Oncology Flashcards
(124 cards)
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
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
3
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)
4
Q
What additional endocrine monitoring is indicated for ipilimumab?
A
ACTH, LH, FSH, E2/testosterone, prolactin given high risk for hypophisitis
5
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
6
Q
Are patients with pre-existing endocrinopathies at increased risk of developing an endocrinopathy with an ICI?
A
No
7
Q
What is the management of ICI-related endocrinopathy?
A
Referral to endocrinologist unless isolated primary hypothyroidism
No evidence fo high dose steroids
8
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
9
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
10
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 intractable 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
11
Q
What ICI is most commonly associated with thyroid endocrinopathy?
A
Anti-PD1 inhibitors
12
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
13
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
14
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
15
Q
What ICIs are associated with autoimmune diabetes?
A
Anti-PD1 = most common
Anti-PDL1
Anti-CTLA4 = less common8
16
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
17
Q
What are features of ICI associated adrenal insufficiency?
A
- very rare
- associated with antiPD1/PDL1
18
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
19
Q
What are clinical features of ICI-related hypoparathyroidism?
A
Very rare
Present with hypocalcaemia with low PTH
Require permanent calcium requirement and calcitriol
20
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
21
Q
What is the most common side effect of immunotherapy?
A
Skin toxicities
22
Q
What is the most significant toxicity of. immunotherapy?
A
Colitis
23
Q
What side effects are most common with anti-PD1?
A
Hypothyroidism
Pneumonitis
Myocarditis
Arthralgia
Autoimmune diabetes
24
Q
What side effects are commonly associated with anti-CTLA4?
A
Hypophysitis
Rash/dermatitis
Enteritis
Colitis
25
What is the type timing of onset for anti-CTLA4 related toxicities?
4-10 weeks
26
What is the type timing of onset for anti-PD1 related toxicities?
4-14 weeks
27
What is the mechanism of immunotherapy adverse events?
Exact mechanism unknown
- may relate to T-cell activation
- increase auto-antibody production
- maybe cytokine or complement mediated
28
How should immunotherapy-related skin toxicities be managed?
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
29
How should ICI related hepatotoxicity be managed?
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
30
How should ICI related GI toxicity be managed?
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
31
How is ICI-related pneumonitis managed?
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
32
What are radiological features of ICI-related pneumonitis?
-Ground glass opacities
- cryptogenic organising penumonia or interstitial pneumonia pattern
33
How are ICI-related nephrotoxicitues managed?
IV hydration + PO steroid for AKI up to 3xbaseline
Consider other causes
IV methylprednisone + nephrology consult if >3xbaseline
34
What is the most potent carcinogen in cigarette smoke?
Polycyclic aromatic hydrocarbons
35
How are stage 1 and 2 lung cancers treated?
Surgically = lobectomy + LN resection
(if not fit then with radiotherapy)
36
What is the indication for atezolizumab as adjuvant therapy in lung cancer?
Resected stage II or IIIA with >50% PDL1 expression on tumour
37
How is stage III lung cancer managed?
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)
38
What lung cancers are associated with targeted driver mutation?
Cancers in non-smokers
39
How is an acneiform rash from TKI managed?
Topical or oral tetracyclines, topical steroids, sun protection
40
What TKIs can be used in Stage IV NSCLC EGFR mutant?
- erlotinib
- gefitinib
- osimertinib (T790 mutation only)
41
What TKIs can be used in Stage IV NSCLC ALK translocation (EML4-ALK fusion oncogene)?
- Alectinib
- Brigatinib
- Loratinib
- crizotinib
42
What TKIs can be used in Stage IV NSCLC with ROS1 translocation?
- crizotinib
- Entrectinib
43
What TKIs are used in Stage IV NSCLC with MET exon 14 mutation (splice site of exon14)?
- Capmatinib
- Tepotinib
44
What are common side effects of gefitinib and erlotinib?
- aceniform rash
- diarrhoea
- ocular changes
- alopecia
- nail changes
- pulmonary toxicity
45
What is the main toxicity of tepotinib?
Peripheral oedema
46
What treatment can be given to Stage IV lung adenocarcinoma with > 50% PDL1+ and performance status of 2?
Single agent immunotherapy
47
What treatment can be given to Stage IV lung squamous cell carcinoma with > 50% PDL1+ and performance status of 2?
Single agent immunotherapy
48
What is the big difference in treating lung adenocarcinoma and lung squamous cell carcinoma with regard to immunotherapy?
No role for immunotherapy in low PDL1 (<50% expression) in squamous cell, but a benefit seen for adenocarcinoma with any expression
49
How do you treat extensive stage small cell lung cancer?
Atezolizumab + platinum (cisplatin or carboplatin) + etoposide (total 4 cycles)
+/- radiotherapy for brain mets
50
How is small cell lung cancer staged?
Limited = can fit within one radiotherapy field
Extensive = cannot
51
How do you treat limited stage small cell lung cancer?
Cisplatin + etoposide + radiotherapy from cycle 2 (total 4 cycles)
52
How do you teat mesothelioma?
Ipilimumab + nivolumab
OR
Cisplatin + pemetrexed
(palliative intent)
53
What breast cancers are treated with curative and palliative intent?
- curative = resectable disease (Stage I-III)
- palliative - Stage IV
54
What is the most common subtype of breast cancer
Hormone receptor positive, HER2- negative
55
What treatments are used for the following types of breast cancer?
- Hormone receptor positive, HER2-negative
- HER2-positive
- Triple negative
Hormone receptor positive, HER2-negative:
- Endocrine therapy +/- chemo
HER2-positive:
- HER2 targeted, chemo +-/ endocrine
Triple negative:
- chemo
56
What percentage of breast cancers are hormone receptor positive?
70%
57
What clinical features are associated with hormone receptor positive breast cancer?
- indolent disease
- bone mets
- late recurrence
58
How is early breast cancer treated?
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
59
What treatment can be used for HER2+ breast cancer?
Trastuzumab (prevents HER2 homodimerization to inhibit signalling)
60
What are side effects of trastuzumab?
- cardiotoxicity (LVEF reduced)
- infusion rection
- nephrotic syndrome
61
What endocrine therapies can be used for breast cancer?
- tamoxifen (ER antagonist)
- aromatase inhibitors (letrozole, anastrozole) - only in post menopausal women (biologic or chemical)
- fulvestrant (inhibits ER dimerisation)
62
What are common toxicities of endocrine therapies for breast cancer?
- hot flushes
- arthralgia, myalgia (AI > Tam)
- vaginal atrophy (AI > Tam)
Tamoxifen:
- VTE
- endometrial cancer
Aromatase inhibitors:
- accelerated bone loss
63
How is metastatic breast cancer treated?
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)
64
What is the mechanism of action of CDK4/6i (abemaciclib, palbociclib, ribociclib)?
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
65
What are common side effects of CDK4/6i?
- leukopenia, neutropenia
- fatigue
- QTC prolongation
- diarrhoea (abemaciclib)
66
What are the 3 components of an antibody drug conjugate?
- Antibody
- linker
- payload (cytotoxic)
(allows for intracellular release of drug)
67
What antibody-drug conjugates can be used in breast cancer?
- trastuzumab emtansine (HER2 mAb + anti-tubulin DM1)
- trastuzumab deruxtecan (HER2 mAb + topoisomerase I inhibitor)
- sacituzumab govitecan (TROP2 mAB + topoisomerase I (SN-38) inhibitor)
68
How are stage I-III melanomas treated?
Sentinel removal
Stage IIIb or IIIc can receive anti-PD1 immunotherapy and/or BRAF + MEK inhibitor therapy
69
What mutations are associated with cutaneous melanoma?
- BRAF
- NRAS
- NF1
70
What mutations are associated with Uveal melanoma?
G proteins (GNAQ, GNA11)
71
What are the BRAF+MEK inhibitor combinations used to treat metastatic melanoma?
- Vemurafenib (BRAF) + cobimetanib (MEK)
- Dabrafenib (BRAF) + trametinib (MEK)
- Encorafenib (BRAF) + binimetinib (MEK)
72
What is the mechanism of action of anti-CTLA-4?
Binds CTLA-4 molecule on T-cell, allowing B7 to bind C28 and act as co-stimulatory receptor for T-cells
73
What is castrate levels of testosterone used to help define castrate sensitivity of prostate cancer?
Testosterone < 1.7 nmol/L (50 ng/dL)
74
What forms of androgen deprivation therapy are used to treat prostate cancer?
- GnRH agonists (goserelin, leuprolide)
- GnRH antagonists (degarelix), causes rapid reduction in serum testosterone, avoids clinical flare
- bilateral orchidectomy
75
What is the standard of care for metastatic castration-sensitive prostate cancer?
Doublet therapy:
ADT + ARSi OR ADT + docetaxel
ARSi = androgen receptor signalling inhibitor
76
What are treatment options for metastatic castrate-resistant prostate cancer?
- chemo (docetaxel, carbazitaxel)
- Abiraterone acetate, enzalutamide
- radipharmaceuticals (Radium-223, letetium-PSMA)
- PARP inhibitors (olaparib if BRCA1/BRCA2 mutation)
77
What is the mechanism of action of docetaxel and cabazitaxel used for prostate cancer?
Both are taxane chemotherapies
Stabilise microtubules during mitosis/interphase leading to mitotic arrest and cell death
78
What are the toxicities of:
- Docetaxel
- Cabazitaxel
Docetaxel:
- sensory/motor peripheral neuropathy
- cytopenias
- hypersensitivity reactions
Cabazitaxel:
- diarrhoea
- cytopenias
- sensory/motor peripheral neuropathy (less than docetaxel)
- less alopecia
79
What is the mechanism of action of abiraterone acetate?
Inhibits the 17-a-hydroxylase enzyme preventing the adrenal and tumour autocrine synthesis of androgens
80
What are important toxicities of abiraterone acetate?
Also inhibits c17,20 lyase
- Hypertension
- Hypokalaemia
- peripheral oedema
- transminitis
Managed with low dose prednisone to avoid mineralocorticoid effects
81
What is the mechanism of action of enzalutamide/apalutamide?
1. Androgen receptor antagonist (prevents androgen binding)
2. Inhibit nuclear translocation of activated AR
3. Inhibit association of activated AR with DNA
82
What are important toxicities of enzalutamide/apalutamide?
- Hypertension
- fatigue
- cognitive changes
- falls
83
What characteristic of darolutamide distinguishes it from other androgen receptor inhibitors?
Low blood-brain barrier penetration -> less CNS toxicity
84
What proportion of patients with metastatic prostate cancer have defects in DNA damage response genes?
15-25%
(BRCA2 is prominent and has a poor prognosis)
85
What is the mechanism of action of olaparib?
PARPi
Inhibits poly(ADP‐ribose) polymerase, thereby blocking the repair of single‐strand DNA break (esp in BRCA mutations)
86
What is the most common variant of renal cell carcinoma?
Clear cell
87
What proportion of clear cell carcinomas have aberrations in the vHL gene?
50-90%
88
What are the 6 variables of the IMDC used for risk stratifying metastatic renal cell carcinoma?
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
89
What drugs are used to treat metastatic renal cell carcinoma?
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)
90
What are common VEGFR TKI toxicities?
- 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
91
What are the most common side effects of immunotherapy?
Fatigue
Rash
Thyroiditis
92
What is the mainstay of management of muscle invasive bladder cancer?
Radical cystectomy
93
What is erdafitinib and its role in metastatic urothelial carcinoma?
Pan-FGF-R inhibitor, 3rd line treatment
94
What are common toxicities of erdafitinib?
Fatigue
Hyperphosphataemia
Nail changes
GI side effects
Drye eys
Central serous retinopathy (reversible)
95
How are seminomas treated?
Surgical resection + single high-dose carboplatin
96
How are non-seminoma testicular cancers treated?
Surgical resection + 1-2 cycles BEP (bleomycin, etoposide, cisplatin)
97
What is the standard treatment of epithelial ovarian cancer?
Surgery + chemo
Staging laparotomy, followed by TAH +BSO + debulking
Adjuvant or neoadjuvant carboplatin + Paclitaxel
98
What is the standard treatment of non-epithelial ovarian cancer?
Conservative surgery + chemo
(very chemo-sensitive)
99
What patients with cancer should be tested for BRCA1 and BRCA2 gene mutations?
- TN breast cancer < 50y
- TN breast cancer with close relative with breast or ovarian cancer
- high grade ovarian cancer any age
100
What is the role of olapraib in ovarian cancer?
1st line maintenance therapy
101
What is the standard chemotherapy for advanced endometrial cancer?
Carboplatin/paclitaxel
102
What hormonal therapy is used in the treatment of endometrial cancer?
Provera for ER/PR positive
Tamoxifen if provera fails
103
What adjuvant treatment is used for locally advanced cervical cancer?
Cisplatin + radiotherapy concurrently
104
What is the role of anti-PD1 in the treatment of locally advanced oesophageal cancers?
Adjuvant therapy post resection
(better response seen for SCC)
105
What is the role of trastuzumab in gastric cancer?
Used in combination with chemotherapy for HER2+ tumours
106
What is the role of cetuximab in CRC?
Used alongside chemo in RAS/RAF wildtype
107
What is the treatment for rectal cancer?
Resection
Neoadjuvant chemoradiotherapy for T3-T4 disease (5FU or capecitabine)
108
What are CRC guidelines post treatment?
- colonoscopy at 3 and 5 years
- physical + CEA 3-monthly for 3 years, then 6 monthly
- CT CAP annually for 3 years
109
How is stage 4b CRC treated?
Palliative intent:
- FOLOFX (5FU + oxaliplatin) or FOLFIRI (5FU + irinotecan = topoisomerase 1 inhibitor) OR capecitabine chemo
- Bevacizumab (VEGFi)
- cetuximab (EGFR)
110
What are toxicities of 5FU and capecitabine?
Mucositis
Diarrhoea
Nausea
Vomiting
Coronary artery vasospasm
Myelosuppression
2-8% population have deficiency of dihydropyrimidine dehydrogenase which metabolises, resulting in severe toxicity
111
What are toxicities of irinotecan?
Diarrhoea
Myelosuppression
Fatigue
UAT181 enzyme metabolises, deficiency (seen in Gilbert's syndrome) results in severe toxicity
112
What screening is recommended for BRCA1/2 or PALB2 positive family memebers?
- Breast screening age 25
- BSO age 40
(or 5 years younger than earliest affected)
113
What screening is recommended for families with Lynch syndrome?
- MLH1/MSH2: colonoscopy from 25y
-PMS2/MSH6: clonooscopy from 30y
- TAHBSO from age 40
(or 5 year earlier than youngest impacted)
114
What screening is recommended for families with FAP?
Colonoscopy from 12y (or from 18y in AFAP) until colectomy
115
What screening is recommended for families with VHL?
- yearly BP from 2y
- Annual plasma or urine metanephrine from 2y
- Annual abdo USS/MRI from 10y
116
Increased blood pressure with sunitinib and rash with cetuximab or gefitinib are both examples of what type of toxicity?
On-target toxicity
117
What mAbs target EGFR and what toxicities do they have?
Cetuximab
Panitumumab
Acneiform rash (on-target effect)
Diarrhoea
Stomatitis
Low magnesium
118
What TKIs target EGFR and what toxicities do they have?
Erlotinib
Gefitinib
Afatinib
Acneiform rash
Diarrhoea
Fatigue
Ocular changes
Alopecia
Nail changes
Pulmonary toxicity
Transaminitis
119
What is the mechanism of action of osimertinib and its toxicities?
EGFR TKI (esp T790M mutation)
Less skin toxicity
Greater risk QTc prolongation
120
What are the side effects of trastuzumab deruxtecan?
Pneumonitis
Nausea
Alopecia
Cytopenias
Fatigue
Diarrhoea
121
What are the side effects of Sacituzumab govitecan?
Cytopenias
Diarrhoea
Nausea
Alopecia
Fatigue
122
What do the following TKIs have in common?
Sorafenib
Sunitinib
Pazopanib
Axitinib
Cabozatinib
Lenvatinib
Vandetanib
All multikinase inhibitors
123
What are examples and side effects of selective CDK 4/6i?
Ribociclin
Palbociclib
Abemaciclib
Neutropenia
LFT derangement
Nausea
Rash
Pruritus
Diarrhoea
124
What are examples of PARP inhibitors and their side effects?
Olaparib
Niraparib
Nausea
Diarrhoea
Fatigue
Myelosuppression
