years get 10mg
3-8.99 years get 12mg
greater than or equal to 9 years get 15mg
ALL - Induction - 4 drug regimen -2
Use the 3 drug regimen, plus daunorubicin 25mg/m2 IV on days 2, 8 and +/- 15
If daunorubicin is used, then the steroid must be prednisone because the combo of daunorubicin and dexamethasone poses a greater risk of fungal infections
ALL - monitoring response -3
Do BM aspiration at day 7 or 14 and at day 28
ALL - Post-Remission Therapy: aka Consolidation, early or delayed intensification - concepts -5
IS OPTIMAL REGIMEN KNOWN?
WHAT IS INTENSITY AND DURATION OF TX BASED ON?
Begins if the patient is in remission after induction
ALL - Post-Remission Therapy: aka Consolidation, early or delayed intensification - regimens -6
PROBABLY NOT ON TEST - NO SOC
Methotrexate 1gm/m2 IV q3 weeks x 6 doses
Escalating dose methotrexate plus Pegaspargase
Cyclophosphamide1gm/m2 followed by cytarabine 75mg/m2 SQ or IV x 10 days with thioguanine x 14 days
Vincristine/pred pulses, doxorubicin, various doses of asparaginase
High risk kids get more aggressive treatment for a longer duration, regimens include high dose MTX 5gm/m2 and high dose asparaginase (25,000 units/m2) IM
Longer duration for boys due to risk of testicular relapse
ALL - Post-Remission Therapy: mainenance concepts -3
Without maintenance therapy, most kids with ALL will relapse - compliance also effects relapse
Can still have undetectable disease after induction and consolidation (MRD)
Trying to knock off cells coming out of G0 phase over a couple of years
ALL - Post-Remission Therapy: mainenance regimen -5
WHAT IS USED FOR DOSE ADJUSTMENT?
ANC’s are best to see if pt taking drug. used to dose adjust.
Methotrexate 20mg/m2 usually by mouth once a week x 1.5-2 years
Mercaptopurine 50-75mg/m2 daily x 1.5-2 years
Doses adjusted to keep ANC between 500-1500/mm3
Periodic IT methotrexate (example = every 16 weeks)
Periodic Vincristine x1 plus 7 day pred or dex pulses (VP pulse)
Relapsed ALL -2
WHERE DOES DZ RELAPSE?
CNS relapse – treat with cranial radiation and re-induction/re-consolidation therapy and then maintenance
BM relapse- if they relapse on therapy or within 1 year post chemo completion, BMT is a better option than more chemo. Chance of 2nd remission is good, but long term survival is often less than 50%
ALL -Radiation concepts -2
WHAT IS MAIN USE?
ADR?
Cranial XRT used in kids with T-cell ALL
Main use is for CNS relapse
Causes growth deficiency and impaired intellectual development
ALL prognosis -7
WHAT AGE IS BEST?
WHAT WBC IS BEST?
85-90% long term survival
Age 1-9 years is best
Initial WBC < 50K is favorable
MRD (if detected, is bad) is used to tailor post-remission therapy
favorable: hyperdiploid; trisomy 4, 10, or 17 have lower risk of relapse, TEL/AML1 t(12;21)
Unfavorable: t(9;22) = Philadelphia chromosome, MLL rearrangements: t(4;11), t(11;19) and t(1;11)
Early response; bone marrow remission on day 7 or 14 is favorable
AML regimen -3
Cytarabine 3000mg/m2 IV over 3 hours every 12 hours for 6 doses alternating with the next course at 100mg/m2/day continuous infusion for 7 days
Daunorubicin 45-60mg/m2 IV daily for 2-3 days per course
Courses repeated for 4-6 months
AML concepts -6
WHERE IS MOST COMMON RELAPSE?
DO YOU USE MAINTENANCE?
chemo is of shorter duration overall vs ALL, but it is much more toxic
AML: post induction tx -3
WHAT IS PREFERRED?
WHAT IS CONSOLIDATION VS INTENSIFICATION?
If the patient has a living related donor who matches, they go to BMT once in complete remission
Consolidation: if different agents (vs induction agents) are used
Intensification: if the same agents are used but at higher doses
AML prognosis (6pts)
50% long term survival
60% OS with HSCT from living related donor
Some subtypes have more favorable prognosis
Poor prognosis with monosomy 7, -5/5q-, or FLT3/ITD allelic ratio
BM blasts at day 15 and MRD of 1% or more after 1st induction are bad prognostic indicators
Age less than 1 and WBC > 20,000/mm3 have worse prognosis (3-10yo have best prognosis)
Late effects with ALL and AML (4pts)
anthracycline cardiotoxicity
secondary AML (for ALL patients who got epipodopylotoxins - LESS BECAUSE NOT BEING USED MUCH ANYMORE)
decreased bone mineral density (steroids)
leukoencephalopathy (high dose methotrexate) - lifetime learning problems
XRT neurocog problems LESS as this tx is avoided as much as possible, especially if <5yo
Pediatric CNS tumors (3 main types)
Medulloblastoma
Astrocytoma
Brain stem gliomas
Pediatric CNS tumors- Medulloblastoma -5
A primitive neuroectodermal tumor (PNET)
Median age at diagnosis = 5-6 years
Arises in cerebellum
25-45% have leptomeningeal mets at diagnosis
Rapidly growing, so short duration of symptoms - BECAUSE OF THIS AMENABLE TO CHEMO
Pediatric CNS tumors- Medulloblastoma - signs and sx -6
Early symptoms:
signs and symptoms of increased ICP, headache, emesis, lethargy, hydrocephalus
Late symptoms : ataxia, diplopia, weakness, papilledema, strabismus
Pediatric CNS tumors- Medulloblastoma - staging : favorable vs high risk -4
WHAT DOES RESIDUAL DZ MEAN TO RISK?
DOES AGE MATTER?
Favorable disease:
1. children older than 3 years of age,
- localized disease that has complete or near total resection
High risk:
1. invasive disease that limits total resection (greater than 1.5cm2 residual disease)
- overt metastatic disease (subarachnoid seeding)
Pediatric CNS tumors- Medulloblastoma - staging -Chang Classification (prognostic value) -5
M IS PROGNOSTIC NOT T
M0 = No gross subarachnoid or heme mets
M1 Microscopic tumor cells in CSF
M2 Gross nodular seeding in cerebellum, cerebral subarachnoid space, or in third or fourth ventricles
M3 Gross nodular seeding in spinal subarachnoid space
M4 Extraneuraxial metastasis
Pediatric CNS tumors- Medulloblastoma - treatment - surgery -3
TX IS SURGERY+XRT+CHEMO
Surgery is KEY! Need complete or near complete resection.
Can do post-op MRI to detect residual disease and operate a second time to improve resection.
Bone marrow aspirate and biopsy (5% have systemic mets)
Pediatric CNS tumors- Medulloblastoma - treatment - XRT -4
wonderful addition, but only if you are at least 3 years of age, IDEALLY OVER 5 YO
Attempting to use chemo to decrease dose of XRT or avoid it altogether.
inability to give XRT to younger kids hurts their chances of survival
Some low risk patients can be cured with post-op radiation
Pediatric CNS tumors- Medulloblastoma - treatment - chemo -5
IS THERE A SOC?
NO SOC
Cisplatin, vincristine, prednisone, cyclophosphamide, lomustine and topotecan have been used post-op.
Chemo used to avoid XRT in very young (<3)
Chemo can be used with XRT to decrease the dose of XRT used in low risk patients
Unclear if chemo improves survival in low risk patients
Pediatric CNS tumors- Medulloblastoma - treatment - chemo examples -2
CVP
lomustine (CCNU) 100mg/m2 po x 1
vincristine 1.5mg/m2 IV weekly x 3
prednisone 40mg/m2 po x 14 days
Cisplatin 90mg/m2 IV x 1
Lomustine 100mg/m2 PO x 1
Vincristine 1.5mg/m2 weekly x 3
Most important prognostic factors for medulloblastoma -3
metastatic stage M
adjuvant treatment
residual tumor
Pediatric CNS tumors- Medulloblastoma - prognosis -7
60-80% survival rate based on how aggressive surgery was as well as chemo, XRT
Poor risk: less than 3 years of age, subarachnoid seeding, greater than 1.5cm2 tumor remaining post-op, histology, diploid DNA content, C-myc amplification, deletion of 17p
Pediatric CNS tumors- Astrocytomas - background
NOT COVERED IN VIDEO
#Most are slow growing (low grade): I and II #About 20% are malignant (anaplastic astrocytoma or glioblastoma) # 2 histologic types: juvenile pilocytic astrocytomas and diffuse astrocytomas
Pediatric CNS tumors- Astrocytomas - signs and sx
associated with increased ICP, seizures, visual disturbances, can be similar to medulloblastoma depending on their location
Pediatric CNS tumors- Astrocytomas - treatment - surgery
#curative intent for Cerebellar astrocytomas # malignant astrocytomas and glioblastoma, the goal is maximal resection
Pediatric CNS tumors- Astrocytomas - tx - XRT
# avoid in kids <3-5 if possible #prolong time to tumor progression if there was an incomplete resection of malignant astrocytoma or glioblastoma
Pediatric CNS tumors- Astrocytomas - tx - chemo
#multiagent, dose-intense #cyclophosphamide, cisplatin, carboplatin, etoposide, vincristine, carmustine (carboplatin is in most regimens since it is among the most active) #Chemo used where radiation deferred or failed or where surgery not a good option
Pediatric CNS tumors- Astrocytomas - tx - chemo example regimen
Carboplatin 175mg/m2 IV weekly x 4
Vincristine 1.5mg/m2 (0.05mg/kg if less than 12kg) IV weekly
Pediatric CNS tumors- Astrocytomas - prognosis
#Worst prognosis: malignant astrocytoma and glioblastoma #Extent of resection important for cerebellar gliomas #The older the patient, the worse the prognosis
Pediatric CNS tumors- Brain stem gliomas - background
NOT COVERED IN VIDEO
#Most frequently occur between 5-10 yo #Usually in pons, can be in medulla and midbrain
Pediatric CNS tumors- Brain stem gliomas - signs and sx
rarely cause increased ICP until late in course
Extra ocular muscle paresis and diplopia, facial weakness, cranial nerve dysfunction, personality changes
Spastic gait, hemiparesis
Pediatric CNS tumors- Brain stem gliomas - staging and prognosis
#diffuse infiltrative (usually in pons, poor prognosis, median OS <1yr) #focal (in medulla or midbrain) - good prognosis if can be removed surgically +/- radiation – survival 50-100%
Pediatric CNS tumors- Brain stem gliomas - tx - surgery
remove as much as possible while preserving neurologic function
Pediatric CNS tumors- Brain stem gliomas - tx - XRT
Mainstay of treatment for diffuse infiltrative, also for palliation and to control neurologic symptoms
neuroblastoma - background and incidence -4
Only 650 cases/year in US
36% occur before 1 year of age
90% occur before 5 years of age
Median age at diagnosis is 22 months old
neuroblastoma - pathophysiology -5
Arise in the adrenal medulla or paraspinal sites of sympathetic nervous system tissue (anywhere along the sympathetic tract)
neuroblastoma - risk stratification -6
40% of kids have low to intermediate risk dz which is cured by surgery or surgery plus chemo
Based on age, stage, and tumor biology
neuroblastoma - prognosis -3
5 yr OS for infants is about 90% and about 55% for older children
Age 95%
5 yr DFS for kids with Stage 4 is about 35%
neuroblastoma -Positive prognostic factors (8pts)
hyperdiploidy
normal n-myc copy number (THIS IS INTRINSIC TO DZ)
low LDH
low ferritin
high VMA/HVA ratio
neuron-specific enolase <100ng/ml
DNA CONTENT: HYPERDIPLOID (POOR= DIPLOID)
expression of HA-ras p21 or TRK gene
neuroblastoma - diagnosis -3
Urine catecholamines vanillylmandelic acid (VMA) and homovanillic acid (HVA) are elevated in at least 85% of patients. The higher the VMA:HVA ratio, the better the prognosis.
Neuron specific enolase elevated in 95% pts with widespread disease.
Ferritin is produced by neuroblastoma cells and is elevated in 50% of patients with Stage III and IV disease.
neuroblastoma - staging -3
Stage 1-4, plus 4S (which doesn’t fit the scheme of higher number = worse prognosis)
4S is localized primary tumor with dissemination limited to skin, liver and/or bone marrow (limited to infants less than 1 year of age) Usually hyperdiploid without N-myc amplification. GOOD OUTCOME.
Mostly stage 3 or 4
neuroblastoma - tx - surgery -1
resection can cure localized disease
neuroblastoma - tx - XRT -1
not useful for disseminated disease even though neuroblastoma is radiosensitive
neuroblastoma - tx -chemo -2
MOST AGRESSIVE DOSING OF ALL PEDS ONC
Used in all but stage 1 and 4S disease
Cyclophosphamide, ifosfamide, doxorubicin, cisplatin, carboplatin, vincristine and epipodophyllotoxins have been used.
neuroblastoma - tx -Biologic response modifiers (4pts)
MAY DOUBLE OS OUTCOMES FROM 30 TO 66% - SO FAR EARLY DATA
Differentiating agents (retinoic acid): used after stem cell transplant
mIBG to target radiotherapy for metastatic neuroblastoma
anti-GD2 ganglioside = ch14.18 monoclonal antibody USE AFTER TRANSPLANTATION (TX CAUSES A LOT OF PAIN - STIMULATES NERVES - USE OPIOIDS)
USE retinoic acid + anti-GD2 ganglioside AFTER STEM CELL TX to improve OS
neuroblastoma - tx - stage 1 -2
THINK AGE AND STAGE +N-MYC
Surgery cures > 90%.
N-myc positive requires chemo
neuroblastoma - tx -Stage 2A, infant 2B and 3 -5
THINK AGE AND STAGE +N-MYC
surgery
Chemo if N-myc amplified or recurrence.
Chemo includes cyclophosphamide and doxorubicin. Failures get cisplatin and etoposide.
Can use XRT for residual disease after second look surgery
cyclophosphamide 150mg/m2/day IV x 7 days
doxorubicin 35mg/m2 IV on day 8
Repeat q3 wks x 5
neuroblastoma - tx - Stage 2B, 3 (tumors with positive nodes) -3
THINK AGE AND STAGE +N-MYC
50-70% cure rate with intensive therapy.
Surgery, chemo, and possible radiation
Ex:
vincristine 1.5mg/m2 IV on day 1
cisplatin 80mg/m2 IV over 24 hours on day 1
etoposide 200mg/m2 IV over 4 hours on day 3
alternate with
vincristine 1.5mg/m2 IV on day 1
cyclophosphamide 600mg/m2 IV on day 1
etoposide 200mg/m2 IV over 4 hours on day 1
carboplatin 500mg/m2 IV on day 1
neuroblastoma - tx - Stage IV - concepts -4
THINK AGE AND STAGE +N-MYC
Least responsive to chemo
Survival depends strongly on age, infants respond to less aggressive courses than older kids
Even with aggressive treatment, OS usually no better than 20%
High risk = Stage 4, and stage 2,3,4S with N-myc amplification
neuroblastoma - tx - Stage IV - tx plan -3
THINK AGE AND STAGE +N-MYC
Aggressive induction chemo
Consolidation with intensive chemo OR high dose chemo, TBI, and HSCT
SCT can be allo if there is a matched sibling, or auto
neuroblastoma - tx - Stage IV - chemo regimen -2
KNOW
VINCRISTINE MAX 2MG OVER 72H
KNOW HOLD PARAMETERS
cyclophos 2.1gm/m2/day with mesna on days 1 and 2 (HUGE DOSE)
doxorubicin 25mg/m2 on days 1,2, and 3
vincristine 0.67mg/m2/day as bolus or continuous infusion on days 1, 2, and 3 (max of 2mg over 72 hours)
ALTERNATE with
Cisplatin 50mg/m2/day on days 1 to 4
etoposide 200mg/m2/day on days 1 to 3
HOLD TX IF ANC <100K
neuroblastoma - tx - Stage IV - biologic response modifiers -3
Retinoic acid 160mg/m2/day x 14 days for 4 courses (helps neuroblastoma cells differentiate)
Monoclonal antibodies to neuroblastoma antigens
USE AFTER HSCT
neuroblastoma - tx - Stage 4S - concepts -2
Surgical resection will cure most
Clinical course depends on age and liver involvement at diagnosis. If N-myc amplification, treat as high risk
wilms tumor -5
#Due to loss of function in tumor suppressor genes ~500 cases/year in US
Peaks at 2-3 years of age, rare after 6 years
sporadic and familial types
Familial types tend to be bilateral and occur at younger age (1-2% of cases)
Usually detected by caregiver who notices an abdominal mass
25% have hypertension
Wilms tumor - pathophysiology -6
Favorable histopathology (85% of cases): well differentiated and resembles developing embryonic tissue
Unfavorable histopathology: anaplastic, clear cell, rhabdoid
Local spread – infiltrated renal capsule, involvement of renal sinus, tumor in intrarenal vessels
Distant spread to: lungs, regional lymph nodes and liver
Neuroblastoma displaces the kidney but Wilm’s distorts the kidney
Use ultrasound to check for thrombus in renal veins and inferior vena cava. Stage is increased if thrombus attached to vessel walls
Wilms tumor - staging -5
I = limited to kidney, complete excision, intact capsule, not ruptures, no residual
II = extends beyond kidney, but completely excised. Lymph nodes negative
III = Residual tumor present
IV = hematogenous mets or lymph node mets outside abdomen
V = bilateral disease
Wilms tumor - surgery -3
most important, ALL STAGES
check both kidneys,
can use chemo first to shrink tumor or if extensive vena cava involvement
Wilms tumor - XRT -3
if nodes involved or metastatic disease,
peritoneal seeding,
spillage during surgery or rupture (No abdominal exams)
2 DRUGS ARE RADIOSENSITIZERS - THESE DRUGS ARE HELD DURING CHEM
Wilms tumor - chemo -3
vincristine, dactinomycin, doxorubicin, and cyclophosphamide are the most active
1m2 kid = 30kg
For kids less than 1yo, doses are cut in half after converted to mg/kg to reduce toxicity - KEY
Wilms tumor - chemo by stage - I and II (favorable) -2
TREATMENT IS BY STAGE AND RISK STRATIFICATION (HISTOLOGY)
FOR VINCRISTINE NEED TO BE ON A GOOD BOWEL REGIMEN AND WATCH NEUROTOX
DACTINOMYCIN IS HIGHLY EMETOGENIC
Dactinomycin 0.045mg/kg/dose (1.35mg/m2 for patients > 30kg (max 2.3mg) start within 5 days of nephrectomy during week 0 and then week 3,6,9,12,15,18
Wilms tumor -chemo by stage -Stage III + IV and stage II-IV focal anaplasia (favorable histology) -4
HOLD DACTINOMYCIN AND DOXORUBICIN DURING XRT
TREATMENT IS BY STAGE AND RISK STRATIFICATION (HISTOLOGY)
Dactinomycin 0.045mg/kg IV (max 2.3mg) within 5 days of nephrectomy during week 0, then on weeks 6, 12, 18, and 24
Wilms tumor - chemo by stage - Stage II to IV, stage I-IV clear cell, and stage II-IV diffuse anaplasia, unfavorable -5
HOLD DACTINOMYCIN AND DOXORUBICIN DURING XRT
TREATMENT IS BY STAGE AND RISK STRATIFICATION (HISTOLOGY)
Surgery and post op radiation to tumor bed
Wilms tumor - prognosis -5
Based on stage and histology
Rhabdosarcoma - background -4
Can occur anywhere, usual sites are GU, extremity, head and neck, trunk, orbit and retroperitoneum, prostate
Rhabdosarcoma - natural history -2
Spreads locally and via lymph and blood.
Primary sites of metastatis are regional lymph nodes, lungs, bone and bone marrow (lung is most common)
Rhabdosarcoma - surgery -1
if tumor is resectable
only 1/3 resectable
all will relapse with surgery alone
Rhabdosarcoma - XRT -1
for local control (have to hold dactinomycin for radiation)
routine for higher stages =group 2-4
Rhabdosarcoma - chemo -5
IRS clinical grouping system - based on how much tumor you clear with surgery
most relapse without chemo - given by group
Rhabdosarcoma - VAC chemo -3
PAY ATTENTION TO MAX DOSES
vincristine 1.5mg/m2 IV weekly
dactinomycin 1.5mg/m2 or 0.045mg/kg (2.5mg max) IV every 3 weeks. (Using mg/kg due to increased risk of VOD in younger kids)
cyclophosphamide 1.2 or 2.2 gm/m2 IV every 3 weeks (using 1.2gm/m2 currently to try to decrease toxicity (sterility) without affecting survival rates)
Rhabdosarcoma - prognosis -5
Overall 70% long term survival
Most important variable is clinical group or extent of disease at diagnosis, second most important is primary site.
Histology is also of prognostic significance. Best to worst: Botryoid, embryonal, alveolar, undifferentiated
Without complete tumor obliteration, cure is not possible.
HSCT doesn’t improve survival in high risk patients
Rhabdosarcoma - late effects of chemo -6
Hemorrhagic cystitis
Infertility
Cardiomyopathy
Adhesions
Secondary malignancy (ex. radiation-related sarcomas and secondary AML
Renal Fanconi’s syndrome with ifosfamide
retinoblastoma - background -5
300 cases in US each year
75% of cases are unilateral (ONLY GERM MUTATIONS CAUSE BILATERAL)
Majority in very young children 95% before 5 years and 66% before 2 years
The RB gene is a tumor suppressor gene and it gets inactivated
2 Types: hereditary (40%) and sporadic (60%)
retinoblastoma - signs and sx -3
Leukokoria (lack of red reflex in eye) – white pupil
Strabismus (having a squint)
Red/painful eye
retinoblastoma - screening -2
Kids with a positive family history have full eye exams shortly after birth and at 6 weeks of age and every 2-3 months until 2 years old.
This is one of the very few pediatric tumors that can be screened.
retinoblastoma - natural hx -4
Arises in retina
Can extend locally or spread distantly
Local spread = growth in intraocular space
Mets occur when tumor grows along optic nerve, spread to CNS or spread via lymph or blood
retinoblastoma - dx and staging -4
Eye exam with ophthalmoscope
Ultrasound
CT
Staging based on number and size of tumors and whether or not there is vitreous seeding
retinoblastoma - surgery -2
enucleation for advanced disease (not done as much as in the past).
Can use laser photocoagulation or cryotherapy if the tumor is small enough
retinoblastoma - XRT -2
to try to control the disease and retain the eye and useful vision.
increased risk of second cancers (OSTEOSARCOMA)
retinoblastoma - chemo -6
IV and or IT chemo if metastatic disease present.
Can use it to minimize need for XRT or enucleation.
Vincristine 1.5mg/m2 (0.05mg/kg if less than 36 mo) IV x 1
Etoposide 150mg/m2 (5mg/kg if less than 36mo) IV daily x 2
Carboplatin 560mg/m2 (18.6mg/kg if less than 36mo) x 1
Combination chemo and radiation is used for stage IV and V
retinoblastoma - prognosis -2
90% survive retinoblastoma, but patients with germinal mutation tend to get second non-ocular malignancy (osteogenic sarcoma)
Retention of vision depends on the size of the tumor and its location
osteosarcoma - background -4
Primarily seen in adolescents (during growth spurt)
A high-grade sarcoma
Usually occurs in distal femur, proximal tibia, or proximal humerus. Most common is distal femur
Can involve flat bones (ex pelvis)
osteosarcoma - risk factors (4pts)
Bone diseases (osteogenesis imperfecta and Paget’s disease) predispose elderly to osteosarcoma
Ionizing radiation
Genetic predisposition (ex retinoblastoma and risk of secondary osteosarcoma)
Alkylating agents
osteosarcoma - signs and sx -3
Pain/mass/swelling over the involved area
About 20-25% present with metastatic disease.
Most common site is the lungs
osteosarcoma - dx w/u -4
x-rays
CT/MRI
Biopsy
Can see increased alkaline phosphatase and LDH
osteosarcoma - staging
Stage 1 (low grade)
Stage II (high grade) – most are high grade
Stage III (distant mets)
A OR B is if extramedullary (broken out of bone)
osteosarcoma - surgery -4
NEED CLEAN MARGINS FOR LONG TERM OS
CAN YOU USE ALONE?
must remove the primary tumor for local control.
Limb salvage or amputation
Metastatic disease must be completely removed in order to get a cure
need chemo also otherwise 80% recurrence
osteosarcoma - XRT
INCLUDE OR NOT?
Osteosarcoma is not radiosensitive, so radiation is not used this is a difference vs Ewing’s sarcoma
osteosarcoma - chemo principles -3
relatively drug-resistant due to p-glycoprotein
Few drugs are effective
High dose methotrexate alternating with doxorubicin and cisplatin - NEED CLOSE MONITORING OF RENAL FUNCTION AND MTX LEVELS
osteosarcoma - chemo regimen -3
GIVE TO ALL CYCLES
IF RENAL TOX - WORK UP PRIOR TO CHEMO
Cisplatin 120mg/m2 IV over 4 hrs on day 1
Doxorubicin 25mg/m2/day on days 1, 2, and 3 as a continuous infusion
Alternate with methotrexate 12gm/m2 IV over 4 hours on days 21 and 28 with leucovorin starting 24 hours from the start of methotrexate. (MAX methotrexate dose is 20 grams)
osteosarcoma - neoadj chemo principles -4
Give chemo for a few cycles, then assess tumor response at time of resection.
Less than 90-95% tumor necrosis is associated with poor risk disease
Shrinking the tumor with chemo prior to surgery improves the chances of limb salvage instead of amputation
Overall, neoadjuvant chemo hasn’t improved outcome vs post-surgical chemo
osteosarcoma - prognosis (6pts)
Surgery and adjuvant chemo have 50-75% disease-free survival at 2-5 years.
Overt metastatic disease has poor outcome
Axial primaries (pelvis) have worse outcomes
Age >20 is better, <10 is worse
Females have better outcome
Increased levels of alkaline phosphatase are associated with increased risk of metastatic disease and poor prognosis
Ewing’s Sarcoma - background (6pts)
Also most commonly seen in adolescents
Considered a bone tumor, but can arise in soft tissue
Primitive neuroectodermal cell tumor, small round blue cell tumor (unique translocation is t(11;22)
Most frequent site is pelvis, then the femur, tibia, and humerus
Can arise in any bone
Osteosarcoma is usually in long bones in extremities, while Ewing’s is usually in the axial skeleton
Ewing’s Sarcoma - signs and sx -3
Pain and swelling of the affected area
May have systemic signs and symptoms (unlike osteosarcoma), especially with metastatic disease: fatigue, anorexia, weight loss and fevers
Can be an extraosseous tumor (no bone involvement)
Ewing’s Sarcoma - natural hx and staging- (unusual) (7pts)
Without systemic treatment, over 90% of patients develop mets, mostly in the lungs. Can also spread to other bones and the bone marrow
Highly malignant
No universally accepted staging system
Presence of metastatic disease is the important issue
Elevated LDH is associated with metastatic disease and a poor prognosis
Spread to lymph nodes is rare (as opposed to rhabdo, osteo and PNET which involve lymph nodes more commonly)
Mets to paraspinal area are common
Ewing’s Sarcoma - surgery -6
WHAT DOES THIS DEPEND ON?
USUALLY DO SURGERY OR XRT WITH CHEMO
POSSIBILITY FOR COMPLETE RESECTION AND ANATOMY (QOL ISSUES, CHANCE FOR CURE)
Role is for local control
Can use surgery or radiation for local control
Neoadjuvant chemo is given to assess tumor responsiveness and treat micrometastatic disease.
Neoadjuvant chemo may improve resectability of tumor
Can do limb sparing or amputation
Ewing’s Sarcoma - XRT -3
USUALLY DO SURGERY OR XRT WITH CHEMO
very radiosensitive.
Use for lesions that are difficult to remove surgically
can be used if surgery would result in loss of nerve function
Ewing’s Sarcoma - chemo
VCR regimen alternating with IE
HOW DO YOU GIVE IN NON-METS DZ?
Vincristine 1.5mg/m2 IV
Doxorubicin 75mg/m2 IV over 48 hours
Cyclophosphamide 1200mg/m2 IV
Alternating with:
Etoposide 100mg/m2 IV daily x 5 days
Ifosfamide 1.8gm/m2 IV daily x 5 days
ONLY GIVE IE IN NON-METS DZ.
DO NOT HOLD FOR MYELOSUPPRESSION
Ewing’s Sarcoma - HSCT
Patients with multifocal or metastatic disease at diagnosis have very poor prognosis
High dose chemo and HSCT is now front line tx
Ewing’s Sarcoma - prognosis
DRIVEN LARGELY BY EXTENT OF DZ
#Most important factor is extent of disease at diagnosis #Increased LDH predicts metastatic disease and poor prognosis #Mets to bone marrow or bone has a poor prognosis #Multifocal disease at presentation has bad prognosis #Patients less than 10yo have better prognosis than older patients #Distal sites are more favorable #Unfavorable sites include pelvic or sacral lesions, intermediate sites include humerus, femur, and rib. #OS for distal extremity is 60-70% and pelvic is 35% #Tumor volume 100ml #Pathologic response to neoadjuvant chemo (good response is favorable prognostic sign)
nuances in peds onc -7
no established screening tests
anthracycline - delayed cardio tox more common
cisplat - hydration 2x maintenance, correct CrCl for size
ifos - renal Fanconi’s = spill electolytes, mostly phos, and spill glucose (see at doses >70g/m2)
infant dosing - reduce or by kg (with BSA nomogram can overdose kids) ~30kg = 1m2 BSA
IT dosing - based on age (a dose in mg/m2 WOULD BE INCORRECT)
slow use of new agents in clinical trials despite high clinical trial enrollment (~85%)
how much is ~30kg equal to in BSA?
1 m2
How do you manage Fanconi’s? hypophos, glucose in urine
change ifos to cyclophos
