Diagnosis and Management of Bladder Cancer

Gold standards in bladder cancer diagnosis

• Cytology

• Cystocopy plus biopsy

staging classification (UICC 1997) - primary tumour

superficial muscle-invasive

(papillary) (solid)

urothelium

lamina propria

superficial muscle

deep muscle

pTapT1

CIS

pT2apT2b

pT3

perivesical

periureteral

perirenal

fat

Diagnosis and Management in Urology 6th September 2010

Management of Bladder TCC - Superficial Disease -

risk of progression treatment

low ( 2 - 11%) TUR-BT -unifocal, pTa G1/2 +/- intravesical chemotherapy

intermediate ( 29 - 39%) TUR-BT + intravesical

-multifocal pTa, pT1 G1/2, chemo- / immunotherapy recurrences

high ( 40 - 83%) TUR-BT + intravesical

-CIS, pTa/1G3 chemo- / immunotherapy radical cystectomy radiation therapy

Tumour

Bladder Wall

Prostate

Cystoscope

Transurethral resection of the bladder TURB

Diagnosis and Management in Urology 6th September 2010

Non- Surgical Management of Bladder Cancer

CASE HISTORY 1

• 51 yo barman

• 1 episode frank haematuria

• No past Hx

• Smoker, 20/d x 30y

CASE HISTORY 1

• Investigations:

– FBC, U+E

– MSU for C+S

– IVU

– Cystoscopy + Biopsy

CASE HISTORY 1

• Bladder lesion seen at cystoscopy

• Biopsy: Grade 3 TCC, pT1

– But no muscle in sample

• Next step?

CASE HISTORY 1

• TURBT

• Tumour resected

– pT2a (at least)

• Staging investigations?

Treatment Options Localised Muscle Invasive Bladder Cancer

• Radical Cystoprostatectomy

+/- Neo adjuvant chemotherapy

• Radical Radiotherapy

+/- Neo adjuvant chemotherapy

Multi-Disciplinary Team Meeting

• Surgeons, Oncologists, Radiologists, Pathologists, Nurses

• Treatment options discussed

Radiotherapy Versus Surgery

FOR

• Organ Preservation

• Sexual Function

• No anaesthetic

• Suitable for less fit patients

Against

• No randomised data

• Less pathological information

CASE HISTORY 1

• Patient opted for radical radiotherapy with neo-adjuvant chemotherapy

Neo-Adjuvant Chemotherapy

Neo-Adjuvant Chemotherapy Definitive Treatment

Surgery/Radiotherapy

Rationale: Down-staging, micro-metastatic disease control, radiosensitising

Why chemotherapy in invasive bladder cancer?

• 5 yr survival only 50%

• Pattern of recurrence usually distant mets rather than local recurrence

• Suggests treatment failure mainly due to presence of occult metastatic disease present at the time of definitive local treatment, with 20-30% of patients failing locally

Chemotherapy

• Cisplatin initially was the most active single agent used

• As single agent, response rates only 10-30%

• Combination chemotherapy centred around Cisplatin was studied in RCT’s in 1990’s & shown to have ↑ response rates & ↑ OS

Combination Chemotherapy

• Methotrexate,Vinblastine,Doxorubicin and Cisplatin (M-VAC) had been the gold standard until recently

• Limited greatly by toxicity-up to 63% of patients may require dose-reduction

• Long term survival benefit is modest-median survival consistently less than 13 months

Gemcitabine-Cisplatin

• Randomized phase III trial comparing standard M-VAC with Gemcitabine/Cisplatin

• Patients were stage T4b or any N/any M TCC bladder with no previous chemotherapy

• 405 pts enrolled

M-VAC Gem/Cis

No. of patients 202 203

Overall RR 46 49

Complete RR 12 12

Median Survival 14.8 13.8

Rx related dths 3% 1%

Neut. Sepsis 12% 1%

G3-4 mucositis 22% 1%

Mucositis/Cycle 3.6 days 0.5 days

Advantages & Disadvantages of Neo-adjuvant Chemotherapy

• Improved drug delivery before possible interference caused by local treatments

• Better tolerability & compliance due to improved PS

• Immediate Rx of micro-mets • Prognostic information by

observing response to chemotherapy

• May allow bladder preservation in complete responders

• Delayed definitive Rx

• Toxicity & possible lowering of PS before local treatment

• Difficult to assess response in primary

• Possibility of inaccurate clinical staging before treatment

• May treat some patients unnecessarily

Bladder Chemotherapy -Common Side-Effects

• Neutropenia

• Anaemia

• Alopecia

• Nausea and Vomiting

• Peripheral nerve damage

• Renal impairment

• Mucositis

Case 1: Patient Management

• Completed 3 cycles of Gemcitabine-Cisplatin Chemotherapy

• Cystoscopy: complete response

• Plan Proceed to Radiotherapy

Radical Radiotherapy

• CT planned volume – bladder empty

Radiotherapy

• Radiotherapy delivered by Linear Accelerators

• Usually one treatment (fraction) per day for 6-8 weeks

Contouring on multiple CT slices – typically 40 slices

Radiotherapy

• Treated supine with 3 field arrangement

– Anterior,R lateral wedged,& L lateral wedged fields

• 64 Gy / 32 F/ 6.5 wks

Radiotherapy

Acute Side Effects • Diarrhoea

• Proctitis- Urgency, PR bleeding, Mucous Discharge

• Dysuria

• Frequency

• Urgency

• Tiredness

Radiotherapy

Late Side Effects • Reduced bladder capacity

• Reduced erectile function

• Rectal bleeding

• Altered bowel habit

• Second cancer risk

CASE 1

• Tolerated treatment well

• Alive and well 18 months later, cystoscopy clear

CASE HISTORY 2

• 45yr old plumber.

• September 2004

• 1 year history of recurrent macroscopic haematuria, unresponsive to antibiotic therapy.

CASE HISTORY 2

• Cystoscopy

– Tumour at the left ureteric orifice.

• Histology

– Grade 3 Transitional cell carcinoma.

– Muscle invasive.

CASE HISTORY 2

• Pre-operative CT

– Tumour at the left side of bladder with left hydronephrosis

– Small pelvic nodes and two small equivocal pulmonary nodules

CASE HISTORY 2

• Cystectomy

– Frozen section of 2 pelvic nodes

• Positive for metastatic TCC

• pT2b N2 …… M1?

• Referred to oncology

CASE HISTORY 2

Symptoms of Lung Metastases

• Symptoms?

Bladder Metastases

• Other sites of metastases:

– Nodes

– Liver

– Brain

– Bone

– Skin

Treatment Options

• Chemotherapy

– Gemcitabine + Cisplatin

• Radiotherapy for pain/bleeding

Gemcitabine Cisplatin

• Cycle 1-3 well tolerated.

– 2 Lung lesions had remained stable but 2 new 3mm lung lesions found.

– No other disease

• Proceed with Cycle 4-6.

– Stable disease

INDEPENDENT PROGNOSTIC FACTORS

• KPS

– >80 MS 18.5

– <80 MS 10.5

• VISCERAL METASTASIS

– YES MS 11.1

– NO MS 22.3

CASE HISTORY 2

• Stopped chemotherapy July 05

– Pursued an active fitness program

• Returned 3mths later – asymptomatic

• Repeat CT requested for Jan 06

– Progression in the lung lesions

Gemcitabine Cisplatin

• Returned February to start chemo

• Cycle 1-3 (7-9)

– Lesions improved

• Cycle 4-6 (10-12)

– Further improvement

• September 2006 - Stopped chemotherapy

CASE HISTORY 2

• October 2006 - Attended GP

– Numbness in Left Arm for 1½ minute associated with confusion

• Urgent CT brain

CASE HISTORY 2

MRI

WBRT

• Oct 06- 30Gy 10fractions 2weeks

• April 07- RIP

WBRT

– Neurological improvement 50-70%

– Improved survival 3-6mths vs BSC

– Surgery or Stereotactic radiosurgery

• 80% will have CNS relapse.

– WBRT following Sx or SRS

• 20% will have CNS relapse.

Lancet 2004, 363 1665-1672

J Uro 1993, 149, 480-483

CONCLUSION

• Organ preservation is possible with radiotherapy

• Neo-Adjuvant Chemotherapy improves outcome

• Chemotherapy provides excellent palliation in metastatic bladder cancer

• Radiotherapy is useful for palliation of bladder cancer symptoms