Oncological Aspects of Urological Cancer - Dr Jonathan Shamash (Full Page )

8/19/2019 Oncological Aspects of Urological Cancer - Dr Jonathan Shamash (Full Page )

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Oncological aspects ofurological cancer

Dr Jonathan ShamashConsultant Oncologist


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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:

ProstateRenalTesticular (germ cell)Bladder Penile


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Approaches to treatment of cancer

ScreeningTo detect cancer in it’s early stagesOften patient may be asymptomaticEarly detection leads to better cure rates

Surgery

To remove as much of the tumour as possible

Adjuvant therapyTo treat micrometastases and prevent recurrence

RadiotherapyChemotherapy (cytotoxic/cytostatic)Endocrine TreatmentsBiological therapy (targeted therapy)


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Prostate Cancer


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Prostate Cancer

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

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

ScreeningControversy over using Prostate Specific Antigen (PSA)May not be an adequate screening test as significant numbers of false negatives and falsepositivesPSA has age dependent cut offsPSA is most useful in monitoring response to treatmentDigital rectal examination (DRE) by an experienced person, in combination with PSA is moreuseful for screening

Transurethral Ultrasound (TRUS) biopsy is used to confirm diagnosis


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Prostate cancer-symptoms and signs

Lower urinary tract symptoms (LUTS)nocturia, frequency, poor stream, hesitancy, terminal dribbling

Symptoms from metastatic diseasebone pain (esp in back) spinal cord compression, anaemia

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


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Prostate cancer: treatment - 1

Localised TherapyNo extensive diseasePSA < 30Low Gleason Score

This is a score of the most common histological pattern seen + the highestgrade of tumour histology seenLower Gleason score + better prognosis

Options for treatment are:Surgery – often a transurethral resection of the prostate (TURP)RadiotherapyCryotherapy – freezing and thawing of prostate cells to kill malignanttissue


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SurgeryEspecially for patients with life expectancy > 15 years(ie < 75 years old)

PSA


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RadiotherapyExternal beamBrachytherapy – implanting radioactive seeds intoprostate

Adjuvant hormonal therapyHas been shown to improve survival (3-5 years ofandrogen deprivation)


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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 mostpatients

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 ofthe disease

Following the initiation of androgen deprivation, symptoms should resolve rapidly andPSA 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 thistreatment.


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Endocrine therapy

Following failure of castration, the disease is termed castrate resistant (orandrogen independent )

Blockade of adrenal androgens using a peripheral androgen receptorantagonist drug (eg bicalutamide) is effective in around 20% of these castrateresistant patients

More potent interference with androgen receptor ligands has been studiedfollowing evidence that intratumoural levels of androgens may be relatively

preserved despite castration, and that other androgenic precursors mayfunction as agonists in these settings

Drugs used in castrate resistance include: Androgen receptor antagonists - bicalutamide, enzalutamideCorticosteroids - prednisone,dexamethasoneOestrogens - oestradiol, diethylstilbestrolCyp 17 inhibitors - Abiraterone – very high response rate recorded; but suggestion oflower response after corticosteroids/diethylstilbestrol


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The enzyme complexblocks a hydroxylation ofpregnenolone andremoves the carbon chainon the steroid ringconverting a C 21 steroid toa C 17 steroid - androgen

precursors reduce andpregnenolone rises

If dexamethasone givenas well then thissuppresses ACTH andtherefore pregnenolone

will fall.

Inhibition of Cyp17


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estradiol

Diethylstilbestrol

dihydroepiandrosterone

testosterone

Classicalendocrine

options

Dihydrotestosterone

Dexamethasone


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Endocrine therapy

In castrate resistance, oestrogens and corticosteroids are known to helpapproximately 50% of patients for on average 6-12 months

Cyp 17 inhibition (abiraterone) prevents the synthesis of estrogens andandrogens – 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 ( 11vs5.6 months) or 16 vs 8 months when measured in terms of time to radiographicprogression


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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-naïve and 50% in chemotherapy treatedpatients


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Chemotherapy for prostate cancer -taxanes

Docetaxel a microtubule acting cytotoxic has been shown to improvesurvival by an average of 3 months in patients who are castrateresistant

Docetaxel has significant side effects including-infection, tiredness,hair loss

Cabazetaxel – modified taxane to overcome docetaxel resistance – prolongs life by 2-3 months


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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 vs14.8 months)

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


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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


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Kidney Cancer


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Renal cell cancer

6000 cases a year in UK

50% have metastatic disease

Multiple presentations: Abdominal painMacro- / microscopic haematuria

Fevers / pyrexia of unknown originWeight loss

Anaemia or Polycythaemia (due to erythropoeitin production)

Risk factors:OverweightHypertension

Various rare inherited conditions


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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


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Management of metastatic disease

Chemotherapy is rarely successful in RCC

Overactivation of various protein kinases is thought to be a majorfactor in many cancers

Blocking these pathways may lead to reduced progression / cure

Tyrosine kinase inhibitorssunitinib, sorafenib, pazopanib

Immunotherapyhigh dose Interleukin 2

Mammalian target of rapamycin (mTOR) inhibitorseverolimus, sirolimus


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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 beingadministered


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Tyrosine kinase inhibitors

Sunitinib (tyrosine kinaseinhibitor) improves prognosisin RCC patients compared tothose treated with interferno-alpha

If sunitinib fails, axitinibshowed a prolongedprogession-free survivaladvantage when comparedto sorafenib


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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 – progression–free 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 advantagefollowing failure of a tyrosine kinase inhibitor

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


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Germ cell tumours


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Testicular germ cell tumoursPresent 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)


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Testicular germ cell tumours

Stage 1 disease - confined to the testis

Most common presentation

Treatment optionsOrchidectomy 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 mediastinum-principles of management are similar


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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


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Germ cell tumours - relapse management

The timing and pattern of relapse affect outcome

Poorer survival in:Shorter initial remission timeVery high tumour markersExtra-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 onsecond or subsequent relapse

Often high dose carboplatin and etoposide are used


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Bladder cancer


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Bladder cancer

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

In areas where schistosomiasis is endemic squamous carcinomas are the morecommon

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

The main risk factors:aniline dyessmoking


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Bladder Cancer

Any episode of haematuria must be investigated to exclude bladdercancer as the cause

Tumours begin in the urothelium, and become deeper eventuallypenetrating the muscle and getting fixed to other pelvic structures e.grectum

Many cases are low grade and superficial and may be managed bycystoscopic resection


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Bladder cancer

Several approaches have been shown to reduce the risk of recurrenceIntravesical BCG vaccineIntravesical chemotherapy

High grade tumours, those which have invaded the muscle wall generally require moredefinitive 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 improvesurvival

Bladder cancers are chemosensitive and various combinations have been proposedgemcitabine and cisplatincisplatin and methotrexate

Median survival is 12-15 months

Approximately 8% of those with metastatic disease will be cured


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Penile Cancer


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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


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Conclusions

The management of cancer is becoming more complex

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

The optimal approaches for different tumours often can only be established bycomplex randomised controlled trials as differences in survival may be quitesmall

Oncological Aspects of Urological Cancer - Dr Jonathan Shamash (Full Page )

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