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Epidemiology
Very rare, but top of 4 causes of death < 17 (unintentional injury,
homicide, suicide as other)
Discuss the most common pediatric solid tumors, their molecular
characteristics, clinical presentation, and general treatment options:
Neuroblastoma : Most common extracranial solid tumor in child
Most in young children (22 months), equal M:F ratio, all in first 5
years of life
1-2% with fx history
Neuroblasts are neural crest origin, and develop along the sympathetic nervous system
65% in abdomen, others in chest, neck, pelvis
40% localized disease, 60% mets
Symptoms: Asymptomatic abdominal mass, SVC syndrome, Horner’s syndrome, spinal cord compression
Metastatic: systemic: fatigue, weight loss, skin nodules
Opsoclonus-myoclonus syndrome (OMS) – dancing eyes, dancing feet – REMs, ataxia, myoclonic jerking
Associated with favorable disease, but LT neurological problems
Probabbly because of anti-neural antibodies
Vasoactive intestinal peptide syndrome – watery diarrhea, resolves with tumor resection
Imaging: If you find a mass, do CT/MRI of the spot
MIBG – NE analog and is in 90% of the neuroblastoma cells, and iodine -123 can be used to find
bony/occult soft tissue disease, using iodine 131 is good for targeted therapy
Evaulation: Ferritin elevated, urine HVA/VMA (catecholamines) – DOPA percursors which secreted in urine
All Nb patients have Increased HVA/VMA, and good marker of response to therapy
Dx: take it out locally, core needle biopsy if enough
If in the spinal cord: Avoid laminectomy (remove portion of lamina vertebral
bone)
Pathology: Round blue cells, form rosettes? Less differentiated = higher risk
Neuroblastoma: immature small, round, blue cells with little cytoplasm
If more maturing = ganglioneuroblastoma – fully differentiated so benign
Prognosis and treatment:
MYCn or ALK amplication is bad!!!
DNA ploidy – more DNA, is better prognostic?
Low risk: no chemo, no myc, just take it out and its fine
Radiation: only if spinal cord compression
Just do enough, not too much
Intermediate risk: chemo, but 95% is fine
Younger is better < 18 months, low DNA ploidy, other stuff
Just do enough, not too much
High risk: Long term Overall survival (40-50%), Nb accounts for 15% peds death
MYCn high risk, OVER 18 MONTHS = high risk
Older kids who progress, become high risk
Novel agents/combo – high dose chemo + stem cell rescue!
Give cis retinoic acid – helps with differentiation to make them
differentiate
Anti-GD2 monoclonal antibodies – specific for Nb cells
o IL2 stimulation inc ADCC which good for killing
with the Anti-GD2
Osteosarcoma: older childs
Most common primary bone tumor, peak incidence is during growth puberty –
time of greatest growth velocity, more prominent in boys
70% of patients present with localized pain, and a lot of teens don’t say anything
Sites: long bones, extra-axial, outside of knee, 50% are around the knee
Metastatsis 10-20% in pulmonary/bony sites
Dx: bone scan (for mets), MRI (for entire lesion)
Labs: LDH elevated, ESR is normal (As opposed to EWS), ALK phos elevated in 50%
Pathology: Basically all high grade, need for osteoid to be present..
Bio/Genetics:
Extremely complex karyotype, usually problems with cell cycle control,
apoptosis
Rb deletion (70%), P53 mutation (50%), DNA helicase mutations
Prognosis
Localized (70-80%): prior to use of chemo, usually always comes back
in lungs (so use chemo)
Metastatic (20-30%): NOT GOOD if it comes back
Site of your tumor matters because that’s how well you can get it out,
Good response to chemo
Tx: Surgery!!!! Chemo, (OS radio resistant)
Need reconstruction because take out the bone: limb-salvage procedure /
amputation
NEOADJUVANT CHEMO!
MAP (methotrexate, Adriamycin (doxorubicin) and Platin (cisplatin)
Side effects: Nausea, vomiting, hearing, renal/neurologic, otoxicity
Ewing’s sarcoma: Involves AXIAL skeleton
Second most common bone tumor, more boys, more often in Australia and brazil, and low in Africans
Presentation: Pain! More systemic than osteosarcoma, neuropathy (spinal cord compression) – night time pain
Sites: Axial skeleton more common (pelvis and spine), long bones more common, chest wall, ribs
Imaging: do PET scan: can see more mets,, Chest CT for pulmonary metastasis
MRI are better for primary tumor
Prognosis
Younger is better, Axial is worse because cannot resect better, increased LDH is worse
Tx: Can do RADIATION! (OS cannot), mutilagent neoadjuvant chemo
Vincistine, doxorubicin, cyclophosphamide, ifosfamide, etopside (VDC and IE alternating
Secondary meliganancies
XRT related relapse, and 2nd only to rb in terms of relapse)
Wilm’s Tumor
600 cases/year, 95% of all renal tumors in kids , 5% of all cancers < 15, more in females
African American highest rate, Asians lowest rate
5% have bilateral disease, 10% have malformations additionally (no iris, overgrowth, GU – horse/single
kidney, etc)
genes: Wilms tumor 1 (WT1) and WT2
WT1 – 10-20% sporatic, more likely to have bilateral disease
WT2- 30% in sporadic WT
Beckwith-Wiedemann Syndrome: WT2 – big organs, big tongues, liver tumor
So if you have big organs, this puts them at risk!
WTX – inactivated in 30%
Associated syndromes
Beckwith-Wiedemann syndrome
BLOOD SYNDROME, LI-FRAUMENI SYNDROME
WAGR: gondal and renal development: Wilms, aniridia, GU, mental retardation
Ch 16q – MORE LIKELY TO RELAPSE
Presentation:
Abdominal mass by caregiver, abdominal pain, fever, anorexia, weight loss, Hypertension (problems
with renin)
Initial Evaluation: Labs, some have acquired von willibrand disease – because tumor binds on the factor
MRI abdomen, CT chest, surgery (resection, biopsy, tx implication)
Pathology: Triphasic pattern (undifferentiated cells, epithelial, and stromal elements) – this is 90% of
WT, MOST ARE FAVORABLE – more tubules, glomeruli
better if less than 2 years, good histology, no LOH at 1p and 16q
UNFAVORABLE: the tumor is resistant to chemo, anaplasia – see big multinucleated things
Staging
Stage 1: only at kidney, in renal capsule (40% of wilms)
Stage 2: in renal fossa – penetration of the capsule, no lymph nodes (30%)
S3: surgery not completely resected, lymph nodes, tumor has spilled/ruptured during surgery (20%)
S4: Metastatsis lung, liver bone, (10%)
Tx: SURGERY (radical nephrectomy – take the kidney out)
sometimes do renal sparing if there is bilateral disease, or only one kidney
Chemo: Very sensitive: Vincristine, doxorubicin, cyclosphoamide, etopside
Radiation – VERY SENSITIVE!!: only do the flank, or the abdomen if spilled
Complications
Secondary malignancies: Breast (because of abdominal XRT), or underlying syndrome
Fertility compromise, cardiac, renal failure (at age 20, only 3.1%)
CNS and Hematological malignancies will not be reviewed here (covered in MBB and the Hematology Course,
respectively) – 50% of childhood cancers
Discuss long-term complications of chemo/radiotherapy and recommended screening by Primary care physicians
Secondary malignancies: 13% of deaths in childhood cancer survivors, 6x more likely
Most because of radiation for HL, sarcoma breast, Rb – has other symptoms
Breast: Highest risk if gotten between 10-30 in the mediastinal/chest: especially HL
o Screening: monthly self exam, mammography starting 8 years or start age 25, or
annual breast MRI
Thryoid cancer: increased risk from radiation: excellent prognosis
o Screening: annual palpitation
Sarcoma: primary sarcoma inc risk for 2nd – 400x if you treated Rb with radiation
Leukemia – increased risk with alkylating agents, topo II inhibitors
CNS: previous cranial radiation
Skin cancer: MOST COMMON: screening: routing skin exam and sun protection
Cardio: anthracycline: increased risk – screen with regular ECHOs, more in females and younger
Hormonal and reproductive deficiencies
growth retardation
metabolic syndrome
Bone disorders: decreased bone density – give more calcium, vitamin D, Bone scan, estrogen for
menopause
Thryoid disorders: do yearly skilled exam, TSH
Fertility:
Premature menopause/ovarian failure, male infertility from radiation
Screening: FSH, LH, estradiol/testosterone monitor, upfront fertility preservation if possible
neuro-cognitive deficits: from radiation, methotrexate, surgical intervations
Problems with memory, visual-motor integration, can do neuropsychological testing
Hearing loss: cisplatin or radiation related
pulmonary dysfunction
Younger age exposure increases risk, meds: bleomycin, busulfan, nitrosoureas
Do yearly lung function tests
Cardiac dysfunction, including premature coronary artery disease and congestive heart failure
Because of radiation: but is getting better – be more aggressive with management of HTN, diabetes,
obesity, dyslipidemia
Arrhythmia – from chemo
Understand the long-term psychological/physiological impact of surviving cancer
Increased risk for depression, anxiety, PTSD, more likely to have discrimination for insuraunce, employment,
marital dissatisfaction, poor health related QOLok
Lecture 17: Clinical research in Oncology
Discuss clinical trial design in oncology (Phase I, II, III, IV)
o In vitro studies, animal testing efficacy
o Phase 1: 20-100 subjects: IS IT SAFE
What is the maximum tolerated drug, start at a low dose with dose escalating
If there is no dose-limiting toxicity, then do dose increase to next cohort
Enroll 3 + 3, see if there is toxicities, then go to the next one
See tumor marker levels pre and post phase 1
o Phase 2: 100-200 subjects: Does it work in patients
More proof if it is safe, efficacy and proof of concept
Can do one arm (just drug) or two arm (placebo vs positive)
o Phase 3: 1000 – 6000 Does it work, double blind
Drug vs standard of care! See which treatment is better than other
Double blind, patient and physician doesn’t know, stratification
Usually funded by the pharmaceuticals
o Phase 4: Postmarketing surveillance, post FDA approval
Long term safety and side effects, rare toxicities
Review terms used in analysis of survival and response to therapy
o Hypothesis testing: null hypothesis: no difference in survival vs alternative: there is difference in survival
____% in patients with this cancer txed with drug A: the percentage has to be set in the beginning, depending
on what the survival already is with current standard of care
Bring up the problems associated with endpoint selection, patient selection, data interpretation
o EXAMPLES OF TRIAL ENDPOINTS:
Overall survival (time of start of trial to death)
Doesn’t matter why you died
Progression-free survival (time from start of trial to disease progression/death)
If your overall survival doesn’t improve, but your progression-free survival without the
disease does, then it can still be approved because it is useful
Disease free survival (time of randomization to development of recurrent disease)
Tumor response: using standard measure RECIST in prior slides
o Endpoint selection: need to pick the appropriate endpoint to get right answer
Response rate vs overall survival vs progression-free survival
o Patient selection
Phase II – want to enroll those who will response
Phase III – broad eligibility so results can be applicable to many
Is it ethical to do phase III, and you do 2 vs 3 drugs, and a person who is getting 2 drugs is doing badly
and those who are getting 3 drugs seem to be doing well, is it ethical to let them only have 2 drugs…
Talk about the purpose of clinical and pathological staging for patient selection
o Clinical Staging: By imaging alone (CT, US, MRI, PET)
o Pathological staging (tissue: biopsy, surgical resection – how far did it invade)
o Grading
Grade 1: mild, no intervention needed
Grade 2: moderate, local noninvasive intervention
Grade 3: severe but not life threatening but need to go hospital
Grade 4: life-threatening, need help
Grade 5: death
Discuss principles and problems associated with endpoint selection, response assessment, early trial closures
o Reasons for early trial closure
Drug is doing too well, must give it to everyone
Not enough patients
Drug is too toxic
Discuss examples of cancer prevention trials (e.g. chemoprevention, vaccines, diet)
o Chemoprevention: take aspirin everyday and see if it reduces risk
o This takes like.. years
o Environment: Diet and lifestyle, obesity and alcohol, red meat = colon cancer
o HPV vaccine: clinical trials lead to approval of the vaccines
In this trial, cancer is not endpoint in these trials, but it is unethical to allow the lesion to occur
Cancer endpoint would require a long time follow up
Give examples of (un) successful therapeutic trials in early & advanced disease, and discuss how to interpret
magnitude of benefit Discuss ethical issues with clinical trials in oncology
o Staging matters – some drugs only work in some stages
o Three principles
1. Respect for person: informed consent from research participants, maintain confidentiality
2. Beneficence – risk of research are acceptable in relation to likely benefit
3. Justice – benefits and burdens of research are given fairly
o Other ethical issues
Cancer patients are more vulnerable – do anything to go into phase I clinical trials
Those who are prisoners, children, cannot pay for it
Use of placebo – ethical if harm of foregoing effective treatment is not big deal
Randomization: need to accept intervention based on chance
Conflict of interest – research is funded by industry
Lecture 18: Paraneoplastic Syndromes
Paraneoplastic syndrome – disease/symptom that is consequence of presence of cancer in
body but not related to the mass effect/invasion
o Humoral factors by tumor cells or immune cells
o Most common in lung, breast, etc
Discuss clinical presentation and treatment of common endocrine paraneoplastic
syndromes
o SIADH: syndrome of inappropriate secrete of ADH
Cancer makes increased release of ADH (from lung cancer) so
you retain water, decreased Na
Symptoms: asymptomatic, nausea and malaise, seizure, coma
respiratory arrest
Tx: Fluid restriction while you treat cancer, ADH inhibitors and
V2 receptor antagonist, or hypertonic saline/salt tablets, do not
correct too quickly or else the cell will explode
o Hypercalcemia (increased bone breakdown)
PTH increases, increased absorption, increased bone breakdown
Bone stones, groans, and psychic moans
Tx: Remove the calcium, diruetics, phosphorus, give calcitonin
for rapid correction
o Adrenal insufficiency, hypoglycemia, Cushings, Carcinoid syndrome and pheochromocytoma (Endocrine Block)
Review briefly +explain hematologic paraneoplastic syndromes of solid tumors: too many red cells, platelets, WBC
o Erythrocytosis
Normal rxn: high altitudes, pulmonary hypoxia, abnormal hb, carboxyhemoglobin
Not okay: malignancies, androgen abuse, renal disease, EPO abuse
Caused by Hepatocellular carcinoma (increased EPO), renal cell carcinoma (VHL inc EPO),
pheochromocytoma, cerebellar hemangioblastoma
Symptoms: flushing of skin, Red red hands
o Granulocytosis: neutrophils
Causes: infection, drugs, stress, ciagarettes smoking, post-splenectomy
If they do not look infected, see what changes have been made
If this is high, shows widely metastatic cancer, bad prognosis with high counts, or could happen from
G-CSF production
o Thrombocytosis: too many platelets, too much clumping
Post-splenectomy or surgery , or malignancies
If you have this, not good for survival prognosis
MOA: tumor paracrine signaling IL6 liver TPO platelets
Patients with cancer are hypercoagualable (inc VTE), exposure to tissue factor or procoagulants
Trousseau’s syndrome: spontaneous recurrent or migratory thrombosis in pt with cancer
Caused by: pancreas, lung, prostate, stomach
Symptoms: DVT and PE, and 3rd cause DIC, use low molecular weight heparin (LMWH)
o Leukocytosis
Explain one example of a neurologic paraneoplastic syndrome with its pathogenesis
o Lambert-Eaton syndrome (myasthenia gravis will be discussed in the Neurology Block)
NMJ resulting from antibodies against VGCa channels
So you get proximal muscle weakness
Dx: EMG, low muscle action potential amplitude
Sx: leg weakness, drooping eyelids
o MOA of general neurologic disorder
Tumor expresses neuronal protein that immune sees as non-self, and are eaten by DC, which activate
B cells in the lymph nodes. CD8 then react with portions of the NS outside BBB
So Ab go against tumor and the neurons
o Other encephalitis/myelitis syndromes, including cerebellar degeneration will be mentioned in the Tumor
Immunology lecture
Lecture 19: Supportive Oncology
Personalized Medicine: Consider all aspects of people to tailor the treatment
o Do whole-person care: manage social, spiritual, practical issues, financial things, grief
Pain = unpleasant sensory and emotional experience with actual/potential tissue damage
o Questions to ask: location, severity, treatments?
o Do not delay pain management for investigations, just give something and then figure out why
You do not mask the problem if you remove their pain
o Nociceptive pain: Direct stimulation of intact nociceptors
Sharp, aching, throbbing dull,
Somatic (localized) vs visceral (diffuse – idk where it is coming from)
Management: opiates, and adjuvant
o Neuropathic pain – abnormal signal on injured nerves
Pain may exceed observable injury
Described as burning, tingling, shooting, stabbing, electrical
Management: opiates, adjuvants
o Oral vs IV, (oral is 3x higher because 2/3 is lost through first pass metabolism)
IV dose (10-30 minutes) kicks in faster than oral (1 hr to take), at Cmax what you see what you get
Half-life of oral opiod = 4 hours, a lot of drug clearance is through renal, some hepatic
Therapies
o Opiate side effects
Constipation, dry mouth, nausea/vomiting (add dopamine agonist), dysphoria, myoclonus, respiratory
depression
Concerns about opiates: Addiction/psychological dependent, physical dependence (withdrawal)
Tolerance – need to increase amount of drug to have same effect
Pseudo-addiction – want more drug because they have undertreated pain, desperate to get relief
o Others drugs
Adjuvant analgesics: antidepressants (neuropathic), anticonvulsant, local anesthetic, corticosteroids,
NSAIDS, acetaminophen
Nerve blocks, epidural/intrathecal analgesics – cathether into spine
Vertebroplasty (super painful because endplates of the vertebral plates grind against each other – put in a
thing to they will not rub against each other)
o Non-pharmacologic techniques
CBT – relaxation, imagery
Vascular Access
o Reasons for central line: give meds, hemodialysis, poor/limited peripheral venous access, frequent blood draws,
hemodynamic monitoring
o Types of vascular access
Tunneled = goes under the skin for a while, and then into the vein/artery – good for dec infection risk
PICC line – goes into heart/near heart, peripherally inserted central catheter
o Complications
Mechanical problems, pneumothorax, infection (non-tunneled > PICC > tunneled > implanted)
Thrombosis, line occlusion, contact dermatitis
Nutritional support
o Cachexia: lose more fat than muscle – loss lots of body mass, cancer or chemo related
Increased metabolism, no appetite, or affected swallowing and absorption, bowel obstruction
o Management: give nausea management, Dietary counseling, corticosteroids (inc appetite), TPN, entereal
nutrition (feeding tubes for those who cannot swallow), parenteral nutrition (no functioning gut but everything
is fine – give through IV)
If pt doesn’t want to eat, and the swallowing and gut are fine, then theres nothing you can do
Infections
o Risk for neutropenia, reactivate of virus, can give G-CSF
Affects natural barriers to infection = bronchial, biliary, GI obstruction,
mucositis
Stem cell transplant: allogenic > autologous (give immunosuppression in so they don’t reject it)
Anemia: chronic inflammation, blood loss, nutrient deficiency, chemo-related anemia (give transfusion, EPO)
Lecture 20: Psycho-Social Oncology: what physician can provide beyond medicines
Colon cancer: partial colectomy, adjuvant chemo: 5FU/leucovorin, oxaliplatin
Good doctors: looked as human being, listened
Bad doctors: god complex, when they walk into the room, they think they own everything (residents)
Helpful: take an extra moment to show empathy and treat with respect, power difference, sit at eye level