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Flashcards in Urological cancers Deck (71)
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1

Describe prostate cancer screening trials

 

Two large randomised trials:

ERSPC trial –21% relative reduction in prostate cancer mortality 

PLCO trial–no prostate cancer mortality reduction. High PSA screening rate in control arm

 

  • Prostate cancer screening still controversial
  • Effectiveness is uncertain
  • No studies have proven a survival benefit:
  • ↑ PSA may precede clinical disease by 5‐10 years
  • DRE only palpates posterior & lateral aspects
  • TRUS not recommended as a primary screening test
  • Low sensitivity & PPV

2

What is the complex issue surrounding prostate cancer screening? 

 

Early detection and treatment does not always equate to benefit (i.e. risk of dying from prostate cancer)

Insufficient evidence to support population based screening with PSA +/-DRE

Concern over false positives, false negatives, overtreatment, toxicity (incontinence, erectile dysfunction)

3

What is the current recommendation re prostate cancer screening? 

 

 

Men should discuss with their doctor (risks vs. benefit)

4

Describe 2 types of prostate cancer

 

Castration-sensitive/hormone-sensitive vs. castration-resistant disease

  • Prostate cancer growth despite castrate levels of testosterone
  • Castrate testosterone < 1.7 nmol/L (50ng/dL)

 

  • Growth may be represented through multiple ways
  • Clinical progression: worsening of cancer-related symptoms
  • Radiographic progression: typically on bone scan +/-CT scans
  • Biochemical: Rise in PSA level

5

Describe metastatic castration-sensitive prostate cancer

 

 

Androgen deprivation therapy (ADT): testosterone suppression mainstay of treatment, active but variable durability

 

GnRH agonists (goserelin, leuprolide)

GnRH antagonists (degarelix): rapid reduction in serum testosterone; avoids clinical flare phenomenon 

6

Describe androgen deprivation therapy

 

GnRH agonists (goserelin, leuprolide): initial agonism leads to tranisent flare of increased testosterone & therefore cancer symptoms

If high risk of retention/severe bone pain, high visceral burden disease, recommend GnRH antagonist. 

GnRH antagonists (degarelix): rapid reduction in serum testosterone; avoids clinical flare phenomenon.

7

Who have poor prognosis in metastatic castration-sensitive prostate cancer? 

 

De novo metastatic disease

High volume metastasis

 

8

Mx of metastatic castration sensitive prostate cancer

 

  • MAJOR change in last 5 years is the intensification of therapy for men with castrate-sensitive metastatic prostate cancer -> upfront combination chemohormonal therapy for high volume disease 
  • Androgen deprivation therapy e.g. GnRH agonist or antagonist 

AND

  • Docetaxel chemotherapy (6 cycles) - upfront 
    • taxane, IV
    • inhibits disassembly of microtubules during cell cycle progression
    • also inactivates bcl-2 -> apoptosis
    • SE: hair loss, N/V, pancytopaenia, diarrhoea, lethargy, fluid retention, arthralgia, peripheral neuropathy
    • better pain control, QOL and PSA responses

9

Mx of metastatic castration-resistant prostate cancer

- classes of agents and examples

 

  • Total androgen blockade: GnRH agonist + bicalutamide (testosterone agonist)
  • Chemotherapy: docetaxel, cabazitaxel
  • Abiraterone acetate + prednisolone:
    • an inhibitor of CYP17 (17a- hydroxylase/C17,20-lyase)
    • blocks synthesis of testosterone in adrenal gland. oral
    • steroid synthesis shunted to mineralocorticoid pathway. needs to be taken with prednisolone 
    • overall survival benefit compared to placebo post docetaxel and prechemotherapy 
    • C/I: cardiac disease, diabetes 
    • SE: HTN, exac CCF, fluid retention, hypokalaemia due to increased aldosterone levels, abnormal LFT, adrenal insufficiency, prednisolone toxicity 
  • Enzalutamide 
    • androgen receptor antagonist. oral
    • overall survival benefit ver placebo post docetaxel and prechemotherapy 
    • C/I: neurological hx/seizures, memory/cognitive impairment
    • SE: dry skin/rash, gynaecomastia, fatigue, diarrhoea, headache, HTN, neutropaenia, seizures, memory impairment 
  • Radiopharmaceuticals: radium-223, (Lutetium-PSMA)
  • Immunotherapy: Sipuleucel-T(modest activity)
  • (Poly-ADP ribose polymerase (PARP) inhibitors)

10

Describe docetaxel/cabazitaxel in metastatic prostate cancer mx

- classes of agents

- mechanism of action

- efficacy

- important toxicities

 

  • chemotherapy 
  • MoA: stabilisesmicrotubules during mitosis/interphase -> mitotic arrest and cell death
  • Efficacy:
    • Docetaxel (TAX327): 1stchemo to show OS benefit; vs. mitoxantrone (19.2 vs. 16.3 mo)
    • Cabazitaxel (TROPIC): post-docetaxel progression; improved OS vs. mitoxantrone (15.1 vs 12.7 mo) 
  • Important toxicities:
    • Docetaxel: sensory/motor PN, cytopenias (neutropenic sepsis), hypersensitivity reactions
    • Cabazitaxel: diarrhoea, cytopenias, sensory/motor PN (less common than D), less alopecia

11

Describe mechanism of action of abiraterone used in metastatic prostate cancer

  • novel androgen receptor targeted therapy
  • blocks synthesis of testosterone in adrenal gland. 
    • cortisol synthesis also reduced -> needs to be taken with prednisolone due to addisonian crisis risk and reduce shunting effect to mineralocorticoid
    • low cortisol leads to high ACTH -> steroid synthesis shunted to mineralocorticoid pathway 
  • overall survival benefit compared to placebo post docetaxel and prechemotherapy 
  • oral 
  • C/I: cardiac disease, diabetes 
  • SE:
    • HTN, exac CCF, fluid retention, hypokalaemia due to increased aldosterone levels
    • abnormal LFT
    • adrenal insufficiency
    • (external) prednisolone toxicity 

12

Describe enzalutamide in metastatic prostate cancer mx

- type

- SE

- SE compared to abiraterone 

novel androgen receptor targeted therapies

not just an AR antagonist

inhibits AR testosterone binding, blocks activational change, inhibits AR nuclear translocation & inhibits AR mediated transcription 

effects: reduces PSA, growth.

SE: fatigue more prominent. hypertension. 

Contraindicated in seizures

 

13

Describe novel androgen receptor targeted therapies in metastatic prostate cancer

Both post docetaxel 

 

1. Abiraterone + prednisolone

  • Post-docetaxel (COU-AA-301): improved OS vs. placebo/pred; 15.8 vs 11.2 mo
  • Pre-docetaxel (COU-AA-302): improved OS vs. placebo/pred; 34.7 vs 30.3 mo

 

2. Enzalutamide

  • Post-docetaxel (AFFIRM): improved OS vs. placebo; 18.4 vs 13.6 mo
  • Pre-docetaxel (PREVAIL): 35.3 vs 31.3 mo

 

Australia: PBS restricted to use after docetaxel chemotherapy, unless there is proven/predicted intolerance

14

Describe DNA repair defects in metastatic prostate cancer

 

  • Mismatch repair defects (5-10%)
  • Homologous recombination repair defects (10-15%)

e.g. BRCA2, ATM, FANCA, CHEK2, BRCA1, PALB2, HDAC2, RAD51

  • ~12% of patients have a germline DNA-repair gene mutation
  • Should all prostate cancer patients be referred to the FCC for germline testing?
  • Big issues for our patients and their families 

 

May be susceptible to certain agents targeting DNA repair mechanisms 

15

Describe prostate specific membrane antigen (PSMA)

overexpressed in prostate cancer cells

increased throughout natural history

 

allows use of lutetium-PSMA for therapeutic purposes & gallium-PSMA can be used for diagnostic purposes

16

Describe different types of renal cell cancer

- different types

- their percentages

1. clear cell: 75%. a/w VHL

2. papillary type 1: 5%. a/w Met

3. papillary type 2: 10%. a/w FH

4. Chromophobe: 5%. a/w BHD

5. oncocytoma: 5%. a/w BHD

 

aberrations in the von Hippel-Lindau gene are observed in 50-90% of clear cell renal cell cancer

17

Describe pathogenesis of Von Hippel Lindau protein in renal cell cancer

 

Aberrations in the von Hippel-Lindau (vHL) gene are observed in 50-90% of clear cell RCC

 

VHL keeps HIF in check

HIF promotes angiogenesis, cell proliferation

Excessive HIF promotes carcinogenesis 

18

Describe prognosis score in metastatic renal cell cancer

- which leads to poor prognosis 

 

MSKCC (Motzer score): Poor PS, high LDH, high Ca2+, low Hb, <12-mo between dx and tx

 

International Metastatic RCC Database Consortium (IMDC):  Again Poor PS, high N°, high Plts, high Ca2+, low Hb, <12-mo between dx and tx

19

Describe mx of metastatic clear cell renal cell cancer 

 

Historically = Cytokines

  • High-dose IL-2: 5-8% CR –durable at 10 years. Severe acute toxicity
  • Interferon-α: less toxic, but responses not durable

 

Current

1) Tyrosine kinase inhibitors (TKIs) –6 TGA approved agents e.g. sunitinib, pazopanib, cabozantinib, axitinib, lenvatinib, sorafenib 

  • Against vascular endothelial growth factor receptor (VEGF-R)
  • Against multiple targets (AXL, c-MET)

 

2) Immunotherapy e.g. nivolumab, ipilimumab

  • PD1 mAbmonotherapy
  • CTLA-4 + PD1 mAbcombination

 

3) Mammalian target of rapamycin (mTOR) inhibitors (small role)

20

Describe VEGF-R tyrosine kinase inhibitor toxicities

e.g. sorafenib, sunitinib, pazopanib, bevacizumab

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

21

Describe immune checkpoint inhibitor toxicities 

 

PD1 mAb monotherapy

CTLA-4 + PD1 mAb combination

e.g. nivolumab, ipilimumab. 

less common, unpredictable, often high grade

  • Early recognition is critical
  • Exclude differential diagnosis
  • With-hold checkpoint inhibitors
  • High dose glucocorticoids
  • Follow established guidelines (ASCO, ESMO)

22

Algorithm of metastatic renal cell cancer mx

23

Describe role of cytoreductive nephrectomy in metastatic renal cell carcinoma

 

Cytoreductive Nephrectomy was prior standard of care

CARMENA study questions the role of upfront CN: 

proved not inferior to have sunitinib alone compared to nephrectomy + sunitinib. 

 

Cytoreductive therapy may still be considered if symptomatic primary tumour, very large primary tumours and small volume metastatic disease. 

24

Describe classifications of bladder cancer

- histologic

- anatomical

- muscle invasion 

 

  • Histologic classification
    • Urothelial carcinoma (“transitional cell carcinoma): 90% of bladder cancers in developed countries
    • Non-urothelial carcinoma Squamous: most common worldwide (schistosomiasis)
    • Adenocarcinoma: arises from urachal remnant, treat like GI cancers)
  • Anatomical classification
    • Upper urinary tract: kidney, ureters
    • Lower urinary tract: bladder, urethra
  • Muscle invasion
    • Non-muscle invasive (NMIBC): 50-70% recur superficially; 10-30% progress to MIBC
    • Muscle invasive (MIBC): 25% present with MIBC or metastatic disease, poor prognosis

25

Desribe neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC)

 

  • Radical cystectomy not without its complications
    • UTI/sepsis, wound breakdown, hernias, stones, renal failure, bowel obstruction, ureteric stricture
    • Up to 30% unable to receive adjuvant chemotherapy
  • 2015: Meta-analysis of 11 trials
    • 5-year survival rate increased from 45 to 50%
    • Higher rates of pathological complete response
    • Cisplatin/gemcitabine preferred regimen due to tolerability

26

Descrigbe surgical & non-surgical management of muscle invasive bladder cancer 

- ?preferred approach 

Radical cystectomy remains the preferred approach

 

However, if patients unwell for radical cystectomy, or prefer bladder presevation, can have combined chemo-radiotherapy as an alternative instead 

27

Describe chemotherapy in advanced bladder cancer 

 

platinum/gemcitabine remains SoC for 1st line metastatic disease

 

howvever need adequate renal function 

 

28

Describe cisplatin ineligibility for bladder cancer

 

  • Bladder cancer is a disease of the elderly
  • Many competing comorbidities

 

  • Global consensus definition of cisplatin-ineligibility –any of:
    • ECOG ≥ 2
    • CrCl< 60ml/min
    • Grade ≥ 2 hearing loss (Gd2: hearing loss but hearing aid not indicated)
    • Grade ≥ 2 neuropathy (Gd2: moderate sx, limiting instrumental ADLs)
    • NYHA Class III or greater heart failure
  • 50% of de-novo metastatic disease patients fulfil this criteria
  • Led to the emerging role of immunotherapy for bladder cancer

29

Checkpoint immunotherapy best suited for which conditions? 

tumours with high number of somatic sequence burden

 

30

Describe immunotherapy for bladder cancer

 

  • Multiple US FDA approved immunotherapy agents
    • PD-1 inhibitors: nivolumab, pembrolizumab
    • PD-L1 inhibitors: atezolizumab, durvalumab, Avelumab
  • Supporting evidence predominantly from second-line treatment after progression on platinum
    • Second line chemo has generally poor response rates (0-29%): paclitaxel, vinflunine, pemetrexed, etc
  • In general, I/O is much better tolerated, with similar/better outcomes
    • Long-term responders are now a possibility
    • Predictive biomarkers for response are lacking
  • 0-29% effective. usually well tolerated.