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Haem/Onc > Clinical Pharmacology, ASPHO > Flashcards

Clinical Pharmacology, ASPHO Flashcards

1
Q

Gray =?

A

amount of radiation depositining 1 joule of energy into 1 kg

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2
Q

benefit of proton radiation?

A

Plateau dose distribution‐ deposit 90‐100% of dose at the point they
stop in tissue (Bragg peak); avoids exit dose

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3
Q

dose of TBI? waht does it do? (2)

A 
12‐15Gy in 8‐12 fractions
• Eliminate residual cancer
cells
• Make space in bone
marrow compartment
• Immune suppression
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4
Q

what is teh gross tumour volume?

A

volume occpied by tumor at diagnosis

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5
Q

what is the clincial target volume?

A

• Includes gross tumor volume (GTV) and sites of suspected occult disease and involved adjacent lymph nodes

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6
Q

what is the planning target volume?

A

Planning Target Volume (PTV)
• Includes CTV including surrounding geometric area accounting for variability in set up,
breathing and motion during treatment
• PTV is not the same as photons for protons
• PTV is same as CTV for brachytherapy

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7
Q

3 sources of radiation for therapy?

A

photons, protons, gamma rays

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8
Q

3 types of IV radiotherpay?

A

Systemic Delivery (IV) Radiotherapy (Radiopharmaceuticals)
• Radio‐Iodine (RAI, 131Iodine) Gamma and Beta particles, Thyroid cancer
• 131I‐Meta‐iodobenylguanidine (131I‐MIBG): delivers beta particles via neuroendocrine
transporter to Neuroblastoma or Pheochormocytoma
• 177Lu‐ DOTO‐TATE: Beta emitting, somatostatin receptor positive GI neuroendocrine
tumors (Peptide Receptor Radiouclotide Therapy, PRRT)

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9
Q

which familiy of drug met enzymes is responseible for 70-80% of all phase drug metabolism (activate/deactivate)? which specific enzyme is most commonly used?

A

cytochrome p450; cyp3a

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10
Q

which enzyme is mutated in people who have increased sensitivity to 6MP?

A

Thiopurine Methyl Transferase (TPMT), seen in 1/300

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11
Q

which enzume is mutatied in gilberts disease?

A

• UDP‐glucuronosyl‐transferase 1A1

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12
Q

3 ways to overcome blood brain barrier for CNS disease?

A
  1. High‐dose chemotherapy
    • Methotrexate, cytarabine
  2. Identifying drugs which penetrate the BBB based on
    lipophilicity, molecular weight, degree of ionization, plasma
    concentration of free drug (protein binding)
    • nitrosoureas, thiotepa, topotecan
  3. Disruption of the blood‐brain barrier
    • Osmotic, radiation, vasoactive compounds,
  4. Regional Chemotherapy
    • Intra‐carotid chemotherapy (cisplatin, methotrexate)
    • Intrathecal injection (methotrexate, cytarabine)
    • Intra‐tumoral (carmustine)
    • Convection Enhanced Delivery
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13
Q

IT chemo dosing based on? exception?

A
  • Intrathecal (IT) chemotherapy dose is based on age

* IT MTX dosing based on BSA, children < 18 months had higher rate of isolated CNS

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14
Q

what is the goldie-coldman hypothesis? 3 points

A

• Cancer cells mutate and become resistance to therapy at a rate that
depends on the cancer’s inherent genetic instability
• Probability that a cancer contains a resistant clone is dependent on the
mutation rate and size of the tumor
• Even when tumor burden is low there is likely to be at least one drug
resistant clone

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15
Q

main principle of chemo #1: give combo therapy: what does this mean? eg?

A

Concurrent administration of multiple anticancer drugs with non‐overlapping
mechanism of action and non‐overlapping toxicity profiles…Acute Lymphoblastic Leukemia: transient response rates of 60% with single agents
(MTX, MP, Prednisone, VCR, Dauno, or L‐ASP); 3‐4 drug combination induction
regimens produce durable response rate of 95%

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16
Q

main principel of chemo #2: adjuvant therapy: what is this?

A

Administration of chemotherapy when disease burden is
minimal but risk of recurrence is high (Goldie‐Coldman Hypothesis)
• Continuation of system therapy after local control in localized cancer
• Osteosarcoma: Improved 3 y EFS when chemotherapy administered after complete resection of
localized tumor (20% surgery alone vs 65% surgery + chemotherapy) Eilber et al J Clin Oncol 1987;5:21‐6
• Maintenance Therapy
• ALL: Methotrexate, 6‐Mercopatopurine
• RMS: vinorelbine + cyclophosphamide.

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17
Q

Regarding adjuvant therapy, what is neoadj therapy? benefits (2)

A

Neoadjuvant Setting: Administration of systemic chemotherapy prior to
definitive local control
• Reduce tumor burden at the primary site prior to definitive local therapy
(surgery/radiation)
• Control disease not amenable to local therapy (metastases)
• Assess the sensitivity of the tumor to chemotherapy by measuring tumor response

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18
Q

chemo pirnicple #3: dose intensity: what does this pertain to? eg?

A

Maximize the Dose Rate of chemotherapy
• Highest possible dose at the shortest tolerable interval
• Calculated by normalizing the dose rate (mg/m2/week) for a drug and
comparing to the dose rate of a reference drug or prior regimen.
• Examples:
• Interval Compression improved EFS in localized EWS
• Dose intensity of 4 drug induction in NBL correlates with response and survival
• Children with ALL have improved survival with standard dose vs half dose MTX and MP in
maintenance.

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19
Q

give 4 alkylating agnets

A 
cyclophos
ifofos
cisplatin
busulfan
melphalan
temozolamide
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20
Q

give 2antimetabolities

A

TG

MP

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21
Q

give 7 common toxicities of chemo

A 
SHAM MAN
skin reactions
hepatotox
alopecia
mucositis
myelosupp
allergic rxn
n/v
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22
Q

unique tox of anthras?

A

cardiotox

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23
Q

unique tox fo cyclo, ifos?

A

hemorrhagic cystitis

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24
Q

unqiue tox of alkaloids, cisplatin?

A

peirpheral neuropathy

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25
Q

unique tox of aparaginse?

A

coagulopathy

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26
Q

unique tox of cisplatin?

A

ototox

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27
Q

unique tox of cisplatingand mtx?

A

nephrotox

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28
Q

unique tox of mtx?

A

leucoencephalopahty

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29
Q

how to attenuate myelosupp? (3)

A

G-CSF
stem cell re-infusion
individualized dosing

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30
Q

how to attenuate n/v

A

antiemetics

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31
Q

how to attenuate heomrrhagic cysitis?

A

mesna

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32
Q

how to attenuate nephrotox from cisplatin?

A

hyperteonic saline

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33
Q

how to attenuate cardiotox from anthras?

A

dexrazoxane

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34
Q

how to attenuate myelosupp/mucositis from mtx? (2)

A

Leucovorin

Carboxypeptidase

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35
Q

vesicant= compound that causes severe skin/eye mucosal pain and irritaiton…give 5 high chemos with high vesicant potential

A

think DMV= super irritating

Dauno, doxo, dactino….mitotoxin c…VBL, VCR, vinorelbine

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36
Q

how do alkylating agents work?

A

• Damage to the DNA template (alkyl adducts)
induces apoptosis
• For bifunctional alkylators (nitrogen
mustards), damage results from the formation
of crosslinks (inter‐strand, intra‐strand, DNA‐
protein)

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37
Q

are alkylators dependent on cell cycle?

A

no

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38
Q

give 5 alkylating agents

A 
ifos
cyclophos
cisplatin
carboplatin
busulfan
temozolamide
thiotepa
melphalan
lomustine
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39
Q

give 3 alkylating agents that are pro-drugs

A

Cyclophosphamide
Ifosfamide
Dacarbazine
Temozolomide

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40
Q

in what 4 ways in cisplatin worse than carbo?

A

periopheral neuropathy, n/v, nephrotox, ototox

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41
Q

in what 2 ways is carboplatin worse than cisplatin?

A

myelosupp, hypersens

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42
Q

what do audiograms show in cisplatin-related ototox?

A

Bilateral High
Frequency (Hz > 4000) hearing
loss (dB)

plateau then decreases high in the x-axis

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43
Q

what compound can help with ototox in some groups?

A

Sodium Thiosulfate

44
Q

how does cyclophos –> nephrotox?

A
  • Direct tubular effect–> water retention

- hemorrhagic cystitis due to acrolein= metabolite

45
Q

how does ifos–> GU tox?

A
  • prox tubular damage, ricketts in younger children
  • decreased GFR
  • distal tubular damage with RTA
  • hemorrahgic cystitis due to acrolein= metabolite
46
Q

how does mesna work?

A

chelates acrolein metabolite in the bladder

47
Q

other than GU tox, another organ tox secondary to ifosfamide? how can you tx this?

A

neurotox (esp with aprepritant)…tx iwth methylene blue

48
Q

list 4 alkylating agents

A 
busulfan
carmustine= BCNU
cisplatin
ifosfamide
cyclophosphamide
49
Q

late effects of alkylators? 4

A
  • gonadal atrophy (high dose busulfan)
  • pulmonary fibrosis (busulfan, carmustine)
  • renal dysfunction(cisplatin, ifosfamide)
  • ototox (cisplatin)
  • secondayr cancers
50
Q

mtx mech?

A

inhibits dihydrofolate reductase

51
Q

antimetabolites are cell cycle specific?

A

yes, specific to S phase

52
Q

folate analog?

A

mtx

53
Q

purine analog?

A

6MP, 6TG, fludarabine, clofarabine, cladribine, melarabine=Ara-G

54
Q

pyrimidine analogs?

A

Ara-C, gemcitabine, fluorouracil

55
Q

all anti-metabolites are ___

A

pro-drugs

56
Q

4 frequent toxicities of antimetabolities?

A

myelosupp, hepatotox, mucositis, nausea, vomiting, neurotox, rash, dermatitis, pulm tox

57
Q

specfici tox of HD mtx?

A

nephrotox

58
Q

specific tox of gemcitabine?

A

radiation recall

59
Q

specific tox of 6TG?

A

VOD

60
Q

specific tox of fludarabine?

A

immunosupp

61
Q

specific tox of cladribine?

A

immunosupp

62
Q

specific tox of ara-c?

A

flu-like sx

63
Q

other than ara-c, another drug with AE= flu-like sx?

A

gemcitabine

64
Q

neurotox secondary to mtx? (2) resolution?

A

acute encephalopathy (5-14 days later) with HD– resolution in 1-7 days; 10-50% recur….chronic encephalopathy= permanent

65
Q

cytarabine neutotox?

A

acute cerebellar syndrome…onset 3-8 days days…resolves in 1 week, but 30% have rseidual defect

66
Q

nelarabine neutotx?

A

somnolence, seizures, guillain-barre-like weakness, paresthesia…gradually reversible

67
Q

fludarabine neurotox?

A

progress leukoencephalopahty, can be fatal

68
Q

what is the MAX mtx infusion duration?

A

42 hours…must start leucovorin within this timeframe!!

69
Q

4 ways to maange nephrotox from HD Mtx?

A
  • Hydration and alkalination of urine
  • increase leucovorin/give more often
  • dialysis
  • glucarpidase=carboxypeptidase
70
Q

how does glucarpidase work?

A

cleaves mtx into DAMPA and glutamic acid

71
Q

allopurinol’s effect on 6MP? if giving both at same time do what?

A

allopurinol inhibits xanthine oxidase, which is responsibilie for metabolism of PO 6mp (not iV)–> 6mp becomes more bioavailable…if giving both, decresae 6MP dose by 75%!

72
Q

give 3 drugs that interact with mtx–> decreased secretion of mtx

A

salicylates, pencillin, NSAIDs, ciproflox

73
Q

topoisomerase 1 does what? 2 does wht?

A

–> single strand DNA breaks? ….2–> double stand DNA breaks

74
Q

3 classes of topoisomerase inhibitors?

A

anthracyclines, epipodophyllotoxins, camptothecins, anthracednediones, phenoxazones

75
Q

give 3 anthracyclines

A

doxo, dauno, idarubicin

76
Q

give 2 epipodophyllotoxins

A

etoposide, teniposide

77
Q

mitxantrone= what type of chemo?

A

anthracenedione= topoisomerase 2 inhibitor

78
Q

dactinomycin= what type of chemo?

A

phenoxazone= topoisomerase 2 inhibitor

79
Q

topotecan and irinotecan = what type of chemo?

A

camptothecins…= topoisomeraise ONE inhibitors

80
Q

give 2 antitumour antibiotics

A

anthracyclines, dactinomycin

81
Q

how to tx irinotecan induced diarrhea iwthin 8 hours of starting?

A

atropine

82
Q

how to tx irinotecan diarrhea after 8 hours?

A

loperimide, octreotide

83
Q

how to prevent irinotecan diarreha? how does this work?

A

cefixime; decreases glucuronidase producing bacteria in the gut

84
Q

give 4 tubulin binding agents

A

vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel

85
Q

4 specific AEs of vcr?

A
  • peripheral nueroptahy (loss of DTRs, numbness)
  • CN involvement (double vision)
  • SIADH
  • autonomic neuorpathy= constipation
86
Q

3 drugs that reduce clearance of vinca alkaloids?

A

fluconazole, cipro, grapefruit juice

87
Q

3 drugs taht increase clearance of vinca alkaloids?

A

st johns wort, phenobarb, rifampin

88
Q

5 AEs of steroids?

A

AVN, htn, diabetes, immunouppression, growth failiure, centripedal obesity

89
Q

tox assoicated with bleomycin

A

interstitial pneumonitis, alopecia, reynaud, hyperpigemntation of skin and nails

90
Q

goals of phase 1 trial?

A

establish safe dose, establish tox profile, establish pharmacology

91
Q

population used in phase 1 trials?

A

relapsed cancer, <25 pts

92
Q

phase 2 trial goal?

A

determine response to a certain drug

93
Q

populaiton for phase 2 trial?

A

relapased cancer pts

94
Q

goal of phase 3 trail?

A

efficacy (benefit) of drug, with endpoint being survival

95
Q

population in phase 3 trial?

A

untreated cancer pts

96
Q

3 AEs of Aresnic trioxide?

A

prolonged QTc, leukocytosis, APL differentation syndrome

97
Q

3 AEs of ATRA?

A

differentation syndrome, venous thrombosis, pseudotumour cerebri

98
Q

3 AEs of imatinib?

A

increased transaminases, n/v, fatigue

99
Q

2AEs of crizotinib?

A

hepatotox, AKI

100
Q

NTRK fusion (NTRK-ETV6) seen in which tumours?

A

congential mesoblastic neprhoma, infantile fibrosarcoma

101
Q

give an NTRK inhibitor

A

larotrectinib

102
Q

give an inhibitor of dna methylation

A

azacitidine

103
Q

give an immune hceckpoint inhibitor and an AE of it

A

nivolumab, pleural effusion

104
Q

give 3 MABs used to treat cancer, the cancer they treat, mech, and AE

A
  • avastin=bevacizumab; LGG; blocks angiogenesiss via VEGF inhibition; hypertesnion
  • rituximab; PTLD and b-cell lymphoma; inhibits CD20-> depletes normal b-cells–> hypogammaglobulinemia
  • dintuximab, NBL, anti-GD2–> antibody dependent cell mediated toxicity; neuropathic pain
105
Q

AE of gemtuzumab?

A

infusion-related reaction, myelosupp

106
Q

AE of inotuzumab?

A

infusion-related reaction, myelosupp, VOD

107
Q

AE of brentuximab?

A

neutropenia, neuropathy

Haem/Onc (30 decks)

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