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BLADDER CANCER
Non 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
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Invasive bladder cancer in WA 2012
(note WACR data listed as
“bladder and urinary tract” presume
includes upper tract TCC)
Incidence
Deaths
210 men
75 women
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 the
textile 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 centuries
bladder 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 with
long term catheters get CA bladder, 80% SCC
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Schistosomiasis and SCC
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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 grade
15% 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 presentation
Long 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 cancers
Allegedly associated with chronic UTI
Not chemosensitive or radiosensitive
Treatment surgical – radical cystectomy
Urachal carcinoma
Most adenocarcinoma
Bladder dome
Characteristically massive mucous secretion
Treatment 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
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Leiomyosarcoma
Surgical treatment, cystectomy. 65% five year survival
Pheochromocytoma
Younger, 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 haematuria
85% of presentations
up to 20% of frank haematuria due to malignancy
Irritative LUTS / Bladder pain
frequency, urgency, bladder pain
especially invasive TCC and CIS
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Kidney obstruction
loin pain
impaired renal function
Investigation
Cystoscopy
Flexible cystoscopy, local anaesthetic – initial diagnostic test for haematuria
check 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% positive
High grade TCC 80% positive
Low grade TCC only 30% positive
Not useful in frank haematuria
Minimal 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
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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 - lifelong
frequency pending initial differentiation and behaviour
generally commencing 3 monthly, then back to 6 then 12 monthly
flexible cystoscopy LA
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Intravesical chemotherapy
current 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 advantage
over 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 to
patient $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 superficial bladder
cancer.
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}.
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Intravesical chemotherapy is not a cure, but should reduce frequency of recurrence and need for repeated TURBT.
“The Grey Zone” Between NMIBC and MIBC
High 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 for
therapeutic failures (radiotherapy not effective if CIS present).
USA
AUA Guidelines 2007 recommends intravesical BCG with cystectomy
for 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 range
of protocols
80% cure, but reasonable long term failure rate – proceed to cystectomy
form of immunotherapy
moderate risk – rare systemic BCG life threatening, not if immunosuppressed
bladder scarring with obstructive uropathy requires cystectomy
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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 random
bladder 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 present
Check 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 data
Comparison 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); 6519-24
72 patients with locally advanced bladder cancer (T3-4a, N0 or N+, M0) received either radical cystectomy or chemoradiotherapy. Radical
cystectomy 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 to
pelvis 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.
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TROG trial 02.03
Trans Tasman Radiation Oncology Group
Comparison 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
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Partial cystectomy
Little data
Possible use in small solid tumours in dome (standard for urachal adenocarcinoma).
Radical cystectomy
Cystoprostatectomy 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 690-696
University of Bern, Switzerland
577 patients that had cystectomy and pelvic lymphadenectomy between 1985 and 2000
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Metanalysis circa 2004
pT2 66%
pT3 35%
pT4 27%
Ileal Conduit Urinary Diversion
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Ileal conduit urinary diversion
Standard management for urinary output for 60 years
Complications:
Bleeding
Sepsis – 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 breakdown
Incisional 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 issues
nocturnal 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
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Since early 1990’s
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Improvement in curative outcomes – Tom Ferguson, Medical Oncology