Bladder preservation for muscle- invasive bladder · PDF fileThe Christie NHS Foundation Trust...
Transcript of Bladder preservation for muscle- invasive bladder · PDF fileThe Christie NHS Foundation Trust...
The Christie NHS Foundation Trust NHS
Bladder preservation for muscle-
invasive bladder cancer
Ananya Choudhury
MA, PhD, MRCP, FRCR
Consultant Clinical Oncology and Honorary Senior Lecturer
March 2014
The University of
Manchester
Manchester Cancer
Research Centre
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Controversies in muscle-invasive bladder
cancer
• Surgery the optimal treatment strategy for all
bladder cancers
• The role of chemotherapy in bladder
preservation
• Use of predictive biomarkers to determine
treatment
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Treatment of muscle invasive bladder
cancer (MIBC)
• Depends on TNM staging
• Local v systemic
• Surgery v radiotherapy
• Increasing role of chemotherapy in organ preservation
• 5 year survival ~50%
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Patient who have RT are older
Kotwal. S, Choudhury. A. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 70, pp. 456–463, 2008
Median age
RT: 75 (43-99)
Surg: 68 (37-85)
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Patients who have RT have more
advanced tumours
Kotwal. S, Choudhury. A. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 70, pp. 456–463, 2008
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Similar treatment outcomes for radical
cystectomy and radical radiotherapy in
invasive bladder cancer.
Kotwal. S, Choudhury. A. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 70, pp. 456–463, 2008
5yr survival
RT: 35%
Surg: 41%
Overall Survival
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Similar treatment outcomes for radical
cystectomy and radical radiotherapy in
invasive bladder cancer.
Kotwal. S, Choudhury. A. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 70, pp. 456–463, 2008
5yr Survival
RT: 57%
Surg: 53%
Disease-specific Survival
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The SPARE (Selective bladder
Preservation Against Radical Excision)
study • Attempt to answer the question of surgery v radiotherapy
• Opened in July 2007, closed in Jan 2010
• Poor recruitment – only 45 patients recruited
• Reasons for poor recruitment:
Patient choice
Clinician choice
Lack of equipoise
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Prognostic factors for MIBC
• Age/performance status
• Stage
• Renal function
• Hydronephrosis
• Unifocal disease – no widespread CIS
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Optimal patients for radical radiotherapy
treatment
• Localised-disease muscle-invasive cancer
• Maximal Trans-Urethral Resection of Bladder
• Good bladder function
• WHO PS ≤3
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Neoadjuvant Chemotherapy for MIBC
• Meta-analysis:
• cisplatin-based regimes
• 5% improved overall survival at 5 yrs
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. European Urology 48 (2005) 202–206
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International phase III trial assessing
neoadjuvant cisplatin, methotrexate, and
vinblastine (CMV) chemotherapy for muscle-
invasive bladder cancer
NCRI Bladder Cancer Clinical Studies Group J Clin Oncol. 2011 Jun 1;29(16):2171-7.
Randomised patients
N=976
No CMV
N=485 CMV
N=491
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Neoadjuvant chemotherapy improves
overall survival and metastasis-free
survival p=0.04 p=0.001
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Adjuvant chemotherapy for bladder
cancer
• Meta-analysis of cisplatin-based regimens
• No evidence of benefit
• Cystectomy is a morbid operation – difficult to
recruit patients
Meeks et al. European Urology 2012;62(3):523.
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Standard neoadjuvant chemotherapy
• 1Gemcitabine/cisplatin 3 weekly
Cisplatin 70mg/m2 D1
Gemcitabine 1000mg/m2 D1+8
• 2Accelerated MVAC 2 weekly with G-CSF
Methotrexate 30 mg/m2, Vinblastine 3 mg/m2
Doxorubicin 30 mg/m2, and Cisplatin 70 mg/m2
1. von der Maase H et al. J Clin Oncol. 2005 Jul 20;23(21):4602-8.
2. Boshoff C et al. Eur J Cancer. 1995 Sep;31A(10):1633-6.
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A randomized trial comparing conventional
whole bladder with dose-escalated partial
bladder radiotherapy.
Cowan. R, McBain. C. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 59, pp. 197-207, 2004
5yr Survival
OS: 58%
CSS: 65%
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Ongoing questions
• RT dose and fractionation
• RT Volume : pelvic RT v bladder alone
• RT Technique : adaptive radiotherapy
• Systemic treatment : concurrent chemoradiotherapy
• The role of novel agents
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RT Dose and Fractionation
• Two commonly used regimes:
• 64Gy in 32 fractions and 55 Gy in 20 fractions
• Longer treatment times may lead to less
effective treatment
• Shorter course of radiotherapy may have more
side-effects
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RT Volume : pelvic RT v bladder alone
• No randomised control trials comparing the two
• Increased toxicity with whole pelvis RT due to increased
RT to bowel
• Treating bladder alone does not result in decreased
survival
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UK trials lead the way for bladder
preservation in 2011/12
• BC2001
• BCON
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Radiotherapy with or without chemotherapy in
muscle-invasive bladder cancer
BC2001
• 360 patients – PS0/1, 72yrs, T2
• Centre choice of either 55Gy/20# or 64Gy/32#
• Bladder only RT
• D1: Mitomycin (12mg/m2)
D1-5 and 16-20: 5FU (500mg/m2)
James ND et al: N Engl J Med. 2012 Apr 19;366(16):1477-88
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BC2001: Loco-regional control is better with
chemoradiotherapy
N at risk (events)
0.0
00.2
50.5
00.7
51.0
0
Pro
port
ion locore
gio
nal dis
ease-f
ree
178 94(53) 62(16) 48(4) 25(0) 18(0) 9(1)No CT182 106(34) 71(14) 51(2) 41(1) 23(1) 11(0)CT
0 12 24 36 48 60 72Months since randomisation
CT = 52/182
No CT = 74/178
67% (95% CI: 59%, 74%)
HR = 0.66 (95% CI: 0.46, 0.95); p=0.02
54% (95% CI: 46%, 62%)
2-yr LRDFS
James ND et al: N Engl J Med. 2012 Apr 19;366(16):1477-88
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Radiotherapy with concurrent carbogen
and nicotinamide in bladder carcinoma
BCON
• 333 patients – fit for RT, 74yrs, T2 (1:5 T3)
• Either 55Gy/20# or 64Gy/32#
• Bladder only RT
• RT+/- carbogen (2% CO2/98% O2 at 15 l/min
and nicotinamide (60mg/kg)
Hoskin et al: J Clin Oncol. 2010 Nov 20;28(33):4912-8.
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Overall survival improves with CON
Hoskin et al: J Clin Oncol. 2010 Nov 20;28(33):4912-8.
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Phase II study of conformal hypofractionated
radiotherapy with concurrent gemcitabine in
muscle-invasive bladder cancer
GemX
• 50 patients: PS0/1, 67yrs, T2 (1:5 T3)
• 52.5Gy/20#
• RT to bladder only
• Weekly gemcitabine 100mg/m2
Choudhury et al. J Clin Oncol. 2011 Feb 20;29(6):733-8.
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GemX: Disease-specific survival
• 3yr disease-specific survival: 82%; 5yr DSS: 78%
Choudhury et al. J Clin Oncol. 2011 Feb 20;29(6):733-8.
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GemX does not cause significant patient-
reported late toxicity
Choudhury et al. J Clin Oncol. 2011 Feb 20;29(6):733-8.
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The Christie Bladder Practice
Bladder cancer ~220
Neoadjuvant
chemo ~60
GemX ~60
n~35
Radical RT ~20
Palliative
treatment ~70
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Optimising bladder preservation –
current Christie approach
Urologist: maximal TURBT
neoadjuvant chemo
Radical RT:
55/20 GemX
3/12 cystoscopy
PS 0/1
PS 1/2 PS 2
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• Median age 69 years (range 51-78 years)
• All PS 0 or 1
• 30 patients received cisplatin and gemcitabine
• 3 patients received carboplatin and gemcitabine
• 1 patient received cisplatin and etoposide
• Mean isotope GFR was 89.
Neoadjuvant chemotherapy with GemX
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Toxicity Week 4 Bowel
Week 4 Urinary
6/52 post radiotherapy Bowel
6/52 post radiotherapy Urinary
Grade 1 16 15 7 28
Grade 2 10 4 0 2
Grade 3 3 1 2 0
Grade 4 1 0 0 0
No increase in toxicity for patients
receiving neo-adjuvant chemotherapy
with GemX
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Patients who have salvage cystectomy after
bladder preservation have good outcomes
Addla et al. The Journal of Urology Vol. 181, Issue 4, Supplement, Page 633
0 2 4 6 8 10
Years from cystectomy
0
20
40
60
80
100
Ca
nc
er-
sp
ec
ific
su
rviv
al (%
)
Primary (145/313)
Salvage (118/239)
p=0.39, log-rank test
313 190 118 82 52 42239 130 100 83 63 45
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Novel approaches : New agents and RT
• NCI: Sorafenib + RT Ph I study
• RTOG: Paclitaxel + herceptin in HER2 + bladder cancer
PhI/II study
• NCRN: cetuximab with chemotherapy and radiotherapy
for muscle invasive bladder cancer (TUXEDO) PhI/II
study
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Do Predictive Biomarkers have a role in
the management of bladder cancer ?
• No validated biomarkers predictive for
radiotherapy or chemotherapy response or
toxicity
• BUT, multiple candidates……..
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MRE11 expression is predictive of cause-
specific survival following radical radiotherapy
for muscle-invasive bladder cancer.
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MRE11 as a predictive factor for RT response
Choudhury et al. Cancer Res; 70(18) September 15, 2010
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Could tumour necrosis be a biomarker for hypoxia
and benefit from hypoxia modified treatment ?
Hypoxic region
Necrotic region
Dead cells
Blood vesselBlood vessel
Blood
ves
sel
Tumour
Blood
ves
sel
Tumour
Blood
ves
sel
Tumour
Blood
ves
sel
Tumour
Oxic
region
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Necrosis predicts benefit from hypoxia-modifying
therapy in patients with high risk bladder cancer
enrolled in a phase III randomised trial.
0 1 2 3 4 5
Years
0
20
40
60
80
100
Surv
iva
l (%
)
CON (30/52)RT (28/58)
p=0.32, log-rank test
52 44 35 27 17 958 50 40 29 25 13
0 1 2 3 4 5
Years
0
20
40
60
80
100
Su
rviv
al (%
)
CON (26/60)RT (40/61)
p=0.004, log-rank test
60 51 45 38 27 2161 44 28 19 17 12
Necrosis absent Necrosis present
Tumour necrosis Deaths/N HRUV 95% CI P HRMV 95% CI P
No 58/110 1.30 0.78, 2.18 0.32 1.64 0.95, 2.85 0.08
Yes 66/121 0.49 0.30, 0.80 0.005 0.43 0.25, 0.73 0.002
Eustace et al. Radiotherapy and Oncology 2012
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Ongoing biomarker work
• MOBIBLART – further validation of MRE11
• GemTrans – are gemcitabine metabolites
associated with GemX outcomes?
• MCRC biobank
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Other markers of interest
• DNA repair
• P53, HERII
• Apoptosis
• Androgen receptor
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MRI as a biomarker in MIBC
• Not fully validated
• Multiple parameters
• Multiple protocols
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DCE-MRI predicts response to neoadjuvant
chemotherapy prior to cystectomy
S.B. Donaldson et al EJR 82 (2013) 2161– 2168
Relative signal intensity and plasma perfusion are significantly
associated with post treatment response, confirmed at cystectomy
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But its more complicated in bladder
preservation….
No clear associations between relative signal intensity and plasma
perfusion associated with post treatment response
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Potential national UK bladder
studies
• RAIDER
• Standard v adaptive RT v adaptive RT with
concomitant boost
• Toxicity end point
• BIOPIC
• Hypothesis: “ Does biomarker data influence
patient decision making?”
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Conclusions
• Outcomes with radiotherapy with radiosensitisation are
comparable to surgery
• Neoadjuvant chemotherapy further improves treatment
outcomes without increasing toxicity
• Further validation of predictive biomarkers is ongoing,
but some markers show promise
• Its all about patient selection……
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Acknowledgements
The Christie
Clinical Oncology
JP Logue
C Coyle
JP Wylie
JE Livsey
PA Elliott
N Alam
A Tran
Christie Medical Physics
and Engineering
C Rowbottom
C Boylan
L Kershaw
Radiology
B Carrington
S Bonington
Histopathology
H Denley
Surgery
N Clarke
Institute of
Cancer Sciences
CML West
M Brown
The Gray Institute
Oxford
AE Kiltie
Mount Vernon
Watford
P Hoskin
The Royal Marsden
R Huddart