Genitourinary Cancers

Question 1

Mechanism of action GnRH agonists in prostate cancer

Answer 1

• E.g. Goserelin (zoladex)
• Bind GnRH receptor on pituitary gonadotropin-producing cells
• One week of therapy → GnRH receptors down-regulated → decline in pituitary production of LH and FSH → fall in LH → decrease in serum testosterone within 3-4 weeks of starting therapy
• Initial blocking of pituitary gland may increase secretion LH leading to a flare response → could exacerbate bone pain or precipitate acute spinal cord compression (if bone mets treat with testosterone antagonist 7 days prior and 7 days after starting therapy)
• GnRH antagonists → rapid reduction in serum testosterone and avoids clinical flare

Question 2

Notes on abiraterone use in prostate cancer

Answer 2

• Andorgen biosynthesis inhibitor (inhibits 17a-hydroxylase/C17,20 lyase ) → expressed in testicular, adrenal, prostate tumour tissues
• Enzyme inhibition → increase in ACTH, mineralocorticoids → hypertension, hypokalaemia, oedema
• Co-adminstration of prednisone suppresses ACTH drive and reduces incidence and severity of mineralocorticoid excess

Question 3

Agents used for hypercalcaemia secondary to bony mets in prostate cancer

Answer 3

• Establish euvolaemia with normal saline
• Bisphosphonates - stabilise osteoclast resorption of calcium from bone (may take 1-2 days for efficacy)
• Furosemide can increase calciuresis in euvolaemia
• Nasal or SC calcitonin aids shift of calcium out of intravascular space

Dexamethasone → may be useful in lymphoid malignancies in which mechanism of hypercalcaemia is often related to excess hydroxylation of vitamin D

Question 4

Testicular cancer: subtypes, risk factors

Answer 4

• Non-seminomas vs seminomas
• Non-seminomas
  
  • Embryonal, teratoma, choriocarcinoma, yolk sac
  • Aggressive, tend to metastasise early

Risk factors

• Cryptochidism (abdominal > inguinal)
• Previous testicular ca in one testis
• Testicular feminisation syndromes → Klinefelter

Question 5

Staging of non-seminoma testicular cancer

Answer 5

Staging

• Stage I→ limited to testis and surrounding adnexa
• Stage II → RPLN/para-aortic nodes involved
• Stage III → spread beyond RPLN/para-aortic nodes or extra-nodal spread
• No Stage IV disease in testicular ca

Metastatic disease categorised into 1) favourable, 2) intermediate or 3) poor prognostic based on:

• Histological type → seminoma does better than nonseminoma
• Level of tumour markers (AFP, B-HCG, LDH)
• Site of tumour (mediastinum vs non-medistinum)

Question 6

Management of non-seminomatous testicular cancer

Answer 6

Low risk

• I.e. no vascular invasion, no substantial component of embryonal carcinoma
• Radical orchidectomy and if compliant → active surveillance
  
  • Monthly for first year, 2 monthly for 2nd year, 3 monthly for 3rd year, 6 monthly for 4th year then yearly
• If non-compliant → 1-2 cycles of platinum based chemo or RPLN dissection

High risk

• I.e. vascular invasion or substantial component of embryonal ca
• After resection → adjuvant chemo with 1-2 cycles of platinum based chemo (BEP or EP → bleomycin, etoposide, cisplatin)
• High frequency sensorineural hearing loss most likely long-term complication of BEP therapy (cisplatin) → dose and schedule dependent

Question 7

Management of seminomatous testicular cancer

Answer 7

• Radical orchidectomy
• If compliant → active surveillance (CT scans at 4-6 month intervals)
• If non-compliant or want to minimise risk of relapse → adjuvant chemo with 2 cycles carboplatin
• Radiotherapy to RPLN no longer recommended due to risk of secondary malignancies

Question 8

Mechanism of gynaecomastia in testicular cancer

Answer 8

• Secretion of hCG by tumour

Question 9

Renal cell cancer: Histology, genetic mutations, risk factors, prognostic factors

Answer 9

Histology

• 75% clear cell. Also papillary type I and 2 make up 15%). Arise from proximal convoluted tubule.
• Non-clear cell renal cancers → chromophobe and oncocytoma (5% each)
• Abberrations in VHL gene observed in 50-90% clear cell renal cancer → VHL keeps HIF in check (HIF promotes angiogenesis and cell proliferation)
• Resistant to most chemotherapies → express high levels of P-glycoprotein

Risk factors

• Analgesic nephropathy
• Leather tanning
• Cadmium
• Thorotrast (contrast medium in xray)
• Acquired cystic disease
• VHL
• Smoking
• Obesity
• Hypertension

Poor prognostic features

• High sodium
• High platelets
• High calcium
• Low haemoglobin
• <12 months between diagnosis and treatment

Median survival metastatic RCC = 12 months

Question 10

Treatment options for metastatic renal cell carcinoma

Answer 10

1. TKIs against VEGF-R → sunitinib
   
   1. Hypertension is a marker of response
2. Immunotherapy
   
   1. PD1 monotherapy
   2. CTLA-4 + PD1 combination
3. mTOR inhibitors (small role)

Role of cytoreductive nephrectomy

• Sunitinib alone non-inferior to nephrectomy-sunitnib

Question 11

VEGF-R TKI toxicities

Answer 11

• Gastrointestinal
  
  • Mucositis, stomatitis, diarrhoea
  • Common with all TKIs and mTOR inhibitors
• Skin → hand foot syndrome
• Thyroid → typically hypothyroidism, risk increases with time
• LFT derangement → class effect of all VEGFR TKIs
• Cardiovascular → CCF (2-3%), myocardial ischaemia (2-3%), arterial/venous thromboembolism, QT prolongation

Question 12

Most common cause of death for survivors of testicular tumours

Answer 12

• Secondary malignancies → includes solid tumours (lung, colon, bladder, pancreas, stomach), non melanoma skin cancers, leukaemia, and contralateral testicular cancers (though the latter uncommon)