Genitourinary Cancer Flashcards
Risk factors for renal cancer
- smoking
- obesity
- HTN
- PCKD
Genetic conditions associated with renal cell carcinoma
Genetics:
- Loss of 3p (94%, contains VHL)
- Gain of 5q
VHL (von hippel lindau):
- autosomal dominant syndrome manifested by a variety of benign and malignant tumors- cerebral haemangioblastoma, retinal haemangioblastoma, clear RCC, phaeochromocytoma
Tuberous Sclerosis:
- Neurocutaneous disease (Shagreen patches, hypopigmented plaques)
- TSC2 >TSC1 gene mutation,
- RCC is less common manifestation
Types of RCC
- Clear cell carcinoma (80%) > Papillary > Chromophobic > collecting duct > medullary
- Majority are CLEAR CELL CARCINOMA of which 52% are associated with VHL mutations
- Arise from proximal tubules ; Czechs; M>F
- The risk of a second, metachronous RCC is increased in patients who have been treated for one renal cancer
What is VHL protein
- VHL is part of the oxygen sensing pathway of cells, sits on chromosome 3p
- Adds ubiquitin to HIFs (hypoxia inducible factors) causing proteasomal degradation
- Mutations in VHL (or loss of 3p) cause accumulation of HIFs which then cause transcription of hypoxia inducible genes including VEGF
VHL keeps HIF in check –> HIF promotes angiogenesis and cell proliferation –> excessive HIF promotes carcinogenesis
Clinical features of RCC
Classic triad of RCC:
- flank pain
- hematuria
- palpable abdominal renal mass
Treatment for RCC
- Limited disease: Radical nephrectomy
- Metastatic RCC: Cytoreductive nephrectomy should be performed in all patients when it is clinically feasible and justifiable
(1) HIF related proteins
(A) Tyrosine Kinase Inhibitors - against VEGF-RECEPTOR (VEGF-R)
- Sorafenib [HTN, Hand and foot]
- Sunitinib [n/v, LFT derangement, HF, VTE]
Also acts against AXL and c-MET, platelet derived growth factor (PDGFR - sunitinib, sorafenib)
(B) VEGF Monoclonal Ab: Bevacizumab
(C) FGFR - FIBROBLAST GROWTH FACTOR RECEPTOR
Lenvantinib
(2) Anti PD1: nivolumab
CTLA4 + PD1 combination: ipilimumab + nivolumab
(3) MTOR inhibitor: evorolimus
(4) Palliative nephrectomy
VEGF-R TKI toxicities
eg: Sorafenib, Sunitinib, Pazopanib
Common, predictable, usually low grade
GASTROINTESTINAL
• Mucositis, stomatitis, diarrhoea
• Common with all TKIs (espcabozantinib) and mTOR inhibitors
• Mx: hydration, special-preparation mouth washes, anti-diarrhoeals, dose interruption/reduction
SKIN
• Dry skin, rash, hand-foot syndrome
• Mainly assoc. with TKIs Mx: moisturizer, dose interruption/reduction
THYROID DYSFUNCTION
• Typically hypothyroidism; risk increases with time
LFT DERANGEMENT
• Class effect of all VEGFR TKIs, particular pazopanib
• Typically transaminitis +/-bilirubin elevation
CARDIOVASCULAR
•CCF (2-3%), myocardial ischaemia (2-3%)
• Arterial/venous thromboembolism, QT prolongation
What does sunitinib inhibit?
VEGF receptor
PDGF receptor
c-kit oncogene
- Sunitinib is 1st line treatment for favourable risk disease
- Nivolumab + ipilimumab vs sunitinib in advanced RCC (intermediate + high risk patients): higher response rate, longer OS and greater improvement in QOL
Nivolumab + ipilimumab is 1st line for intermediate + high risk metastatic renal cancer
Main SE: stomatitis, hand/foot syndrome, hepatitis
Metastatic renal cell cancer treatment
(1) Consider nephrectomy
- Low volume metastatic disease
- Symptomatic primary, eg: pain, bleeding
(2) 1st Line therapy
- Good prognosis: TKI - Sunitinib or pazopanib
- Intermediate/Poor Risk Disease: Nivolumab + ipilimumab
(3) 2nd Line
- Nivolumab or sunitinib/pazopanib
- Cabozanitinib
- Everolimus
Features of mTOR
- MTOR: mammalian target of rapamycin
- Functions as a MASTER REGULATOR of the cell
- Transduces extracellular signals that promote cell growth and survival
- Key component of the INTRACELLULAR SIGNALING PATHWAYS in tumour cell proliferation, growth, survival and angiogenesis
- Activated aberrantly in many tumours
- Activated mTOR exacerbates the loss of VHL function
- Activated mTOR increases HIF which increase the expression of genes required for tumour cell growth in a hypoxic environment including VEGF
Side effect of MTOR inhibitors, eg: Everolimus
- Mucositis
- Infection
- Anaemia
- Rash
- Hyperglycaemia + hyperlipidaemia
- Pneumonitis
Risk factors of prostate cancer
- Increasing age
- Smoking
- Obesity
Genetics associated with prostate cancer
- Associated with severe germ line DNA repair mutations
- 12% have germline mutations: BRCA2>ATM> CHEK2>BRCA1
- Androgen receptor aberrations
- BRCA2 mutation carriers estimated to have a risk between 19-61% of diagnosis by 80yo
- BRCA1 carriers have a risk of 7-26% of diagnosis by age 80
Prostate Cancer Management
LOCALISED
- <74yo: radical prostatectomy OR
- Prostate Radiotherapy - external beam or brachytherapy with or without androgen deprivation
- Higher risk patients also benefit from adjuvant androgen deprivation therapy
- Surveillance with 6 monthly PSA
ADVANCED
- Hormonal therapy/bilateral orchidectomy
- Chemotherapy
- Supportive therapy: RT, bisphosphonates, pal care
SUMMARY of METASTATIC prostate cancer therapy
Castrate SENSITIVE: single agent GnRH agonist + chemo
- GnRH AGONIST (gosrelin) given continuously inhibits testosterone production. Given with steroid to prevent acute flare
- GnRH ANTAGONIST: degarelix
Rapid reduction in serum testosterone; avoids clinical flare phenomenon
- If boney mets, need testosterone blocking (bicalutamide) for 14 days prior to prevent flare
- Chemo: docetaxel - improves survival compared to ADT alone
- No evidence for osteoclast inhibitors in castration sensitive disease
Castrate RESISTANT
- Rising PSA, worsening symptoms, radiological progression, new metastases despite on ADT) = ADT + secondary therapy
- Continue androgen deprivation therapy as withdrawal can cause surge in testosterone and disease progression
Secondary Therapy
- Chemotherapy (taxanes): Docetaxel, cabazitaxel; stabilise microtubules and improve OS
• If docetaxcel resistant, consider immunotherapy, pembroluzimab
- PARP inhibitors cause tumour selective cell death
- Androgen receptor targeted therapy
• Abiraterone + steroid. CYP17 also reduces cortisol and increases ACTH causing increase in mineralocorticoid production; which is inhibited by the steroid
• Enzalutamide - androgen receptor blocker - Can’t use abiraterone or enzalutamide unless fail on docetaxel
- Resistance to either abiraterone or enzalutamide means resistance to the other
- Bone metastatic: analgesia, radiotherapy, osteoclast inhibitor (denosumab, zoledronic acid)
- Bisphosphonate and denosumab reduce skeletal events
- Docetaxcel improves survival
In castration-resistant disease bone modifying therapy is recommended to reduce incidence of skeletal related events. Denosumab is more effective than zoledronic acid.
What is castrate resistance disease?
Essentially: prostate cancer growth despite castrate levels of testosterone
Castrate-resistant prostate cancer(CRPC) is when men with advanced prostate cancer have evidence of disease progression
- Clinical Progression: worsening of cancer related symptoms, mets
- Radiological Progression: typically on bone scan +/- CT scans
- Biochemical: rise in PSA level
This occurs while being managed with androgen deprivation therapy (ADT) and who have castrate levels of serum testosterone (<50 ng/dL or <1.7nmol/L)
Features of GnRH agonist
- Usually sex hormones are released in a PULSATILE fashion
- CONTINUOUS release downregulates GnRH receptors
- This then significantly reduces FSH/LH as well as downstream hormones like testosterone
- Can also have a sudden pulse increase in FSH, LH and testosterone with GnRH agonism, can flare metastatic prostate disease
- To avoid flare - patient can be covered with an additional antiandrogen or with steroid
SE:
- Loss of libido
- Impotence
- Hot flushes
- Metabolic syndrome: cerebovascular disease, diabetes, obesity
- Osteoporosis
- Gynecomastia
GnRH antagonists - degarelix
- Degarelix is a GnRH antagonist so DIRECTLY DOWNREGULATES FSH/LH
- Rapid reduction in serum testosterone; avoids clinical flare phenomenon
Note:
GnRH agonists - associated with higher major cardiovascular event compared to GnRH antagonist.
Not completely finalised but in those with CVD history, better to use GnRH antagonist
Antiandrogens (bicalutamide, nilutamide) - used as 2nd line for non-metastatic/metastatic prostate cancer as an adjunct to GnRH agonists/antagonists
Antiandrogens (bicalutamide, nilutamide)
- used as 2nd line for non-metastatic/metastatic prostate cancer as an adjunct to GnRH agonists/antagonists
- Stop DHT (dihydrotestosterone) from binding to androgen receptors (AR)
- When bound to DHT, ARs dimerise, enter the nucleus and activate nuclear transcription factors
- When unbound, the ARs are not functional
**
IF BONY METS, NEED TESTOSTERONE BLOCKING (BICALUTAMIDE) FOR 14 DAYS PRIOR TO GnRH TO PREVENT FLARE
Chemotherapy: docetaxel, carbzitaxel
MOA
SE
- MOA: stabilises microtubules/ inhibits disassembly of microtubules during mitosis/interphase –> mitotic arrest and cell death
- Docetaxel IMPROVES SURVIVAL and is 1ST LINE CHEMO FOR metastatic castrate RESISTANT prostate cancer
SE:
- Docetaxel: neutropenic sepsis, sensory/motor peripheral neuropathy, fluid retention, alopecia
- Cabazitazel: diarrhoea, peripheral neuropathy
Abiraterone + PRED
- novel androgen receptor targeted therapies
- MOA
- SE
- Usually: androgen precursors require 17a HYDROXYLASE to form androgens
MOA: androgen biosynthesis inhibitor by irreversibly inhibiting CYP17/17a- hydroxylase - blocks synthesis of testosterone in the ADRENAL GLAND + PROSTATE + TESTES
- Upstream accumulation of steroid precursors can cause HYPOKALAEMIA AND HYPERTENSION
- CYP17 also reduces cortisol and increases ACTH causing increase in mineralocorticoid production; which is inhibited by the steroid
- Need to be on STEROID
SE
- Hypertension
- Hypokalaemia: due to increased aldosterone pathway
- Peripheral oedema
- Transaminitis/hepatotoxicity
- Exacerbation of CCF
- Fluid retention
- Adrenal insufficiency
Contraindications
- Cardiac disease
- Avoid in diabetics as require long term steroids
Enzalutamide - novel antiandrogen
MOA
SE
MOA:
- Androgen receptor antagonist
- Intranuclear inhibition of androgen receptor dependent DNA transcription coactivators
- Intracellular blockade of downstream signalling
- Competitively inhibits binding of testosterone to the androgen receptor
SE:
- Seizures**
- Cognitive disorders **
- Memory impairment **
- Hypertension
- Fatigue
Contraindications
- Neurological hx especially seizures
- Any memory/cognitive impairment
PARP INHIBITOR - OLAPARIB
- Effective in men with prostate cancer who have a loss of function gene defect in DNA repair genes (eg: BRCA1/2, ATM) after failure of enzalutamide or abiraterone
Radium 223
- For symptomatic bone one mets, LN up to 3cm allowed
- Binds preferentially to hydroxyapatite in bone mets
- Toxicity: diarrhoea, thrombocytopenia
