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Oncology > Genitourinary Cancer > Flashcards

Genitourinary Cancer Flashcards

1
Q

Risk factors for renal cancer

A
  • smoking
  • obesity
  • HTN
  • PCKD
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2
Q

Genetic conditions associated with renal cell carcinoma

A

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
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3
Q

Types of RCC

A
  • 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
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4
Q

What is VHL protein

A
  • 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

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5
Q

Clinical features of RCC

A

Classic triad of RCC:

  • flank pain
  • hematuria
  • palpable abdominal renal mass
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6
Q

Treatment for RCC

A
  • 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

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7
Q

VEGF-R TKI toxicities

eg: Sorafenib, Sunitinib, Pazopanib

A

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

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8
Q

What does sunitinib inhibit?

A

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

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9
Q

Metastatic renal cell cancer treatment

A

(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

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10
Q

Features of mTOR

A
  • 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
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11
Q

Side effect of MTOR inhibitors, eg: Everolimus

A
  • Mucositis
  • Infection
  • Anaemia
  • Rash
  • Hyperglycaemia + hyperlipidaemia
  • Pneumonitis
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12
Q

Risk factors of prostate cancer

A
  • Increasing age
  • Smoking
  • Obesity
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13
Q

Genetics associated with prostate cancer

A
  • 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
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14
Q

Prostate Cancer Management

A

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
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15
Q

SUMMARY of METASTATIC prostate cancer therapy

A

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.

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16
Q

What is castrate resistance disease?

A

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)

17
Q

Features of GnRH agonist

A
  • 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
18
Q

GnRH antagonists - degarelix

A
  • 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

19
Q

Antiandrogens (bicalutamide, nilutamide) - used as 2nd line for non-metastatic/metastatic prostate cancer as an adjunct to GnRH agonists/antagonists

A

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

20
Q

Chemotherapy: docetaxel, carbzitaxel
MOA
SE

A
  • 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
21
Q

Abiraterone + PRED

  • novel androgen receptor targeted therapies
  • MOA
  • SE
A
  • 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
22
Q

Enzalutamide - novel antiandrogen
MOA
SE

A

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
23
Q

PARP INHIBITOR - OLAPARIB

A
  • 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
24
Q

Radium 223

A
  • For symptomatic bone one mets, LN up to 3cm allowed
  • Binds preferentially to hydroxyapatite in bone mets
  • Toxicity: diarrhoea, thrombocytopenia
25
Q

Diagnosis of prostate cancer

A
  • Prostate biopsy - transrectal US guided
  • Grade: Gleason score
  • Imaging: MRI - extension, nodal involvement
26
Q

Prostate cancer vs BPH in terms of location

A
  • Most prostate cancers are located in the peripheral zone (posterior lobe) of the prostate.
  • In contrast, BPH occurs in the transitional zone of the prostate
27
Q

What is the gleason score

A
  • Gleason grade: depending on the degree of differentiation of tumor cells and stromal invasion, tumors are graded from 1 (well-differentiated) to 5 (poorly differentiated)
  • Gleason score (ranges from 2 to 10): the sum of the two most prevalent Gleason grades
  • Grade groups: prognostic categories based on the Gleason score that are used to guide management
28
Q

Sites of mets for prostate cancer

A

liver > lung > bone > node

OSTEOBLASTIC LESIONS IN BONE

29
Q

Complications of prostate cancer

A
  • Acute urinary retention
  • Bilateral ureteric obstruction - acute renal failure
  • Spinal cord compression
  • Pancytopenia from bone marrow infiltration
  • Bilateral LL lymphodema secondary to pelvic obstruction
30
Q

Bladder Cancer Subtypes

A
  • TCC (urothelial cancer): 90% in developed countries
  • Squamous cell carcinoma is common worldwide associated with schistosomiasis
  • Adenocarcinoma: arises from urachal remnant, treat like GI cancer
  • Upper Urinary Tract: kidney, ureters
  • Lower Urinary Tract: bladder, urethra
  • Mainly effecting elderly

Muscle Invasion: non invasive > invasive

  • Non muscle invasive: 50-70% recur superficially, 10-30% progress to muscle invasive
  • Muscle Invasive: 25% present with muscle invasive/mets, poor prognosis
31
Q

Treatment for bladder cancer

A

Limited Disease:

  • Neoadjuvant platinum based tx and radical cystectomy
  • If not for surgery, chemoradiotherapy)

Metastatic Disease:
- Cisplatin+ gemcitabine
- If fails cisplatin + gemcitabine for:
PD1 inhibitors: nivolumab, pembrolizumab
PDL1 inhibitors: atezolizumab, durvalumab

32
Q

Testicular cancer types

A
  • 90% are GERM CELL TUMOURS - SEMINOMAS vs NON-SEMINOMATOUS GERM CELL TUMOUR (NSGCT)
    Usually malignant
  • 10% are non germ cell tumours/sex cord stromal - usually benign

Most common malignancy in young men, 15-35 years of age

33
Q

Risk factors of testicular cancer

A
  • Age: majority occur in 30-40s.
  • Cryptorchidism (prophylactic orchidectomy is recommended) - undescended testes
  • Hypospadias
  • Contralateral testicular cancer
  • Testicular Dysgenesis Syndrome (disorders of development): cryptochidism, hypospadias; including androgen insensitivity syndromes and Klinefelter syndrome
  • Genetic Factors: genetic predisposition is important, with racial differences and familial clustering evident
  • Environmental: exposure to radiation and petrochemicals.
34
Q

What hormone is produced by seminomas vs non seminomas

A

Seminomas:

  • DO NOT PRODUCE AFP
  • May have elevated BHCG or LDH
  • More common than seminoma and slower growing

Non-Seminomas

  • Histology include yolk sac, embryonal, teratoma, choriocarcinoma
  • AFP associated with yolk sac or embryonal

BHCG can be produced by seminomas and non-seminomas

35
Q

Management of testicular cancer

A
  • In general, most patients will undergo active surveillance after orchidectomy
  • Highly curable even in presence of relapse metastatic disease

No consensus on optimal surveillance: involves clinical review, tumour markers, surveillance CXR/CT
Orchidectomy
Semen cryopreservation
Surveillance

  • Seminoma (40%): High B HCG; 10 year recurrence 20%; managed with high dose CARBOPLATIN
  • Non seminoma (60%): High BHCG +/- AFP; 5 year recurrence 50%; higher risk of lymphatic invasion; managed with adjuvant BEP (Bleomycin, etoposide and platinum)

Oncology (7 decks)

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