Lecture 16: childhood Cancers and Long term Problems in Cancer Survivors

 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
