BLADDER CANCERNon Muscle Invasive vs Muscle Invasive

Cystectomy vs Chemoradiotherapy

Incidence

� Fourth most common cancer in men

� Ninth most common cancer in women

� Sustained decline in incidence over recent times

60 % reduction in incidence over past 30 years

• Invasive bladder cancer in WA 2012 Incidence 210 men

(note WACR data listed as 75 women “bladder and urinary tract” presumeincludes upper tract TCC) Deaths 70 men

34 women• 75% of bladder cancers are non muscle invasive (NMIBC) (2014 EAU Guidelines)

Etiology

� The first of the “industrial” cancers in the 19th century

associated with the industrial revolution and the increasing use of chemicals in thetextile industry in the English textile and dye industry

naphthylamine, aminobiphenyl, combustion gases, coal soot

arylamines and aniline dyes β-naphthylamine synthetic dye in the late 1800’s

most bladder carcinogens are aromatic amines

� Smoking also increasing through 18th and 19th centuriesbladder cancers 4 times more common in smokers

Etiology

� Phenacetin in old “APC analgesics, esp upper tract TCC

� Pelvic radiotherapy for CA cervix – 2 to 4 fold increase in bladder cancer

� Chronic cystitis associated with long term catheters 2 – 10% of spinal patients withlong term catheters get CA bladder, 80% SCC

• Schistosomiasis and SCC

• Cyclophosphamide treatment 9 x increased risk

Pathology TCC

� Transitional cell carcinoma (TCC) 90% of bladder cancers

CIS carcinoma in situ= high grade superficial TCC

Papillary TCC low grade15% progression to invasive disease

Papillary TCC high grade

commonly invasive, life threatening

Nested form TCC

higher risk than standard TCC, chemosensitive

Micropapillary TCC

higher risk than standard TCC, not chemosensitive

Papillary TCC

Pathology SCC

� Squamous cell carcinoma (SCC)

~ 5% bladder cancers, wide geographic presentationLong term IDCs

Schistosomiasis esp Egypt (75%)

Not chemosensitive or radiosensitive

Treatment is surgical – radical cystectomy

Traditionally thought relatively unresponsive to chemotherapy or radiotherapy

Pathology Adenocarcinoma

� Adenocarcinoma

~ 2 % bladder cancersAllegedly associated with chronic UTI

Not chemosensitive or radiosensitiveTreatment surgical – radical cystectomy

� Urachal carcinoma

Most adenocarcinoma

Bladder domeCharacteristically massive mucous secretionTreatment partial cystectomy, bladder dome and urachus up to umbilicus

Pathology Rarer Histologies

� Carcinosarcoma

Aggressive, not chemosensitive or radiosensitive, 20% five year survival

� Small cell, neuroendocrine

Chem/Radiosensitive, Rx chemoradiotherapy, cystectomy if responds, rare cure

• Leiomyosarcoma

Surgical treatment, cystectomy. 65% five year survival

• PheochromocytomaYounger, 20 – 40 years. Adrenergic blockade and care with TURBT

• Leukaemia and lymphoma

• Metastatic tumour

Rare, more recently breast metastases. Occasional direct infiltration colorectal

Staging TNM

� Primary tumor (T) � TX: Primary tumor cannot be assessed � T0: No evidence of primary tumor � Ta: Noninvasive papillary carcinoma � Tis: Carcinoma in situ (i.e., flat tumor) � T1: Tumor invades subepithelial connective tissue � T2: Tumor invades muscle

� pT2a: Tumor invades superficial muscle (inner half) � pT2b: Tumor invades deep muscle (outer half)

� T3: Tumor invades perivesical tissue � pT3a: Microscopically � pT3b: Macroscopically (extravesical mass)

� T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall� T4a: Tumor invades the prostate, uterus, vagina � T4b: Tumor invades the pelvic wall, abdominal wall

� [Note: The suffix “m” should be added to the appropriate T category to indicate multiple lesions. The suffix “is” may be added to any T to indicate the presence of associated carcinoma in situ.]

� Regional lymph nodes (N) � NX: Regional lymph nodes cannot be assessed � N0: No regional lymph node metastasis � N1: Metastasis in a single lymph node 2 cm or smaller in largest dimension � N2: Metastasis in a single lymph node larger than 2 cm but 5 cm or smaller in largest dimension; or multiple lymph nodes 5 cm or smaller in largest

dimension � N3: Metastasis in a lymph node larger than 5 cm in largest dimension � Distant metastasis (M) � MX: Distant metastasis cannot be assessed � M0: No distant metastasis

� M1: Distant metastasis Americn Joint Committee on Cancer (AJCC) 2002

Bladder Cancer Staging

Clinical Presentation

� Symptoms

� Frank haematuria85% of presentations

up to 20% of frank haematuria due to malignancy

� Irritative LUTS / Bladder painfrequency, urgency, bladder pain

especially invasive TCC and CIS

• Kidney obstructionloin painimpaired renal function

Investigation

� Cystoscopy

Flexible cystoscopy, local anaesthetic – initial diagnostic test for haematuriacheck cystoscopy follow up for previous TCC

minimal risk

Rigid cystoscopy GA, usually with “TURBT” trans urethral resection bladder tumour

take random bladder biopsies with clinically invasive disease check for CIS

risks GA, bleeding, infection, bladder perforation

tumour chips sent for histopathology – type, subtype and presence invasion

Investigation

� Urine cytology

CIS 100% positiveHigh grade TCC 80% positive

Low grade TCC only 30% positive

Not useful in frank haematuriaMinimal usefulness in micro haematuria

Most useful in LUTS/Bladder pain if suspect CIS, where cystoscopy may look normal

Investigation - Imaging

� Pyelographic phase important in TCC – “field change” concept and upper tract TCC

generally CT pyelogram = 4 phase contrast CT (or IVP)

3% TCC bladder have or develop upper tract TCC

More upper tract TCC in CIS bladder and high grade TCC

• Staging of invasive bladder cancer

CT abdomen and pelvis, generally 4 phase contrast

Spread to adjacent organs, regional and distant lymph node spread, upper tract TCC

CXR (+/- Chest CT)

PET scan Bone scan

Treatment – Superficial TCC (NMIBC)

� TURBT

� Check cystoscopy - lifelongfrequency pending initial differentiation and behaviour

generally commencing 3 monthly, then back to 6 then 12 monthlyflexible cystoscopy LA

• Intravesical chemotherapycurrent fashion single dose Mitomycin instilled immediate post op

subsequent 6 dose therapy if frequent recurrence to enforce reduced frequency rec

• Upper tract imaging

more so in high grade disease and CIS but consider radiation dose

Treatment – Superficial TCC and Intravesical Chemotherapy

� Frequent recurrence – repeat TURBT problematic Rx intravesical chemo

Usually weekly doses for 6 weeks induction +/- “maintenance” monthly single doses.

Current fashion Mitomycin, but very expensive (? $1,200 for 40mg, not on PBS) dose and no proven advantageover cheaper agents for low grade TCC, claimed benefit because large molecule c/f thiotepa but actually at 329 kd is actually smaller than doxorubicin (Adriamycin) at 544 kd.

Doxorubicin (Adriamycin) dirt cheap on PBS 50 mg in 25 ml (previously $5.60 and repeat, now max cost topatient $37, cost to Government is $137.10 for 135 mg) and probably is probably as effective and a larger molecule than Mitomycin at 544 kd.

Prophylactic intravesical instillation therapy with Adriamycin and Mitomycin C in patients with superf icial bladdercancer. Tsushima et al. Cancer Chemother. Pharmacol. 1987;20 Suppl:S72-6

The cumulative nonrecurrence rates were 73.6% for Adriamycin, 63.4% for MMC, and 22.5% for controls after a follow-up of 24 months. {Note Mitomycin C dose was 30 mg (40 mg now standard dose) and Adriamycin dose was 50 mg}.

• Intravesical chemotherapy is not a cure, but should reduce frequency of recurrence and need for repeated TURBT.

“The Grey Zone” Between NMIBC and MIBCHigh Grade Superficial Disease - T1G3 & CIS

� NMIBC – TURBT and intravesical chemotherapy with check cystoscopy

� High grade superficial disease – T1G3 and CIS

Geographic differences Mainland Europe, especially Germany, EAU guidelines are complicated

but for “Highest risk” (T1G3 + CIS) “explain the risk and consider radical

cystectomy”.

UK and Australia, traditionally BCG (80% effective) with salvage cystectomy fortherapeutic failures (radiotherapy not effective if CIS present).

USA AUA Guidelines 2007 recommends intravesical BCG with cystectomyfor therapeutic failures.

N.B. Careful close follow up required if BCG utilized with “booster dose” protocols.

Treatment - CIS

� Generally high grade and dangerous, high risk of progression to invasive

possibly a milder subgroup, but unable to distinguish

� Can metastasize without clinical invasion

� Treatment intravesical BCG – weekly dose 6 weeks, then “booster” doses with a rangeof protocols

80% cure, but reasonable long term failure rate – proceed to cystectomy

form of immunotherapy

moderate risk – rare systemic BCG life threatening, not if immunosuppressedbladder scarring with obstructive uropathy requires cystectomy

• Mitomycin C 40% cure

Treatment – “T1G3” TCC

� Re resection at 6 weeks of tumour scar to re check for muscle invasion

� Generally BCG in Australia with close follow up high risk of recurrence, progression

� Cystectomy if muscle invasion shown at 6 week re-resect TURBT scar or if recurrence or progression at close follow-up.

� Europe generally early cystectomy for “high risk”group – T1G3 with CIS on randombladder biopsies.

Radiotherapy Alone for Muscle Invasive TCC ≥ T2

� Radiotherapy alone

This was standard first line therapy in UK/Australia up until the 1990’s, with“salvage cystectomy” done for failures found at follow up check cystoscopy.

Surgical advances came from radical prostatectomy dealing with the prostate dorsal vein complex reducing intra-operative blood loss substantially in men.

Now primarily used in cases unfit for cystectomy or in those not wanting

cystectomy, usually combined with “radiosensitizing” chemotherapy.

20% cure rate for radiotherapy alone (depending on staging)

Not effective if CIS presentCheck cystoscopy follow up with “proof of cure cysto” 2 – 3 months post treatment

“Salvage” cystectomy for failure – up to 40% cure overall

Chemoradiotherapy Alone for Muscle Invasive TCC ≥ T2

Tom Ferguson Medical Oncology� Lack of good trial dataComparison of radical cystectomy and chemoradiotherapy in patients with locally advanced bladder cancer. Ikeda M, Matsumoto K, Nishi M, Tabata

K, Fujita T, Ishiyama H, Hayakawa K, Iwamura M - Asian Pac. J. Cancer Prev. - January 1, 2014; 15 (16); 6519-2472 patients with locally advanced bladder cancer (T3-4a, N0 or N+, M0) received either radical cystectomy or chemoradiotherapy. Radicalcystectomy with bilateral pelvic lymph node dissection including the common iliac region as the standard procedure. Patients in the

chemoradiotherapy group received one cycle of MVAC followed by radiotherapy with a half dose of MVAC and then two more cycles of MVAC.Median total radiotherapy dose was 50 Gy.The 3-year progression-free survival (PFS) rates in the radical cystectomy and chemoradiotherapy groups were 56.2% and 25.6%, respectively (p=-0.015) and the 3-year overall survival (OS) rates were 63.5% and 48.1% (p=0.272).

Concurrent chemoradiotherapy for clinical stage T2 bladder cancer: report of a single institution. Peyromaure M, Slama J, Beuzeboc P, Ponvert D, Debré B, Zerbib M - Urology - January 1, 2004; 63 (1); 73-7

From 1996 to 2002, 43 patients were treated with concurrent chemotherapy and radiotherapy for clinical Stage T2 bladder cancer. DXRT 24 Gy topelvis with chemotherapy cisplatinum and 5FU. The overall rate of cystectomy was 25.6%. The rate of cancer specific survival at 3 and 5 years wa

s 75% and 60%, respectively. The overall rate of recurrence-free survival at 3 and 5 years was 63% and 33%, respectively.

Chemoradiotherapy as a bladder-preservation approach for muscle-invasive bladder cancer: current status and perspectives. Sumiyoshi Y - Int. J. Clin. Oncol. - December 1, 2004; 9 (6); 484-90

In patients who achieve a complete response (CR) after trimodality therapy, 5-year survival rates of more than 50%, the same as those of radical cystectomy, can be achieved and 70% of this group will retain an intact functional bladder.

• TROG trial 02.03 Trans Tasman Radiation Oncology GroupComparison of radiotherapy alone (64 Gy) with chemoradiotherapy (weekly infusion of cisplatinum with 64 Gy radiotherapy.

Final acrual 67 patients finished recruitment in 2007 ?

Surgery for Muscle Invasive TCC ≥ T2

• Partial cystectomy

Little dataPossible use in small solid tumours in dome (standard for urachal adenocarcinoma).

• Radical cystectomyCystoprostatectomy in males.

Cystectomy +/- hysterectomy and bilateral salpingo oophorectomy in females.Usually with regional lymphadenectomy.

Major surgery with moderate risks. 2 – 3% mortality.

Many patients unfit for surgery because of co morbidities, mostly cardiorespiratory.Older patients have higher risks.

Cure Rates for Cystectomy

� Overall 5 year recurrence free survival post radical cystectomy for TCC:

pT2 74%

pT3 52%pT4 36%

Radical Cystectomy for Bladder Cancer Today—A Homogeneous Series Without Neoadjuvant Therapy

Madersbacher, Studer et al Journal of Clinical Oncology Vol 21, No 4 (February 15), 2003: pp 690-696University of Bern, Switzerland

577 patients that had cystectomy and pelvic lymphadenectomy between 1985 and 2000

• Metanalysis circa 2004 pT2 66%pT3 35%pT4 27%

Ileal Conduit Urinary Diversion

• Ileal conduit urinary diversion

Standard management for urinary output for 60 years

Complications:

BleedingSepsis – perioperative and long term

Uretero-ileal anastomotic strictures

Para-stomal hernia (recent trial on mesh reinforcement)

Stomal stenosis

Stomal prolapse

Bowel obstruction – early and late

Bowel anastomosis breakdownIncisional hernias

Impotence in men

Sexual dysfunction in women

Metabolic acidosis, especially in those with impaired renal function

Ileal Conduit Urinary Diversion

Bladder Reconstruction

� Bladder reconstruction “neobladder”

Uses “detubularized” bowel segments

Larger procedure, generally done in younger patients

Orthotopic with suture to native urethra

~ 50% void with abdominal straining~ 50% clean intermittent self catheterize

some continence issuesnocturnal incontinence problematic with smaller reservoirs

Heterotopic with continent stoma self catheterized

All have a risk of adenocarcinoma in neobladder, check cystoscopies after 5 years

Bladder Reconstruction

Neo-adjuvant and Adjuvant Chemotherapy with Cystectomy

• Since early 1990’s

• Improvement in curative outcomes – Tom Ferguson, Medical Oncology