Oncological aspects of

urological cancer
Dr Jonathan Shamash
Consultant Oncologist

Learning Objectives

To know the common presentations urological cancer

To know how to investigate urological cancer

To know management strategies for treating urological cancer

Urological cancers:

Prostate
Renal
Testicular (germ cell)
Bladder
Penile

Approaches to treatment of cancer

Screening

Surgery

To detect cancer in its early stages

Often patient may be asymptomatic
Early detection leads to better cure rates

To remove as much of the tumour as possible

Adjuvant therapy

To treat micrometastases and prevent recurrence

Radiotherapy
Chemotherapy (cytotoxic/cytostatic)
Endocrine Treatments
Biological therapy (targeted therapy)

Prostate Cancer

Prostate Cancer

Prostate cancer is a disease of older men, most are over 70 years old. Many are
asymptomatic.

Prostate cancer is common in autopsy studies, and many men do not have clinically
important disease

Screening

Controversy over using Prostate Specific Antigen (PSA)

May not be an adequate screening test as significant numbers of false negatives and false
positives
PSA has age dependent cut offs
PSA is most useful in monitoring response to treatment
Digital rectal examination (DRE) by an experienced person, in combination with PSA is more
useful for screening

Transurethral Ultrasound (TRUS) biopsy is used to confirm diagnosis

Prostate cancer-symptoms and signs

Lower urinary tract symptoms (LUTS)

Symptoms from metastatic disease

nocturia, frequency, poor stream, hesitancy, terminal dribbling

bone pain (esp in back) spinal cord compression, anaemia

Locally advanced disease can lead to rectal symptoms and renal failure due to
urinary tract outflow obstruction

Prostate cancer: treatment - 1

Localised Therapy

No extensive disease
PSA < 30
Low Gleason Score

This is a score of the most common histological pattern seen + the highest
grade of tumour histology seen
Lower Gleason score + better prognosis

Options for treatment are:

Surgery often a transurethral resection of the prostate (TURP)

Radiotherapy
Cryotherapy freezing and thawing of prostate cells to kill malignant
tissue

Prostate cancer: treatment - 2

Surgery

Especially for patients with life expectancy > 15 years

(ie < 75 years old)
PSA <15
No co-morbidity e.g. heart disease, cerebrovascular
disease etc

Prostate cancer: treatment - 3

Radiotherapy

External beam
Brachytherapy implanting radioactive seeds into
prostate

Adjuvant hormonal therapy

Has been shown to improve survival (3-5 years of

androgen deprivation)

Endocrine therapy

Most prostate cancer is responsive to the withdrawal of androgens

This used to be achieved by surgical castration, but is often not acceptable for most
patients

Medical castration can be achieved using Gonadotrophin Releasing Hormone

(GnRH) analogues e.g goserelin

This group of drugs is most commonly used in the initial systemic management of
the disease

Following the initiation of androgen deprivation, symptoms should resolve rapidly and
PSA should fall

A rapid fall in PSA and a nadir of < 1 suggests a good long term outcome

The period of control varies from 1 -3 years. Overall 80% of patients respond to this
treatment.

Endocrine therapy

Following failure of castration, the disease is termed castrate resistant (or

androgen independent)

Blockade of adrenal androgens using a peripheral androgen receptor

antagonist drug (eg bicalutamide) is effective in around 20% of these castrate
resistant patients

More potent interference with androgen receptor ligands has been studied
following evidence that intratumoural levels of androgens may be relatively
preserved despite castration, and that other androgenic precursors may
function as agonists in these settings

Drugs used in castrate resistance include:

Androgen receptor antagonists - bicalutamide, enzalutamide

Corticosteroids - prednisone,dexamethasone
Oestrogens - oestradiol, diethylstilbestrol
Cyp 17 inhibitors - Abiraterone very high response rate recorded; but suggestion of
lower response after corticosteroids/diethylstilbestrol

Inhibition of Cyp17

The enzyme complex

blocks a hydroxylation of
pregnenolone and
removes the carbon chain
on the steroid ring
converting a C21steroid to
a C17 steroid - androgen
precursors reduce and
pregnenolone rises

If dexamethasone given
as well then this
suppresses ACTH and
therefore pregnenolone
will fall.

dihydroepiandrosterone

Classical
endocrine
options

Dihydrotestosterone

testosterone
estradiol

Dexamethasone

Diethylstilbestrol

Endocrine therapy

In castrate resistance, oestrogens and corticosteroids are known to help

approximately 50% of patients for on average 6-12 months

Cyp 17 inhibition (abiraterone) prevents the synthesis of estrogens and

androgens it seems useful in this setting

Abiraterone with prednisone has been compared to prednisone alone in the

initial management of castration-resistant disease

A doubling in time to progression when measured by PSA was recorded ( 11vs

5.6 months) or 16 vs 8 months when measured in terms of time to radiographic
progression

Enzalutamide

Androgen receptor antagonist ( 5x affinity of bicalutamide)

Also prevents androgen receptor binding DNA and co-activator proteins

Able to overcome bicalutamide resistance

67% response rate in chemo-nave and 50% in chemotherapy treated

patients

Chemotherapy for prostate cancer taxanes

Docetaxel a microtubule acting cytotoxic has been shown to improve

survival by an average of 3 months in patients who are castrate
resistant

Docetaxel has significant side effects including-infection, tiredness,

hair loss

Cabazetaxel modified taxane to overcome docetaxel resistance

prolongs life by 2-3 months

Results of recent studies

Both abiraterone and enzalutamide have been used post docetaxel

Both drugs have shown improved survival compared to best supportive care

Abiraterone has shown median prolongation of life by 3.9 months (10.9 vs

14.8 months)

Enzalutamide has shown prolongation of life of 5.2 months ( 18.4 vs 13.6

months)

Palliation of symptoms in prostate cancer

Palliative treatment options include:

Palliative radiotherapy

Bisphosphonates for bone disease zoledronate

RANKL inhibitor for metastatic disease denosumab

Analgesics

Blood transfusion for anaemia

Palliative care team support

Kidney Cancer

Renal cell cancer

6000 cases a year in UK

50% have metastatic disease

Multiple presentations:

Abdominal pain
Macro- / microscopic haematuria
Fevers / pyrexia of unknown origin
Weight loss
Anaemia or Polycythaemia (due to erythropoeitin production)

Risk factors:

Overweight
Hypertension
Various rare inherited conditions

Renal cell carcinoma

Histology / Genetics:

Clear cell carcinoma (80%) - Von-Hippel Lindau mutation

Papillary type 2 (10%) - Fumarate / Hydratase mutation

Papillary type 1 (5%) - C-met activation

Chromophobe (5%) - C-kit

Diagnosed on CT scan
Treatment:

Nephrectomy, but metastatic disease is common

Management of metastatic disease

Chemotherapy is rarely successful in RCC

Overactivation of various protein kinases is thought to be a major

factor in many cancers

Blocking these pathways may lead to reduced progression / cure

Tyrosine kinase inhibitors

Immunotherapy

sunitinib, sorafenib, pazopanib

high dose Interleukin 2

Mammalian target of rapamycin (mTOR) inhibitors

everolimus, sirolimus

Renal cell carcinoma - therapy

High dose interleukin 2 (IL2)

For fit patients- not anaemic, normal WBC and platelets

IL2 Response rate 3-40%

10% cure rate - often durable

Requires in patient admission very toxic whilst being

administered

Tyrosine kinase inhibitors

Sunitinib (tyrosine kinase

inhibitor) improves prognosis
in RCC patients compared to
those treated with interfernoalpha

If sunitinib fails, axitinib

showed a prolonged
progession-free survival
advantage when compared
to sorafenib

Renal cell carcinoma-targeted therapy

In untreated group response rate of 25-40% seen with sunitinib

Following failure of sunitinib axitinib has shown evidence of prolonged

progressionfree survival particularly in cytokine-pretreated patients

Stabilisation and prolongation of life seen with the mTOR inhibitor sirolimus
(rapamycin) - the analogue everolimus has shown a survival advantage
following failure of a tyrosine kinase inhibitor

Prolongation of life seen with the VEGF inhibitor bevacizumab when combined
with interferon

Germ cell tumours

Testicular germ cell tumours

Present in young men (age 20-40)

Most commonly as an enlarging mass in testicle

If confined to the testicle may be treated by orchidectomy alone

Seminoma or Non-seminoma

Adjuvant therapy reduces risk of relapse but does not improve overall
survival

Metastasizes to lungs, lymph nodes, liver and brain

Most (but not all) produce tumour markers

Alpha fetoprotein (AFP)

-human chorionic gonadotrophin (-HCG)
Lactate dehydrogenase (LDH)

Testicular germ cell tumours

Stage 1 disease - confined to the testis

Most common presentation

Treatment options

Orchidectomy followed by:

Surveillance
Adjuvant chemotherapy - reduces risk of relaps
Cure rate overall is the same

Cure rate is very high -99% for stage 1 tumours

85-90% for those with metastatic disease can expect to be cured

Even those with very advanced disease have a 50% cure rate

Germ cell tumours may arise in the retroperitoneum or mediastinumprinciples of management are similar

Germ cell tumours - chemotherapy

Seminoma single dose treatment

Non-seminoma may require single dose multidrug treatment

Intensive cisplatin based chemotherapy has revolutionised therapy for the disease

The most established protocol combines cisplatin + etoposide + bleomycin

Four courses of chemotherapy achieves the maximum result

Tumour markers should normalise in most

CT scan may not return to normal

After completion of chemotherapy residual masses often persist, which should be resected

Germ cell tumours - relapse management

The timing and pattern of relapse affect outcome

Poorer survival in:

Shorter initial remission time

Very high tumour markers
Extra-gonadal primary sites
Although overall around 50% will be cured

Cisplatin based therapy is usual

High dose chemotherapy with autologous stem cell rescue is often used on
second or subsequent relapse

Often high dose carboplatin and etoposide are used

Bladder cancer

Bladder cancer

Most bladder cancers in this country are transitional cell carcinomas (TCC)

In areas where schistosomiasis is endemic squamous carcinomas are the more

common

Tumours affecting the urothelium may occur anywhere between the renal pelvis and
the urethra

The main risk factors:

aniline dyes
smoking

Bladder Cancer

Any episode of haematuria must be investigated to exclude bladder

cancer as the cause

Tumours begin in the urothelium, and become deeper eventually

penetrating the muscle and getting fixed to other pelvic structures e.g
rectum

Many cases are low grade and superficial and may be managed by
cystoscopic resection

Bladder cancer

Several approaches have been shown to reduce the risk of recurrence

Intravesical BCG vaccine

Intravesical chemotherapy

High grade tumours, those which have invaded the muscle wall generally require more
definitive treatment - cystectomy or radical radiotherapy

Neoadjuvant chemotherapy prior to cystectomy has been shown to improve survival

If radiotherapy is being used concurrent chemo-irradiation has been shown to improve

survival

Bladder cancers are chemosensitive and various combinations have been proposed

gemcitabine and cisplatin

cisplatin and methotrexate

Median survival is 12-15 months

Approximately 8% of those with metastatic disease will be cured

Penile Cancer

Penile cancer

Human papilloma virus (HPV) is main risk factor

Squamous cancer develops in glans

Virtually unheard of if undergone neonatal circumcision

Surgical removal - including nodal block dissection

Radiotherapy to draining inguinal nodes

Chemotherapy- cisplatin, fluorouracil, docetaxel

Conclusions

The management of cancer is becoming more complex

The use of combinations of different modalities is increasingly used to achieve

cure

The optimal approaches for different tumours often can only be established by
complex randomised controlled trials as differences in survival may be quite
small