Case 1

• A 65 yr old man is referred with painless haematuria

• Clinical examination, DRE, bloods unremarkable
• USS, IVU and flexible cystoscopy show a bladder tumour by
the left ureteric orifice
What now?
Rigid cystoscopy
Bimanual EUA pre and post-biopsy
TURBT – including deep biopsies into muscularis propria
Additional blind biopsies around bladder
Visualisation of ureters and passage of scope into ureters if possible
Lack of muscle requires a repeat TURBT
Immediate intravesical chemotherapy
European Association of Urology (EAU) guidelines (2001) advise:
single administration intravescial chemo (MMC, anthracyclines) for all patients
within 6 hours of resection
SIGN guidelines 2005 disagree with no need in single small fully resected lesions

Pathology report shows: Papillary G2 typical urothelial carcinoma

adeno (urachal remnant at dome)
linitus plastica type
squamous cell (bilharzia, infection, long term catheters)
small cell
carcinosarcomas
sarcomas
lymphoma
metastases
direct extension (rectal cancer and cervical cancer)

Invasion through basement membrane into subepithelial connective

tissue
What stage?
Tx Tumour cannot be assessed
T0 No evidence of tumour
Tis Carcinoma in situ
Ta Noninvasive papillary tumour
T1 Subepithelial connective tissue: pT1 at least
T2a Inner half of muscularis
T2b Outer half of muscularis
T3a Perivesical tissues (micro)
T3b Perivesical tissues (macro)
T4a Prostate, uterus, or vagina
T4b Pelvic or abdominal wall

What else do you need to know?

Presence or absence of deep muscle
Multifocality
Carcinoma in situ
Ureteric involvement
Pathology review confirms multiple pT2 at least, G3 TCC of the
bladder
How are you going to stage him?

Guides: RCR Recommendations for cross-sectional imaging in Cancer

Management
If fit for radical therapy need to assess:
Mural invasion
Extravesical extension
Pelvic (internal and external iliac) and metastatic (paraaortic and
retroperitoneal) nodal involvement
Peritoneal disease, liver metastases and hydronephrosis
Ideal: MRI abdomen and pelvis (T1W, T2W with contrast) as it offers improved
demonstration of muscle wall invasion and multiplanar reconstruction to assess organ
invasion.
If locally advanced/metastatic: CT abdomen/pelvis
CT chest if unusual pathology (e.g. small cell)
Good practice: CXR for all patients with CT chest if abnormal
Bone scan if raised alk phos or bone pain
Our MDT: CT chest, abd, pelvis and bone scan for all muscle invasive disease ps
Nodal staging
Nx Nodes cannot be assessed
N0 Nodes free of tumour
N1 Single node positive (<2cm)
N2 Single node positive (2-5cm)
N2 Multiple nodes positive (<5cm)
N3 Node positive (>5cm)
Metastatic staging
Mx Metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
Estimation of EDTA

Final MDT stage: T2B N0 M0

What is his approximate 5 year survival?
T2: 60% to 65% - with chemo
T3: 40% to 45% - with chemo
T4: 15% to 20% - with chemo
All comers muscle invasive: 50%, increased to 55% with 3 cycles of platinum-
containing combination chemotherapy
If N1: reduces to about 10%

Final MDT stage: T3B N0 M0

What are his treatment options?
neoadjuvant chemotherapy for all vs T3-4 vs surgery for all and adj if T3-4 or N1
cystectomy vs radiotherapy
concurrent chemotherapy or not
whole bladder vs partial bladder boost
pelvic nodes or not
What is the evidence for neoadj chemotherapy?
2 metanalyses of cisplatin-containing multi-agent combination
11 trials, n = 2688 pts : 5% absolute improvement in 5 yr OS, 50% to 55%; HR=0.87
16 trials, 6.5% absolute improvement in 5 yr OS
Largest trial was MRC 3 cycles CMV (cisplatin, methotrexate and vinblastine) n=976
pts: 5.5% improvement at 3 yr (p=NS), both radiotherapy and surgery patients
SWOG 0080: 3 x MVAC

Concepts: rapid start, high dose intensity and short overall duration (in case PD), re-
assessment to decide final radical approach

Which regimen and how many cycles?

3 cycles neoadjuvant (4 in SPARE) Gem-cis, MVAC, accel MVAC
Gem cis dose: D1,8 1200 mg/m2 and D1 80mg/m2

Data from metastatic setting includes:

255 patients with metastatic TCC

Randomised to Cisplatin single agent or to M-VAC
Significantly better survival in M-VAC arm (p = 0.00015)

MRC Trial
214 patients with advanced TCC
Randomised to CMV or MV
CMV: 46% response rate (10% CR, 36% PR)
MV: 19% response rate (7% CR, 12% PR)

Von der Masse:

405 patients with advanced TCC
Randomised to MVAC q28 v GC q28
CR 12.2% PR 37.2 % OR 49.4% GC
CR 11.9% PR 33.8% OR 45.7% MVAC
Better QoL with GC
More patients gained weight with GC
Less medical resource utilisation with GC

Also negative benefit of gem-cispl-paclitaxel vs gem-cispl

If poor renal function?

Substitute carboplatin (AUC 5/6) (If GFR<50ml/min) – but consider whether
neoadjuvant approach is correct – possibly proceed to cystectomy

How are you going to monitor him during chemotherapy?

Repeat imaging after 2/3 +/-repeat cystoscopic evaluation to decide whether to
proceed with cystectomy or radiotherapy, radical therapy starting 4 to 6 weeks
after last chemotherapy
If decision being made on treatment preference perhaps just MRI?

SPARE protocol:
proceed to surgery if residual muscle invasive disease
Proceed to radiotherapy if no muscle invasive disease, give 4th cycle chemo
Thus cystoscopic biopsies of site of original disease essential

3 cycles neoadjuvant chemotherapy

Reassess with cystoscopy and rebiopsy
Muscle invasive disease = surgery
No muscle invasive disease = Randomise

4th cycle chemotherapy

Radiotherapy Surgery

What do you do if he gets profound neutropaenic sepsis?

Proceed with chemo with GCSF support or
Proceed to surgery and think about adj chemo

Comes back to MDT after two cycles of chemotherapy with a good

response – no T2 disease
What are his options?
Surgery vs radiotherapy
No randomised comparisons
Radical cystectomy is standard in most countries
Bladder preservation is possible with radiotherapy +/- chemotherapy with salvage
surgery for recurrences
This has been UK preferred option, but surgical skill is increasing
No modern RCT – although modern UK reports (Kotwal, Chahal) suggest
equivalence
Most series suggest equivalence or favour surgery BUT case selection is against RT
Cochrane review of 3 RCT pre-op RT + surgery vs RT with salvage surgery favoured
surgery arms at 3 and 5 yrs

Surgical issues
Cystectomy = removal of bladder and distal ureters and prostate/seminal or
uterus/adnexa
Urethral removal if bladder neck or prostate involved
Regional lymph nodes removed - Suggestion that extended LN dissection improves
survival
Role of prostate sparing (reduce impotence)
Laparascopic/robotic surgery
Reconstructions:
Ileal conduit (Ileal section, ureters implanted, stoma)
Continent pouch (Ileal section, ureters implanted, stoma with tight valve – catheter)
Bladder reconstruction (Ileal section, bladder neck reconstruction, normal voiding or
catheter)
Ureterosigmoidostomy (rare)
30-day and 3-month treatment-associated mortality for radical cystectomy was
3.1% and 8.3%
He has a cystectomy in the private sector and has T3 N1 disease
What will you do?
Option is immediate 3-4 cycles or deferred 4-6 cycles chemotherapy if relapses
Metanalysis: 6 trials 498 patients
Cisplatin combination chemo post-cystectomy
Overall HR 0.75 (0.60-0.96, p=0.019)
Absolute improvement in 3 yr OS 9% (1%-16%)
Conclusion: very little data
EORTC 30994 trial
pT3-4 or N+ TCC
Classical MVAC, High-dose MVAC or GC
4 cycles immediate v 6 cycles on relapse
Poor recruitment

He has a cystectomy in the private sector and has T4 R1 disease

What will you do?
Consider post-operative radiotherapy – 45Gy/25#?
Bladder or bladder and pelvic nodes?
Toxicities: bowel and lymphoedema if node dissection
Consider getting bowel out of the field with a spacer

He wants radiotherapy
What will you discuss during consent?
Potential to preserve intact bladder with equivalent survival requiring cystoscopic
supervision
Salvage cystectomy for recurrent invasive disease has 30-day and 3-month mortality
of 8.8% and 15.7%
Risk of non-invasive recurrence
Acute and late side-effects, with gastrointestinal QoL issues predominating
Late toxicities: Contracted bladder, small bowel toxicity, obstruction, stricture,
perforation, diarrhoea, rectal tenesmus, reduced potency
Positive predictors of outcome
Younger age
Low stage
No hydronephrosis
Complete TURBT
High Hb

What do you think about concurrent therapies?

Multiple phase II trials appear to show improved outcome
NCIC n=99 pts: RT 40 Gy +/- cispl 100mg/m2, then cyst or RT
Increased CRR to RT & 3 yr OS, p=NS and Increased pelvic PFS, bladder
preservation p<0.05
Christie GemX: Chowdhury ASTRO 2010 n=50; RT 52.5 + gem 100mg/m2 D1, 8,
15, 22
Endoscopic CR: 88% and 3yr OS: 75%
Bowel toxicity
BC2001: James NEJM 2011 n=360: RT +/- 5FU/MMC and WBRT vs PBRT;
55Gy/20# or 64Gy/32#

BCON: Hoskin, R&O 2009, JC0 2010 n=333: RT +/- carbogen and nicotinamide;
55Gy/20# or 64Gy/32#
Carbogen increases tissue oxygen pressure and nicotinamide prevents transient
closure of small vessels

What is your radiotherapy technique?

Immobilisation – CT planning – ankle supports, knee wedges, tattoos, etc
Voluming – CTV = whole bladder and tumour with 5mm margin, PTV = CTV + 1.5
isotropic margins
Planning: 3FB conformal – spares rectum and bowel, anterior and wedged direct
laterals 6 or 10MV
Dose fractionation: RCR guidelines (assume conformal radiotherapy) 60-64 Gy in 2
Gy fractions or 50-52.5 Gy in 20 fractions we go to 55Gy
Standard EPI with offline matching, NAL of 5mm

Think: variable bladder volume alters superior and anterior margins particularly
Anisotropic margins sensible
Individualised margins sensible – RMH ‘POLO’
IGRT with CBCT (or seeds) an option – Christie ‘field of the day’ or NKI adaptive
using, multiple CT to define composite GTV

What is your follow-up protocol? – local, upper tracts, metatsases

Cystoscopy and TURBT at 3 months
CT CAP at 6 months
Cystoscopy and CT CAP annually to five years then just annual cystoscopy
RCR guidelines: 6 months and 1 year CT Chest abdomen and pelvis
He’s got unifocal T3 disease
Does this change your plans?
Christie trial of WBRT v PBRT and 16# v 20#
No difference in local control at 5 yrs with volume
16# slightly worse outcome

BC2001 – no reduction in LRDFS or toxicity!

Case 3
What can you see on this slide?
• Node positive disease
Little hard data – control rates probably <15%
Concepts: think about full chemotherapy this time – 4 to 6 rather than 3 to 4
Then consider loco-regional therapy
Surgery with node dissection – pretty toxic
Bladder with pelvic nodal RT

Pelvic nodal dose – 44 to 46Gy in 22 to 23#

Bladder dose the same – 64Gy in 32#
Could try to use IMRT to escalate nodal dose but less bowel sparing and tricky issue
of bladder and nodal matching

Case 4
What can you see on this slide?
• Patient relapses after 18 months
Concepts:
Same schedule
Modified platinum schedule – say MVAC this time
Vinflunine – PhII data suggests 18% response rate, median duration of response 9
months: Culine BJC 2006
PhIII data: 6.9m median survival vs 4.6 ms P>0.05; PFS or 3.0 vs 1.5ms. Bellmunt
JCO 2009
Paclitaxel – PhII data suggest 10% response rate, Vaughn JCO 2002
What can you see on this slide?
Less fit patient: offer gem-carbo (AUC5-6): ORR 40% vs 49% Gem-cispl (Dogliotti
Eur Urol 2006)

Case 5
What can you see on this slide?
• Small cell bladder cancer – probably T3B N1
Concepts:
High rate of systemic metastases
Treat as SCLC
Carboplatin / etoposide
Re-assess after 3 to 4 cycles
Continue to 6
Add locoregional radiotherapy (55/20#) and consider PCI (20Gy/5#)
Case 6
What can you see on this slide?
• T3B bladder cancer in a 87 yr old man
Concepts:
Extreme palliation for blood loss: 8 to 10Gy single
Standard palliation: 21Gy/3#/5 days (RCR guidance) or 6Gy/weekly x3-4
High dose palliative: 6Gy/weekly x5-6 planned
MRC BA09: 21Gy/3#/5 days equals 35 Gy in 10 # over 2 weeks for palliation

Case 7
• 65 yr old man with a 9 yr history of non-invasive bladder
cancer
• Now has 2 months history of right flank pain
What can you see on this slide?
Images show a mass in the right kidney and paraaortic node
Concepts:
RCC or renal pelvis TCC

How can you progress?

Biopsy not considered safe
Cystoscopy and selective urine cytology reveals highly suspicious urothelial cells
suspicious of malignancy
Working diagnosis: TCC renal pelvis

How do you manage this?

Palliative TCC chemotherapy?

Case 8
• 51 yr old man with a long history of renal failure following an
RTA
• On haemodialysis
• Permanent catheterisation
• Blood loss over last few months
What can you see on this slide?
• T4 disease tracking onto anterior abdominal wall likely to be
Squamous cell carcinoma
Concepts:
Very hard to treat
I used 1.8Gy/# with boost after 45Gy to bladder total dose 60Gy
with concurrent cisplatin 40mg per week, dialysed off