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RACP 2024 > Oncology > Flashcards

Oncology Flashcards

1
Q

What is the most common immune related adverse event associated with Immune checkpoint blockade and its median onset?

A

10-20% are endocrinopathies, most commonly involving thyroid, 2nd most common is pituitary

Media onset 8 weeks post initiation

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2
Q

What is the consequence of immune-related endocrine adverse events of immune checkpoint inhibitors?

A

Typically result in destruction of endocrine tissue resulting in irreversible endocrine hypofunction

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3
Q

How do endocrine adverse events correlate to survival following immune checkpoint inhibition?

A

Endocrinopathy correlates with better survival (in metastatic melanoma)

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4
Q

What endocrine monitoring is indicated in immune checkpoint inhibition therapy?

A

8-9am serum cortisol, TSH, fT4, glucose, Na, K, CCa at baseline and before each cycle
(HbA1c if pre -exisiting diabetes)

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5
Q

What additional endocrine monitoring is indicated for ipilimumab?

A

ACTH, LH, FSH, E2/testosterone, prolactin given high risk for hypophisitis

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6
Q

Are endocrinopathies contraindications for ICI therapy?

A

Usually no as cancer benefit outweigh endocrinopathy risk EXCEPT for adrenal crisis, thyrotoxicosis, DKA or severe thyroid eye disease

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7
Q

Are patients with pre-existing endocrinopathies at increased risk of developing an endocrinopathy with an ICI?

A

No

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8
Q

What is the management of ICI-related endocrinopathy?

A

Referral to endocrinologist unless isolated primary hypothyroidism
No evidence fo high dose steroids

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9
Q

In what ICI therapies would hypophisitis be suspected and how is it diagnosed?

A

Ipilimumab (20% patients), AntiPD1/PDL1 (1-2%)
- full pituitary panel, typically ACTH deficiency
- pituitary MRI (exclude pituitary mets)
- NB anti-pituitary antibodies not available

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10
Q

Compare and contrast CTLA4i and PDL1/PD1i induced hypophysitis

A

CTLA4:
- onset 10 weeks
- deficient in ACTH, TSH and Gn
- headaches
- 80% show MRI changes

PDL1/PD1:
- onset 27 weeks
- deficient in ACTH
- 20% have MRI change

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11
Q

How should ICI induced hypophysitis be managed?

A
  • cortisol + ACTH levels
  • hydrocortisone 100 mg IV for adrenal crisis
  • high dose steroids in visual loss or intractabel headache
  • initiate maintenance therapy (15-25 mg split across day)
  • sick day plan incl. IM cortisol
  • do not need mineralocorticoid replacement
  • thyroxine replacement if required
  • sex hormone replacement if good prognosis
  • vitamin D replacement (given sex hormone deficiency)
  • Not for Growth hormone replacement as may cause cancer to grow
  • desmopressin if ADH deficiency
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12
Q

What ICI is most commonly associated with thyroid endocrinopathy?

A

Anti-PD1 inhibitors

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13
Q

What is the typical pattern of thyroid endocrinopathy seen with ICI therapy?

A

Transient thyrotoxicosis 6 weeks after treatment due to destructive thyroiditis
Then hypothyroidism 12 weeks after therapy
Rarely Graves’/ophthlamopathy

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14
Q

How should hypothyroidism in ICI therapy be managed?

A

-Diagnosed as low fT4 + TSH > 10
-send anti-TPO
- start thyroxine and aim for normal TSH

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15
Q

How should thyrotoxicosis in ICI therapy be managed?

A

Send TSH receptor antibody
If negative start b-blocker for symptom relief while thyroiditis settles (Consider TRAb-negative Graves if thyroiditis does not improve)
If positive start thionamides for Graves disease
Only role for high dose steroids is in 1) severe thyrotoxicosis to reduce conversion T4 to T3 or 2) ophthalmopathy

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16
Q

What ICIs are associated with autoimmune diabetes?

A

Anti-PD1 = most common
Anti-PDL1
Anti-CTLA4 = less common8

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17
Q

How should autoimmune diabetes in patients on ICI therapy be maanged?

A
  • T1DM antibodies (often negative)
  • C peptide
  • Ketones + VBG to assess for DKA
  • no benefit from high dose steroids
  • start insulin therapy incl hypo advice
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18
Q

What are features of ICI associated adrenal insufficiency?

A
  • very rare
  • associated with antiPD1/PDL1
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19
Q

How should ICI-related adrenal insufficiency be managed?

A
  • Serum cortisol (low) + ACTH (high)
  • short synacthen
  • 21-OHase Ab
  • CT adrenals to exclude Mets (even if 21-OHase positive)
  • start hydrocortisone + fludrocortisone
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20
Q

What are clinical features of ICI-related hypoparathyroidism?

A

Very rare
Present with hypocalcaemia with low PTH
Require permanent calcium requirement and calcitriol

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21
Q

How do immunotherapy side effects differ from chemotherapy side effects?

A
  • overall less toxicities esp grade 3 and 4
  • No bone marrow toxicities
  • distinct immune mediated toxicity
  • less infusion related reactions
  • safer in older population
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22
Q

What is the most common side effect of immunotherapy?

A

Skin toxicities

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23
Q

What is the most significant toxicity of. immunotherapy?

A

Colitis

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24
Q

What side effects are most common with anti-PD1?

A

Hypothyroidism
Pneumonitis
Myocarditis
Arthralgia
Autoimmune diabetes

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25
Q

What side effects are commonly associated with anti-CTLA4?

A

Hypophysitis
Rash/dermatitis
Enteritis
Colitis

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26
Q

What is the type timing of onset for anti-CTLA4 related toxicities?

A

4-10 weeks

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27
Q

What is the type timing of onset for anti-PD1 related toxicities?

A

4-14 weeks

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28
Q

What is the mechanism of immunotherapy adverse events?

A

Exact mechanism unknown
- may relate to T-cell activation
- increase auto-antibody production
- maybe cytokine or complement mediated

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29
Q

How should immunotherapy-related skin toxicities be managed?

A

Grade 1: mild topical steroid + antihistamine
Grade 2: stronger topical steroid + antihistamine
Grade 3: with-hold ICI, PO steroids, dermatology review
GRade 4: stop ICI, IV methylpred, derm review

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30
Q

How should ICI related hepatotoxicity be managed?

A

Grade 1 (ALT or AST < 3xULN) = no specific treatment

Grade 2 (ALT or AST 3-5xULN) = with hold ICI, PO pred, perform liver screen and consider imaging to exclude mets

Grade 3 (ALT or AST 5-20 ULN) = stop ICI, PO prednisone and liver USS

Grade 4 (ALT or AST > 20xULN) = stop ICI, IV methylpred, hepatology consult +/- liver biopsy

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31
Q

How should ICI related GI toxicity be managed?

A

Exclude infection with stool culture, CT scan if abdominal tenderness
Consider starting PO steroid if 4-6 loose stools for more than 3 days
If > 7 stools or fails to respond to PO prednisone given IV methylpred and get colonoscopy
If fails steroids then start infliximab

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32
Q

How is ICI-related pneumonitis managed?

A

For treatment only if symptomatic
-with hold ICI
- start PO steroid (IV if hypoxic)
- HRCT chest
- infliximab if no improvement in 48 hours
- consider broad spectrum antibiotics
- consider bronchoscopy to exclude other causes

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33
Q

What are radiological features of ICI-related pneumonitis?

A

-Ground glass opacities
- cryptogenic organising penumonia or interstitial pneumonia pattern

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34
Q

How are ICI-related nephrotoxicitues managed?

A

IV hydration + PO steroid for AKI up to 3xbaseline
Consider other causes
IV methylprednisone + nephrology consult if >3xbaseline

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35
Q

What is the most potent carcinogen in cigarette smoke?

A

Polycyclic aromatic hydrocarbons

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36
Q

How are stage 1 and 2 lung cancers treated?

A

Surgically = lobectomy + LN resection
(if not fit then with radiotherapy)

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37
Q

What is the indication for atezolizumab as adjuvant therapy in lung cancer?

A

Resected stage II or IIIA with >50% PDL1 expression on tumour

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38
Q

How is stage III lung cancer managed?

A

If IIIA and non bulky then can be managed surgically +/- chemo +/- radio +/- antiPDL1

If bulky IIIA or IIIB then for chemoradiation (platinum based) followed by durvalumab (anti-PDL1)

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39
Q

What lung cancers are associated with targeted driver mutation?

A

Cancers in non-smokers

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40
Q

How is an acneiform rash from TKI managed?

A

Topical or oral tetracyclines, topical steroids, sun protection

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41
Q

What TKIs can be used in Stage IV NSCLC EGFR mutant?

A
  • erlotinib
  • gefitinib
  • osimertinib (T790 mutation only)
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42
Q

What TKIs can be used in Stage IV NSCLC ALK translocation (EML4-ALK fusion oncogene)?

A
  • Alectinib
  • Brigatinib
  • Loratinib
  • crizotinib
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43
Q

What TKIs can be used in Stage IV NSCLC with ROS1 translocation?

A
  • crizotinib
  • Entrectinib
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44
Q

What TKIs are used in Stage IV NSCLC with MET exon 14 mutation (splice site of exon14)?

A
  • Capmatinib
  • Tepotinib
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45
Q

What are common side effects of gefitinib and erlotinib?

A
  • aceniform rash
  • diarrhoea
  • ocular changes
  • alopecia
  • nail changes
  • pulmonary toxicity
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46
Q

What is the main toxicity of tepotinib?

A

Peripheral oedema

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47
Q

What treatment can be given to Stage IV lung adenocarcinoma with > 50% PDL1+ and performance status of 2?

A

Single agent immunotherapy

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48
Q

What treatment can be given to Stage IV lung squamous cell carcinoma with > 50% PDL1+ and performance status of 2?

A

Single agent immunotherapy

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49
Q

What is the big difference in treating lung adenocarcinoma and lung squamous cell carcinoma with regard to immunotherapy?

A

No role for immunotherapy in low PDL1 (<50% expression) in squamous cell, but a benefit seen for adenocarcinoma with any expression

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50
Q

How do you treat extensive stage small cell lung cancer?

A

Atezolizumab + platinum (cisplatin or carboplatin) + etoposide (total 4 cycles)
+/- radiotherapy for brain mets

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51
Q

How is small cell lung cancer staged?

A

Limited = can fit within one radiotherapy field
Extensive = cannot

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52
Q

How do you treat limited stage small cell lung cancer?

A

Cisplatin + etoposide + radiotherapy from cycle 2 (total 4 cycles)

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53
Q

How do you teat mesothelioma?

A

Ipilimumab + nivolumab
OR
Cisplatin + pemetrexed
(palliative intent)

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54
Q

What breast cancers are treated with curative and palliative intent?

A
  • curative = resectable disease (Stage I-III)
  • palliative - Stage IV
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55
Q

What is the most common subtype of breast cancer

A

Hormone receptor positive, HER2- negative

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56
Q

What treatments are used for the following types of breast cancer?
- Hormone receptor positive, HER2-negative
- HER2-positive
- Triple negative

A

Hormone receptor positive, HER2-negative:
- Endocrine therapy +/- chemo

HER2-positive:
- HER2 targeted, chemo +-/ endocrine

Triple negative:
- chemo

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57
Q

What percentage of breast cancers are hormone receptor positive?

A

70%

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58
Q

What clinical features are associated with hormone receptor positive breast cancer?

A
  • indolent disease
  • bone mets
  • late recurrence
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59
Q

How is early breast cancer treated?

A
  1. Surgery (excision vs mastectomy +/- nodal biopsy or clearance)
  2. Neoadjuvant
    - immunotherapy for TN
    - anti-HER2 for HER2+
  3. Adjuvant:
    - chemo +/- anti-HER2
    - radiotherapy
    - endocrine +/- CDK4/6i
    - bisphosphonates
  4. Fertility preservation
    - Ovarian suppression
    - cryopreservation
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60
Q

What treatment can be used for HER2+ breast cancer?

A

Trastuzumab (prevents HER2 homodimerization to inhibit signalling)

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61
Q

What are side effects of trastuzumab?

A
  • cardiotoxicity (LVEF reduced)
  • infusion rection
  • nephrotic syndrome
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62
Q

What endocrine therapies can be used for breast cancer?

A
  • tamoxifen (ER antagonist)
  • aromatase inhibitors (letrozole, anastrozole) - only in post menopausal women (biologic or chemical)
  • fulvestrant (inhibits ER dimerisation)
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63
Q

What are common toxicities of endocrine therapies for breast cancer?

A
  • hot flushes
  • arthralgia, myalgia (AI > Tam)
  • vaginal atrophy (AI > Tam)

Tamoxifen:
- VTE
- endometrial cancer

Aromatase inhibitors:
- accelerated bone loss

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64
Q

How is metastatic breast cancer treated?

A
  1. HR+
    - endocrine therapy +/- CDK4/6i
    - single agent chemo
    - bisphosphonates for bone mets
  2. HER2+
    - trastuzumab + pertuzumab (also binds HER2, inhibits ligand initiated intracellular signalling)
    - singel agent chemo
    - antibody drug conjugates (trastuzumab emtansine, trastuzumab deruxtecan)
  3. TN
    - single agent chemo +/- immunotherapy (pembrolizumab)
    - antibody drug conjugates (sacituzumab govitecan)
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65
Q

What is the mechanism of action of CDK4/6i (abemaciclib, palbociclib, ribociclib)?

A

CDK4/6 forms doublet with cyclin D1, the splitting of this is essential for cell cycle replications to allow phosphorylation of Rb (CDK-Rb1-E2F pathway)

Blocking CDK4/6 prevents phosphorylation of Rb and prevents DNA synthesis

When combined with ER blockade to reduce downstream oestrogen-dependent stimulation fo E2F1, increasing the effectiveness of CDK4/6i

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66
Q

What are common side effects of CDK4/6i?

A
  • leukopenia, neutropenia
  • fatigue
  • QTC prolongation
  • diarrhoea (abemaciclib)
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67
Q

What are the 3 components of an antibody drug conjugate?

A
  • Antibody
  • linker
  • payload (cytotoxic)

(allows for intracellular release of drug)

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68
Q

What antibody-drug conjugates can be used in breast cancer?

A
  • trastuzumab emtansine (HER2 mAb + anti-tubulin DM1)
  • trastuzumab deruxtecan (HER2 mAb + topoisomerase I inhibitor)
  • sacituzumab govitecan (TROP2 mAB + topoisomerase I (SN-38) inhibitor)
69
Q

How are stage I-III melanomas treated?

A

Sentinel removal
Stage IIIb or IIIc can receive anti-PD1 immunotherapy and/or BRAF + MEK inhibitor therapy

70
Q

What mutations are associated with cutaneous melanoma?

A
  • BRAF
  • NRAS
  • NF1
71
Q

What mutations are associated with mucosal melanomas?

A

-KIT
- SF3B1

72
Q

What mutations are associated with Uveal melanoma?

A

G proteins (GNAQ, GNA11)

73
Q

What are the BRAF+MEK inhibitor combinations used to treat metastatic melanoma?

A
  • Vemurafenib (BRAF) + cobimetanib (MEK)
  • Dabrafenib (BRAF) + trametinib (MEK)
  • Encorafenib (BRAF) + binimetinib (MEK)
74
Q

What is the mechanism of action of anti-CTLA-4?

A

Binds CTLA-4 molecule on T-cell, allowing B7 to bind C28 and act as co-stimulatory receptor for T-cells

75
Q

What is castrate levels of testosterone used to help define castrate sensitivity of prostate cancer?

A

Testosterone < 1.7 nmol/L (50 ng/dL)

76
Q

What forms of androgen deprivation therapy are used to treat prostate cancer?

A
  • GnRH agonists (goserelin, leuprolide)
  • GnRH antagonists (degarelix), causes rapid reduction in serum testosterone, avoids clinical flare
  • bilateral orchidectomy
77
Q

What is the standard of care for metastatic castration-sensitive prostate cancer?

A

Doublet therapy:
ADT + ARSi OR ADT + docetaxel

ARSi = androgen receptor signalling inhibitor

78
Q

What are treatment options for metastatic castrate-resistant prostate cancer?

A
  • chemo (docetaxel, carbazitaxel)
  • Abiraterone acetate, enzalutamide
  • radipharmaceuticals (Radium-223, letetium-PSMA)
  • PARP inhibitors (olaparib if BRCA1/BRCA2 mutation)
79
Q

What is the mechanism of action of docetaxel and cabazitaxel used for prostate cancer?

A

Both are taxane chemotherapies
Stabilise microtubules during mitosis/interphase leading to mitotic arrest and cell death

80
Q

What are the toxicities of:
- Docetaxel
- Cabazitaxel

A

Docetaxel:
- sensory/motor peripheral neuropathy
- cytopenias
- hypersensitivity reactions

Cabazitaxel:
- diarrhoea
- cytopenias
- sensory/motor peripheral neuropathy (less than docetaxel)
- less alopecia

81
Q

What is the mechanism of action of abiraterone acetate?

A

Inhibits the 17-a-hydroxylase enzyme preventing the adrenal and tumour autocrine synthesis of androgens

82
Q

What are important toxicities of abiraterone acetate?

A

Also inhibits c17,20 lyase
- Hypertension
- Hypokalaemia
- peripheral oedema
- transminitis

Managed with low dose prednisone to avoid mineralocorticoid effects

83
Q

What is the mechanism of action of enzalutamide/apalutamide?

A
  1. Androgen receptor antagonist (prevents androgen binding)
  2. Inhibit nuclear translocation of activated AR
  3. Inhibit association of activated AR with DNA
84
Q

What are important toxicities of enzalutamide/apalutamide?

A
  • Hypertension
  • fatigue
  • cognitive changes
  • falls
85
Q

What characteristic of darolutamide distinguishes it from other androgen receptor inhibitors?

A

Low blood-brain barrier penetration -> less CNS toxicity

86
Q

What proportion of patients with metastatic prostate cancer have defects in DNA damage response genes?

A

15-25%
(BRCA2 is prominent and has a poor prognosis)

87
Q

What is the mechanism of action of olaparib?

A

PARPi
Inhibits poly(ADP‐ribose) polymerase, thereby blocking the repair of single‐strand DNA break (esp in BRCA mutations)

88
Q

What is the most common variant of renal cell carcinoma?

A

Clear cell

89
Q

What proportion of clear cell carcinomas have aberrations in the vHL gene?

A

50-90%

90
Q

What are the 6 variables of the IMDC used for risk stratifying metastatic renal cell carcinoma?

A
  1. Performance status
  2. High neutrophils
  3. High platelets
  4. High calcium
  5. Low Hb
  6. < 12 months between diagnosis and treatment

Favourable =0
Intermediate = 1-2
Poor =>3

91
Q

What drugs are used to treat metastatic renal cell carcinoma?

A
  1. TKIs (multiple kinase inhibitors), target in the VHL-VEGF pathway
    - sunitinib (PDGF-R, VEGF-R, KIT)
    - pazopanib (VEGFR, PDGFR, c-KIT, FGFR)
    - cabozatinib (VEGFR, KIT, FLT-3, RET, MET)
    -axitinib (VEGFR)
    -lenvatinib (VEGFR, FGFR, PDGFR, RET, c-KIT)
    -sorafenib (RAF, BRAF, VEGFR, PDGFR, KIT, FLT-3, FGFR, RET)
  2. Immunotherapy
    - PD1 mAb
    - CTLA4 + PD1 combination
  3. mTORi (everolimus)
92
Q

What are common VEGFR TKI toxicities?

A
  • mucositis, stomasitis, diarrhoea
  • dry skin, rash, hand- foot syndrome
  • Thyroid dysfunction (increases with time)
  • LFT derangement (esp pazopanib)
  • CCF
  • MI
  • Arterial or VTE
  • QT prolongation
93
Q

What are the most common side effects of immunotherapy?

A

Fatigue
Rash
Thyroiditis

94
Q

What proportion of bladder cancers are urothelial carcinoma in developed countries?

A

90%

95
Q

What is the mainstay of management of muscle invasive bladder cancer?

A

Radical cystectomy

96
Q

What is the first line treatment of advanced bladder cancer?

A

Platinum based chemotherapy (cisplatin or carboplatin)
AND
Gencitabine OR dose-dense MVAC (Methotrexte, vinblastine, doxorubicin, cisplatin)

97
Q

What is avelumab and its role in advanced bladder cancer?

A

Binds anti-PDL1

Used as maintenance therapy in patients who have responded to first line platinum-based chemo

98
Q

What is the role of pembrolizumab in advanced bladder cancer?

A

Used 2nd line for patients progressing on platinum-based chemotherapy

99
Q

What antibody drug conjugates can be used for urothelial carcinoma?

A

-Enfortumab vedotin (binds nectin-4, payload is Monomethyl auristatin E which blocks polymeristation of tubules in mitosis)
- sacituzumab govitecan (bnds TROP-2, payload is topoisomerase I inhibitor SN-38)

100
Q

What are important toxicities of enfortumab vedotin?

A

Rash
Hyperglycaemia
Peripheral neuropathy

101
Q

What is erdafitinib and its role in metastatic urothelial carcinoma?

A

Pan-FGF-R inhibitor, 3rd line treatment

102
Q

What are common toxicities of erdafitinib?

A

Fatigue
Hyperphosphataemia
Nail changes
GI side effects
Drye eys
Central serous retinopathy (reversible)

103
Q

How are seminomas treated?

A

Surgical resection + single high-dose carboplatin

104
Q

How are non-seminoma testicular cancers treated?

A

Surgical resection + 1-2 cycles BEP (bleomycin, etoposide, cisplatin)

105
Q

What testicular tumours produce:
- AFP
-bhCG

A

AFP is produced by non-seminoma (ie not produced by pure seminoma)

bhCG is produced by both seminoma and non-seminoma

106
Q

What types of ovarian tumours arise from surface epithelial cells?

A
  • serous (most common, arise from fallopian tubes)
  • mucinous
  • endometrioid
  • clear cell
  • Brenner tumours
107
Q

What types of ovarian tumours arise from germ cells?

A

Dysgeminoma
Teratoma
Yolk sac
Choriocarcinoma

108
Q

What types of ovarian tumours arise from stroma/sex cord cells?

A

Granulosa cell
Theca cell
Sertoli-Leydig cell
Fibroma

109
Q

What is the FIGO staging of ovarian tumours?

A

1: limited to ovary
2: spread to pelvic organs
3: spread to peritoneal cavity
4: distant Mets

110
Q

What is the standard treatment of epithelial ovarian cancer?

A

Surgery + chemo
Staging laparotomy, followed by TAH +BSO + debulking
Adjuvant or neoadjuvant carboplatin + Paclitaxel

111
Q

What is the standard treatment of non-epithelial ovarian cancer?

A

Conservative surgery + chemo
(very chemo-sensitive)

112
Q

What patients with recurrent ovarian cancer are deemed platinum sensitive?

A

If recurrence occurs > 6 months from treatment

113
Q

What patients with cancer should be tested for BRCA1 and BRCA2 gene mutations?

A
  • TN breast cancer < 50y
  • TN breast cancer with close relative with breast or ovarian cancer
  • high grade ovarian cancer any age
114
Q

What is the role of olapraib in ovarian cancer?

A

1st line maintenance therapy

115
Q

What is the most common gynaecological cancer in Australia?

A

Endometrial

116
Q

What are common presenting characteristics of endometrial cancer?

A

Age 60-65
Present with post menopausal bleeding

117
Q

What is the standard chemotherapy for advanced endometrial cancer?

A

Carboplatin/paclitaxel

118
Q

What hormonal therapy is used in the treatment of endometrial cancer?

A

Provera for ER/PR positive
Tamoxifen if provera fails

119
Q

Which HPV serotypes are high risk for cervical cancer?

A

16, 18 (account for 70% cancers)

120
Q

What is the most common histological type of cervical cancer?

A

Squamous cell (arise at squamo-columnar junction)

121
Q

What adjuvant treatment is used for locally advanced cervical cancer?

A

Cisplatin + radiotherapy concurrently

122
Q

What is the only gynaecological cancer in which bevacizumab has shown a survival advantage?

A

Cervical cancer

123
Q

What is the role of anti-PD1 in the treatment of locally advanced oesophageal cancers?

A

Adjuvant therapy post resection
(better response seen for SCC)

124
Q

What is the role of trastuzumab in gastric cancer?

A

Used in combination with chemotherapy for HER2+ tumours

125
Q

What is the mechanism of action of zolbetuximab?

A

mAb against Claudin 18.2, molecule expressed in gastric mucosa, that results in ADCC and complement mediated cell death

126
Q

What is the most common histological type and site of pancreatic cancer?

A

Adenocarcinoma
Head of pancreas (present with obstructive jaundice)

127
Q

What proportion of pancreatic cancers are BRCA1 or BRCA2 positive?

A

8-10%

128
Q

What genetic factors are associated with biliary tract tumours?

A

Lynch syndrome
BAP1 tumour predisposition syndrome

129
Q

What is the most common histological type of biliary tract cancers?

A

Adenocarcinoma

130
Q

What is typical dobulet chemotherapy for biliary tract tumours?

A

Gemcitabine
Cisplatin

131
Q

What is the basis for the FOBT screening test for CRC?

A

Tests for human globin in stool to assess for microscopic bleeding

Only 1:29 are diagnosed with cancer

132
Q

What are key mutations in the adenoma cancer pathway of CRC?

A
  • APC mutation (WNT)
  • NRAS/KRAS mutation (MAPK)
  • SMAD4 mutation (PI3K, TGFB)
  • TP53 mutation (P53)
133
Q

What are key mutations in the serrated polyps to cancer pathway of CRC?

A

-CTNNB1 (WNT)
-KRAS/BRAF (MAPK)
-PIK3CA (PI3K, TGFB)
-TGFBR2 (P53)

134
Q

What familial cancer syndromes are associated with CRC and their percentages?

A
  1. Polyposis syndromes <1% CRC
    - FAP (APC on Chr5)
    - MAP (MUTYH gene)
  2. Lynch syndrome (HNPCC) 3% CRC
    - MLH1(highest risk), MSH2, PMS2, MSH6
135
Q

What are the two pathways of mismatch repair deficiency in colorectal cancer?

A
  1. Sporadic biallelic MLH1 methylation of CIMP
  2. Germline mutation in MLH1, MSH2, MSH6, PMS2
136
Q

What is the role of cetuximab in CRC?

A

Used alongside chemo in RAS/RAF wildtype

137
Q

How many lymph nodes need to be recovered in CRC resection to guide appropriate staging?

A

Minimum 14

138
Q

What is the treatment for rectal cancer?

A

Resection
Neoadjuvant chemoradiotherapy for T3-T4 disease (5FU or capecitabine)

139
Q

What are CRC guidelines post treatment?

A
  • colonoscopy at 3 and 5 years
  • physical + CEA 3-monthly for 3 years, then 6 monthly
  • CT CAP annually for 3 years
140
Q

What gene variants predict poor prognosis and treatment response in CRC?

A
  • RAS/RAF mutants poor response to EGFR therapy (cetuximab)
  • BRAF mutant, poor prognosis and rapid chemo resistance
    -MSI-H poor prognosis
141
Q

How is stage 4b CRC treated?

A

Palliative intent:
- FOLOFX (5FU + oxaliplatin) or FOLFIRI (5FU + irinotecan = topoisomerase 1 inhibitor) OR capecitabine chemo
- Bevacizumab (VEGFi)
- cetuximab (EGFR)

142
Q

What is the mechanism of action of 5FU and capecitabine?

A

Fluoropyrimidines

Inhibit thymidine synthetase, inhibits thymidine synthesis resulting in metabolites incorporated into DNA and cell apoptosis

143
Q

What are toxicities of 5FU and capecitabine?

A

Mucositis
Diarrhoea
Nausea
Vomiting
Coronary artery vasospasm
Myelosuppression

2-8% population have deficiency of dihydropyrimidine dehydrogenase which metabolises, resulting in severe toxicity

144
Q

What are toxicities of irinotecan?

A

Diarrhoea
Myelosuppression
Fatigue

UAT181 enzyme metabolises, deficiency (seen in Gilbert’s syndrome) results in severe toxicity

145
Q

What is the prevalence of a “common” gene variant?

A

> 1%

146
Q

What is the inheritance pattern for the following hereditary cancer syndromes:
- MYH
- Bloom syndrome
- Fanconi anaemia
- Ataxia telangiectasia

A

All autosomal recessive

147
Q

What is the founder effect?

A

A high frequency of a specific gene variation in a population founded by a small ancestral population

148
Q

What are features of CRC associated with Lynch syndrome?

A
  • mucinous histology
  • poor differentiation
  • right sided
  • lymphocytic infiltrate
  • expanding growth pattern
  • absence of intraglandular neutrophil-rich necrosis
149
Q

What is the role of BRAF V600E in establishing a hereditary cause in CRC?

A

Associated with MLH1 methylation but seen in <1% Lynch syndrome, can be used to make Lynch syndrome low risk
(Not for non-CRC tumours)

150
Q

What screening is recommended for BRCA1/2 or PALB2 positive family memebers?

A
  • Breast screening age 25
  • BSO age 40
    (or 5 years younger than earliest affected)
151
Q

What screening is recommended for families with Lynch syndrome?

A
  • MLH1/MSH2: colonoscopy from 25y
    -PMS2/MSH6: clonooscopy from 30y
  • TAHBSO from age 40
    (or 5 year earlier than youngest impacted)
152
Q

What screening is recommended for families with FAP?

A

Colonoscopy from 12y (or from 18y in AFAP) until colectomy

153
Q

What screening is recommended for families with VHL?

A
  • yearly BP from 2y
  • Annual plasma or urine metanephrine from 2y
  • Annual abdo USS/MRI from 10y
154
Q

What oncogenes as driver mutations are associated with the following cancers:
HER2
BRAF
EGFR
ALK
BCR-ABL

A

HER2 - breast cancers
BRAF - melanoma
EGFR - NSCLC
ALK - NSCLC
BCR-ABL - CML

155
Q

Increased blood pressure with sunitinib and rash with cetuximab or gefitinib are both examples of what type of toxicity?

A

On-target toxicity

156
Q

What mAbs target EGFR and what toxicities do they have?

A

Cetuximab
Panitumumab

Acneiform rash (on-target effect)
Diarrhoea
Stomatitis
Low magnesium

157
Q

What TKIs target EGFR and what toxicities do they have?

A

Erlotinib
Gefitinib
Afatinib

Acneiform rash
Diarrhoea
Fatigue
Ocular changes
Alopecia
Nail changes
Pulmonary toxicity
Transaminitis

158
Q

What is the mechanism of action of osimertinib and its toxicities?

A

EGFR TKI (esp T790M mutation)

Less skin toxicity
Greater risk QTc prolongation

159
Q

What proportion of breast cancers and gastric/GOJ tumours overexpress HER2?

A

Breast 20%
Gastric/GOJ 15%

160
Q

What mAb and TKI target HER2?

A

mAb = trastuzumab, pertuzumab

TKI = lapatinib

161
Q

What is the drug : antibody ratio of trastuzumab deruxtecan?

A

8 : 1

162
Q

What are the side effects of trastuzumab deruxtecan?

A

Pneumonitis
Nausea
Alopecia
Cytopenias
Fatigue
Diarrhoea

163
Q

What are the side effects of Sacituzumab govitecan?

A

Cytopenias
Diarrhoea
Nausea
Alopecia
Fatigue

164
Q

What do the following TKIs have in common?
Sorafenib
Sunitinib
Pazopanib
Axitinib
Cabozatinib
Lenvatinib
Vandetanib

A

All multikinase inhibitors

165
Q

What TKIs inhibit the SHH pathway and what are their toxicities?

A

Sonidegib
Vismodegib
(both used for metastatic or unresectable BCC)

Muscle spasms
Alopecia
Dysgeusia
Nausea
Decreased appetite
Fatigue

166
Q

What are examples and side effects of selective CDK 4/6i?

A

Ribociclin
Palbociclib
Abemaciclib

Neutropenia
LFT derangement
Nausea
Rash
Pruritus
Diarrhoea

167
Q

What is synthetic lethality on relation to BRCA mutation?

A

BRCA mutation results in DNA repair deficiency making cells vulnerable to PARP inhibitors (competent cells are able to survive inhibition as repair can be undertaken by homologous recombination)

168
Q

What are examples of PARP inhibitors and their side effects?

A

Olaparib
Niraparib

Nausea
Diarrhoea
Fatigue
Myelosuppression

RACP 2024 (15 decks)

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