Dr Robert A Huddart Senior Lecturer and Honorary Consultant in Clinical Oncology Institute of Cancer

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Dr Robert A HuddartSenior Lecturer and Honorary
Consultant in Clinical OncologyInstitute of
Cancer Research and Royal Marsden Hospital,
Sutton, Surrey, UK

• Selective Bladder Preservation

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Does the use of neo-adjuvant chemotherapy offer a
rational way of selecting patients for
conservative management?

• Selective Bladder Preservation

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Presentation Overview

• Surgery and Radiotherapy as therapeutic options
  for muscle invasive bladder cancer
• Neo-adjuvant chemotherapy
• Concept of selective bladder preservation
• Experience of Bladder preservation in UK, Europe,
  US
• The SPARE trial

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Cystectomy

• Gold standard
• best chance of cure
• Clearly the best treatment

But on what evidence are these assertions based?
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Advantages of Cystectomy

• Immediate tumour removal
• Detailed pathological staging
• Stabilisation of renal function

But.. does this lead to improved survival?
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Disadvantages of cystectomy

• Need for urostomy or neobladder ?inferior urinary
  function
• Major surgery
• Mortality
• Morbidity
• Sexual function

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NCI SEER registry data 1992 Bladder cancer
co-morbidities
Prout et al Cancer 2005 104 1638-47
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Mortality after cystectomy
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Local Treatment of Invasive Bladder Cancer The
case for radiotherapy.

• Preserves bladder in the majority of patients,
  thus avoiding urostomy.
• Better bladder function than orthotopic
  constructions
• Avoids risks of major operation in elderly
  patient group
• Low treatment related mortality (Chalal et al
  0.3)
• Retains potency in majority of men

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Late effects

• Historical cross sectional studies 74 good long
  term urinary function
• Zietman et al 2003
• QoL urodynamics median 6.3 yrs after SBP
• Median bladder capacity 400cc (221-747)
• 15 reduced flow ( 40 of these had BPH!)
• 20 occasional urinary incontinence
• 20 mild to moderate rectal urgency
• Sexual function 8 dissatisfaction with sex
  life (16 use of sildanafil)

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Problems with radiotherapy as primary treatment
in bladder cancer

• Rate of complete durable responses
• Intensity of treatment
• Treatment toxicity
• Salvage cystectomy for treatment failures

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So what evidence is there for superiority of
surgery?
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Difficulties in comparing primary radiotherapy
and primary surgery in the treatment of bladder
cancer

• Selection biases
• intra center
• inter center
• Pathological v Clinical staging
• Stage migration and the Will Rogers effect

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Clinical understagingFicarra et al 2004 BJU 95
786-790
Based on TUR, bimanual, CXR, CT Abd/pelvis
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Randomised trials of surgery v radiotherapy in
muscle invasive bladder cancer

• None

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Randomised trials of surgery radiotherapy v
radiotherapy in muscle invasive bladder cancer

• 3 trials -meta analysis (Shelley et al 2004)

• Relevance?
• Combined v single modality treatment
• Many patients not received planned treatment
  (small numbers)
• Old techniques/doses

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Yorkshire study

• 398 patients in Yorkshire region 1993-96
• 302 radiotherapy (18.8 salvage cystectomy)
• 96 cystectomy
• 30 day/ 3month mortality
• Cystectomy 3.1, 8.3
• Radiotherapy 0.3, 1.65
• 5 yr Survival
• Cystectomy 36.5
• Radiotherapy 37.4

Chahal et al 2003 Eur Urol 43 246-7
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Current outcome for muscle invasive bladder cancer
Rodel et al 2002 JCO 3061-71 Stein et al JCO
2001 666-675
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NO RANDOMISED DATA TO SUPPORT SURGERY OVER
RADIOTHERAPY
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(My) Conclusions

• No clear evidence of superiority of surgery over
  radiotherapy

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Neoadjuvant chemotherapy
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Neo-adjuvant chemotherapy

• Use of chemotherapy prior to definitive radical
  treatment
• Aims
• Eradication of micrometastases
• Downstaging
• Prevention of tumour seeding

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Lancet meta-analysis 2003

• Why do a meta-analysis?
• Individual trials rarely have power to
  demonstrate small differences
• Avoids publication bias
• Looks at totality of data
• Power of approach demonstrated by impact of
  breast and colorectal cancers analyses

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Lancet meta-analysis 2003 (update 2005)

• Metholodogy
• Updated individual patient data
• Includes data on excluded patients
• Identified all published and unpublished trials
• 14 trials identified, 3 excluded due to
  confounding factors 10 data included

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Lancet meta-analysis 2003 Patient characteristics

• Data on 2688 patients
• Local Rx
• Cystectomy 5
• Radiotherapy 2
• Pre-op RTcyst 1
• Combination 2
• Median fu 6.2 years
• Median age 63 years, 85 male
• T2 33, T3 52, T4 9 G3 61

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Neoadjuvant chemotherapy meta analysis
ABC MAC 2003 Lancet 361 p1927-1934 ABC MAC 2005
Eur Urol 48202-206
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ABC MAC 2005 Eur Urol 48202-206
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Neoadjuvant chemotherapy meta analysisEffect v
type of treatment
ABC MAC 2003 Lancet 361 p1927-1934
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Neoadjuvant or adjuvant?

• Advantages of Adj chemotherapy
• Select patients according to pathological factors
• Doesnt delay definitive treatment
• Doesnt affect pathological assessment

• Disadvantages of Adj chemotherapy
• Morbidity of post surgery (RT) patients
• Delays chemotherapy
• Lack of strong evidence

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Adjuvant chemotherapy Meta analysis 2005 ABC Meta
analysis Collaboration

• 493 patients in 6 trials (5 excluded)
• 90 all patients in cisplatin combination regimes
• 66 patients from all eligible trials

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Meta analysis of adjuvant chemotherapyABC MAC
Eur Urol 2005 48 189201

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But..

• 400 patients- 238 deaths
• Chemotherapy allocation
• No comment on chemotherapy given at relapse in
  surveillance group
• Different regimes
• 3 trials stopped early- ? Why
• Cochrane review 2006
• NO EVIDENCE FOR ROUTINE PRACTICE
• EORTC 30994 study

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Selective bladder preservation
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What are the concerns with using radiotherapy for
invasive bladder cancer?

• Risk of treatment failure?
• Development of inoperable disease
• Additional risk of dissemination
• More difficult/riskier surgery

Radiotherapy would be more attractive if we could
identify early those patients in whom
radiotherapy would be successful and send those
in which success less likely to immediate surgery
and thus minimise these risks
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How can we select patients for conservative
treatment?

• Clinical features
• Biological parameters eg p53 status
• Response to initial treatment

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Principle of using treatment for selective
preservation
Conservative Rx
Response
Invasive Bladder cancer
Treatment failure
Treatment
Response assessment
Poor response
Surgery
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Boston selective bladder preservation results

• Boston approach
• CMV x 2-3 Pelvic RT 40Gy Cisplatin
• Reassess at 4-6 weeks
• Responders 20Gy Boost cisplatin

Disease specific survival all T2-T4a patients
treated MGH 1986-97 From Shipley et al Sem
Radiat onc 2005
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Survival outcomes from contemporary series
(adapted from Shipley et al Sem radiat Oncol
2005)
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Late effects

• Historical cross sectional studies 74 good long
  term urinary function
• Zietman et al 2003
• QoL urodynamics median 6.3 yrs after SBP
• Median bladder capacity 400cc (221-747)
• 15 reduced flow ( 40 of these had BPH!)
• 20 occasional urinary incontinence
• 20 mild to moderate rectal urgency
• Sexual function 8 dissatisfaction with sex
  life (16 use of sildanafil)

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Combined modality treatment of bladder
cancer-European experience (adapted from rodel
et al Sem Radiat Oncol 2005)
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Selective preservation with accelerated MVAC

• Complete TUR 3 cycles of accelerated M-VAC
  chemotherapy (with no radiotherapy).
• 87 patients with T2-T4a bladder cancer
• 40 (51) pTo,
• 19 pTa pT1.
• 55 patients conservative treatment
• 32/55 (58) alive with an intact bladder (median
  follow up 54 months).
• Overall survival
• 70 organ conservation arm
• 60 of patients undergoing cystectomy.

Sternberg CN Cancer 2003 Apr 197(7)1644-52.
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Materials Methods
T2/T3 TCC bladder, PS 0-1Maximal TURBT
14 day cycle, GCSF supportMethotrexate 30
mg/m2Vinblastine 3 mg/m2Adriamycin 30 mg
/m2Cisplatin 70 mg /m2
3 cycles accelerated MVAC
Rigid cystoscopy EUA
pTo/T1
pT2/T3
Radical radiotherapy
Cystectomy
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Results 30 patients 2000-2005
Mainly early patients when re assessment not
mandatory, too ill for cystectomy
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Results Median follow-up 24 months (range 3-53
months)n30
60
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Toxicity
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Dr Robert A HuddartSenior Lecturer and Honorary
Consultant in Clinical OncologyInstitute of
Cancer Research and Royal Marsden Hospital,
Sutton, Surrey, UKOn behalf of SPARE protocol
development group

• A Randomised trial of Selective bladder
  Preservation Against Radical Excision
  (cystectomy) in muscle invasive T2/T3
  transitional cell carcinoma of the bladder
• The SPARE trial

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T2/T3 TCC bladder PS 0-1, fit for cystectomy and
chemotherapy, normal renal function
Neoadjuvant chemotherapy (Gem-Cis 21 day cycle x
3)
SPARE trial Schema
Randomise
Radical surgery
Selective bladder preservation (SBP)
Rigid cystoscopy
pTo, pTa, pT1
pT2 or greater
pTo, pTa, pT1
4th Cycle CT
4th Cycle CT
Radical radiotherapy
Radical cystectomy
Radical cystectomy
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(No Transcript)
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Features of SPARE protocol

• Gemcitabine/cisplatin recommended treatment
• Data on response rates in neo-CT setting
• Randomisation during chemotherapy
• Defined surgical protocol/ quality assurance
• Radiotherapy quality assurance
• Trial training program with trial research nurse
• Qualitative assessment program
• To assess randomisation and recruitment program
  and barriers
• Translational work

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Randomised trial of Selective organ preservation
against radical excision (cystectomy) in muscle
invasive T2/T3 transitional cell carcinoma of the
bladder (SPARE)

• Endpoints (phase II trial)
• Primary
• Number of patients randomised over 2 years
• Proportion of patients undergoing bladder
  preservation in SBP arm
• Proportion of patients undergoing cystectomy in
  surgery arm
• Secondary
• Compliance
• Rate of salvage cystectomy after bladder
  preservation
• Toxicity of treatment in both arms
• Quality of life
• Loco regional progression free, metastasis free
  and overall survival
• N110

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SPARE Phase III trial

• Equivalence study
• N 1015
• Primary endpoint
• Overall Survival

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SPARE OUTCOMES

• Establish neo-CT as best practice in UK
• Establish how effective (or otherwise)
  conservative treatment is compared to surgery.
• Establish Qol after bladder cancer treatment
• Promote best surgical and radiotherapy practice
• Improve understanding of why patients make the
  decisions they do
• Develop biological correlates of chemotherapy and
  radiotherapy response

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Two final messages..
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The more things change.
The more they stay the same.
Courtesy of Dr A Birtle
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BAUSThe Future of Urology 2006-2016

• There will be few predictable changes in
  treatment as distinct from changes in the way
  treatment is delivered. Such changes are clearly
  discernable now. For example
• Bladder cancer will be treated by chemotherapy
  with salvage cystectomy for treatment failures
• Tony Mundy, February 2006

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Please give SPARE your support

• A major contribution to deciding how to manage
  muscle invasive bladder cancer

Contact Kathyrn Briggs ICR CTSU
Kathyrn.Briggs_at_icr.ac.uk Or Dr R A Huddart
(CI) Robert.Huddart_at_icr.ac.uk
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