Oncology Flashcards
Most common causes of positive FOBT result
Haemorrhoids (1), diverticular disease (2)
Only 1/29 positive FOBT diagnosed with cancer
Risk factors for CRC (6)
- IBD (UC, PSC, Crohn’s disease)
- Previous abdominopelvic radiation
- Obesity
- Diabetes & insulin resistance
- Meat consumption esp. processed meats
- Hereditary syndromes
Familial adenomatous polyposis (FAP)
- % of CRC
- Risk of developing CRC
- What gene involved?
<1% of CRC
Characterised by >100 polyps with >90% risk of CRC by age 45
Due to loss of APC gene on Chr 5
100% penetrance
Clinical syndromes:
Gardner’s Syndrome - osteomas, epidermoid cysts, desmoid tumours
Turcot’s Syndrome - CNS malignancies
Attenuated FAP - 100% penetrance, later in life, less polyps
(MAP - MUTYH associated polyposis - loss of MUTYH gene, AR inheritance)
Lynch Syndrome (HNPCC)
- % of CRC
- Risk of developing CRC
- What gene involved?
Approx. 3% of CRC
Greatest risk with MLH1 def - lifetime risk is 50%
Due to loss of MLH1, MSH2, PMS2 or MSH6 - leads to presence of large repeat sequences (microsatellite instability)
AD inheritance
80% penetrance
3-2-1 rule
3 (or more) relatives with HNPCC-related cancer, one of whom is a FDR of the other 2
At least 2 successive affected generrations
1 (or more) diagnosed under age of 50
FAP excluded
MLH1 can also be sporadic mutation - due to promoter methylation (thus if MLH1 methylated - not Lynch)
Cetuximab, panitumumab
Anti-EGFR
Role in RAS/RAF wt CRC
RAS/RAF wt association with anti-EGFR agents?
Crystal study showed that addition of cetuximab to FOLFIRI improved OS in RAS/RAF wt but not in RAS/BRAF mt
Where does rectal cancer more commonly metastasise to c.f. right/left sided bowel?
Pulmonary mets due to direct drainage into IVC
Management of T3-4 rectal Ca
Either short course RTx or long course chemoRTx with radiosensitising 5FU/capecitabine
Long course superior for local tumour response/control
Approx 15-30% will haev complete pathological response
Relevance of ctDNA in CRC
Presence of ctDNA is marker of those who will likely relapse
Surveillance guidelines post curative therapy for CRC
No Australian guidelines but:
C’scope at 3 years post then 5 yearly
CEA every 3 months for 3 years then 6 monthly
CT CAP annually for 3 years
Prognosis of BRAF mt CRC
Poor prognosis - poor response, rapid development of resistance and often nodal spread
Metastatic CRC management
Palliative intent CTx + targeted therapy
FOLFOX or FOLRIRI or capecitabine
+
Anti-EGFR/VEGF etc.
Differences between right and left sided CRC & prognosis
Right sided CRC has poor prognosis
Right colon originates from midgut
Left colon originates from hindgut
BRAF mutations more common in right sided CRC
RAS/RAF wt more common in left sided CRC
How do fluoropyrimidines (e.g. 5FU/capecitabine) work?
Through thymidine synthesis inhibition
Metabolites incorporated into DNA leading to apoptosis
Capecitabine is oral 5FU
Can be single agent or in combination (e.g. FOLFIRI/FOLFOX)
FOLFIRI
5FU + leucovorin + irinotecan
Irinotecan = topoisomeraise-1 inhibitor
Leucovorin = folic acid
FOLFOX
5FU + leucovorin + oxaliplatin
Leucovorin = folic acid
Oxaliplatin = only platinum agent that does not have single agent efficacy, binds directly to DNA impairing replication
Toxicities of fluoropyrimidines (4)
Mucositis, diarrhoea/vomiting, coronary artery spasm and myelosuppression
5FUs metabolised by dihydropyrimidine dehydrogenase (DPD) - deficiency occurs in 2-8% - can cause fatal toxicity (early myelosuppresion & severe mucositis)
Toxicities of irinotecan (3)
Diarrhoea, myelosuppression, fatigue
UAT18 metabolises SN-38 which is active metabolite
Deficiency of UAT181 is seen in Gilbert’s and can lead to fatal toxicity (myelosuppression)
Toxicities of oxaliplatin (4)
Peripheral neuropathy (predominantly sensory), cold dysaesthesia, fatigue and infusion reactions
Unique toxicities of RAS/RAF/HER2 mutations with EGFR inhibitors?
Confers resistance
HypoMg (due to renal loss of Mg)
Cutaneous acneform rash
Toxicities of bevacizumab (5)
Hypertension
Wound breakdown/impaired healing
GI perforation
Proteinuria
Thromboembolic events
Reversible posterior leukoencephalopathy
Mechanism of action of enzalutamide
Androgen receptor (AR) antagonist
CYP3A4 + CYP2C9 inducer
Mechanisms of resistance in CRPC (6)
AR amplification
AR mutation
AR splice varirants
Altered activity of AR coactivators
Intra-tumoral androgen synthesis
Aberrant kinase activation
Definition of castrate level of testosterone
<1.7nmol/L
Management of metastatic castrate sensitive prostate cancer (mCSPC)
Androgen deprivation therapy (ADT)
(1) GnRH agonists - gosereline, leuprolide
- Can have initial clinical flare phenomenon due to increase in LH and testosterone
(2) GnRH antagonists - degarelix
- Rapid reduction in serum testosterone, avoid clinical flare phenomenon
- Increased local injection site reactions
- Lower risk of CV side effects
(3) Bilateral orchidectomy
MAJOR CHANGE - intensification therapy - upfront use of docetaxel/abiraterone/enzalutamide/local RTx - increases OS
- CHAARTED study - docetaxel in CSPC - improved survival
Management of metastatic castrate resistant prostate cancer (mCRPC)
(1) Chemotherapy
- Docetaxel/cabazitaxel
(2) Androgen receptor targeted therapies
- Abiraterone/enzalutamide
(3) Immunotherapy (e.g. sipuleucel)
- Modest effect
(4) Radiopharmaceuticals (Lu-PSMA)
- Lutetium-PSMA
(5) PARP inhibitors
Mechanism of docetaxel/cabazitaxel & side-effects/toxicities associated
Taxane therapy
Stabilises microtubules during mitosis/interphase leading to mitotic arrest/cell death
Toxicities of docetaxel: sensory/motor PN, cytopenias, hypersensitivity reactions
Toxicities of cabazitaxel: diarrhoea, cytopenias, sensory/motor PN (but less than with docetaxel)
Mechanism of abiraterone & toxicities
Androgen biosynthesis inhibitor
- Inhibits 17-alpha-hydroxylase and lyase which coverts ACTH to DHEA
Increases mineralocorticoid hormone production
Side effects: hypertension, hypokalaemia, peripheral oedema [[all related to increased mineralocorticoid ]] + transaminitis
Co-administered with prednisolone
ALK mutation
Translocation, chromosomal rearrangement mutation
Localted on short arm of Chr 2
Alectanib - alk targeted therapy
Stage IV NSCLC
Includes unilateral pleural effusion, contralateral lung involvement or other mets
Asian, non-smoker, female
EGFR mutation
PDL1 status - pembrolizumab
In NSCLC - KRAS mutations most prevalent genomic driver
> Sotorasib irreversibly inhibits KRAS
Osimertinib
3rd generation EGFR TKI
Excellent CNS penetration
Toxicities: skin + diarrhoea, pneumonitis 2% (cannot combine with immunotherapy)
Ipilimumab MoA?
CTLA-4 inhibitor
Bevacizumab MoA?
Anti-VEGF
Ramucirumab MoA?
Anti-VEGFR
Cetuximab MoA?
Anti-EGFR
Chimeric
Head and neck cancer
Metastatic left sided KRASwt CRC
General side effects of tyrosine kinase inhibitors?
Most - cardiotoxicity, hepatotoxicity, pulmonary toxicity
Most - fatigue, diarrhoea, mucositis, nausea, LFT derangement
Many - QTc prolongation, endocrine (thyroid, sugars)
EGFR (including BRAF inhibition) - dermatologic toxicity
VEGF - hypertension, impaired wound healing, GI perforation, proteinuria
What tumour marker is falsely elevated in smokers?
CEA
Example of CDK4/6 inhibitors?
Palbociclib, ribociclib
Radiosensitive neoplasms (for spinal cord compressions)?
Lymphoma
Myeloma
Small cell lung cancer
Germ cell tumours
Prostate cancer
Breast cancer
Radioresistant neoplasms (for spinal cord compressions)?
Melanoma
Renal cell
NSCLC
GI cancers
Sarcoma
Cord compression tumour grading?
