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A Multidisciplinary Approach in Muscle-
Invasive Disease - Novel ChemotherapyCombinations and Targets in
Chemoradiation
Nick James
University of Birmingham
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Conflicts of interest
• Honoraria from Pierre Fabre
Presented by: Nick James
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Learning objectives
• To describe the past and current evidencesupporting chemoradiation as a bladder-
sparing approach and how to incorporate
molecular biomarkers and therapies
Presented by: Nick James
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Overview
• Evidence base for bladder preservation asalternative to surgery
• Chemoradiotherapy compared to
radiotherapy alone• Biomarker data
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Background
• Bladder cancer outcomes have notsignificantly improved for 30 years
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Bladder cancer is a systemic
disease
• No plateau in survival curves – Patients die from metastases
• Treatment needs to address local control
and distant metastases• Local control
– Surgery or RT
• Metastases
– Systemic therapy
Presented by: Nick James
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Breast cancer therapy timelines
1880 1900 1920 1940 1960 1980 2000 2020
Radical
mastectomy
- Halstead
Adjuvant RT
Adjuvant
hormone
therapy
Adjuvant
chemotherap
y
Adjuvant
HER2
targeting
Adjuvantaromatase
inhibitors
Breast cancer
Presented by: Nick James
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Mortality Rates From Breast
Cancer US and the UK
Presented by: Nick James
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NEOADJUVANTCHEMOTHERAPY AND SURVIVAL
Presented by:
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Neoadjuvant chemotherapy
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally
advanced bladder cancer. New England Journal of Medicine 2003;349:859-66.
Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and
vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29:2171-7.
Surgery +/- MVAC chemotherapy Surgery or RT +/- CMV chemotherapy
Presented by: Nick James
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MRC/EORTC Trial - Loco-regional and
metastatic control
Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing
neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder
cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29:2171-7.
Locoregional control Metastatic control
Presented by: Nick James
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IS SURVIVAL BETTER AFTERSURGERY?
Presented by:
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Survival from UK Registry data
• 453 UK pts,1993-1996
• Ratio
RT:cystectomy
3:1
• 10 year survival
RT 22% Surgery
24%
Munro NP, Sundaram SK, Weston PM, et al. A 10-year retrospective review of a nonrandomized cohort of 458 patients
undergoing radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat Oncol Biol Phys 2010;77:119-24.
Presented by: Nick James
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Survival is better after surgery?
• Variations in the use of total cystectomy andin the use of pelvic RT among the regions of
Ontario were not associated with variations
in survival.• Survival was correlated with tumour related
parameters
Hayter CR, Paszat LF, Groome PA, et al: The management and outcome of bladder carcinoma
in Ontario, 1982-1994. Cancer 89: 142-151, 2000
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Age at diagnosis
0
200
400
600
800
1000
1200
1400
1600
0-4 5-9 10-
14
15-
19
20-
24
25-
29
30-
34
35-
39
40-
44
45-
49
50-
54
55-
59
60-
64
65-
69
70-
74
75-
79
80-
84
85+
Male cases
Female cases
Median age in
BA06 & SWOG 8710
Median age inBC2001 and BCON
Median age in
USC series
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Choice of treatment
• Surgery and radiotherapy data relate todifferent segments of the population
• Neoadjuvant therapy data also mainly relate
to younger patients• Hence age/fitness is important factor in
treatment decisions
Presented by:
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CHEMORADIATION VSRADIOTHERAPY ALONE
Presented by: Nick James
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Synchronous Chemo-
radiotherapy
• Numerous phase I/II studies showingfeasibility and safety
• Three phase III studies
– RT vs RT + Cisplatinum (NCIC)
– RT vs RT + nicotinamide/carbogen (BCON)
– RT vs RT + 5FU/MMC (BC2001)
Presented by: Nick James
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Cisplatinum and RT +/- surgery
Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by
concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 1996;14:2901-7
Presented by: Nick James
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BCON: Aim and endpoints
• To determine if thehypoxia-modifiers
carbogen and
nicotinamide increase the
efficacy of RT in TCC
• Primary endpoint
cystoscopic control
• Secondary endpoints:
overall survival (OS), local
relapse-free survival
(RFS), urinary and rectal
morbidity
Presented by: Nick James
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BCON Results
Control arm
Carbogen + Nicotinamide
HR 0.85 (0.73-0.99) p=0.04
Relapse free survival Overall survival
0
20
40
60
80
100
0 12 24 36 48 60
R e l a p s
e - f r e e s u r v i v a l ( % )
Time from randomization (months)
RT + CON
RT alone
164 128 109 82 62 31
161 111 84 62 50 21
LogŠrankp = 0.06
HR 0.86 (0.74-1.0) p=0.06 at 3 years
Presented by: Nick James
Hoskin PJ, Rojas AM, Bentzen SM, et al: Radiotherapy with concurrent carbogen and nicotinamide in
bladder carcinoma. J Clin Oncol 28:4912-8, 2010
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BC2001: Trial design
Reduced high
dose volume RT
+ synchronouschemotherapy
Reduced high
dose volume RT†
Standard volume RT†
+ synchronouschemotherapy
Standard volume RT†
Patients with muscle
invasive bladder cancer
RANDOMISE
CT
No
CT
sRT RHDV RT
Pragmatic design: Centres could offer double or either single randomisation
Patients ineligible for one randomisation could participate in other
Presented by: Nick James
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Chemotherapy regimen
Target volume tumour + bladder + 1.5-2cm
Chemotherapy via peripherally inserted central
line as outpatient therapy
5FU 500mg/m2/d
MMC 12mg/m2
0 1 2 3 4 5 6 7Weeks
RT 55 Gy/20 f or
64 Gy/32 f
Presented by: Nick James
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Patient demographics
• Mean (SD) 70.5 (8.2) years
• Median (IQR) 71.9 (64.1 - 76.2) years
• Older than patients in previously publishedtrials including SWOG 87101(median 63 y)and BA062 (median 64 y)
Performance status
Male = 289/360 (80%)
Age at randomisation
1. Grossman et al NEJM 2003 Volume 349:859-866
2. Lancet 1999; 354: 533-40
0
5 0
<60 60-69 70-79 80+
0
5 0
0 1 2
Presented by: Nick James
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Acute toxicity• Proportions with a grade 3/4 at any time on treatment:
• 62/179 (34.6%) CT vs. 49/172 (28.5%) No CT (% of pts with data)• Stratified Chi-square test p=0.19
RT 64Gy/32F
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7 1 2 3 4 5 6 7
CT No CT
% o f
n o n - m i s s i n g
4
3
2
1
0
RT 55Gy/20F
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 1 2 3 4
CT No CT
% o
f n o n - m i s s i n g
4
3
2
1
0
Worst grade of on-treatment toxicity by week
Presented by: Nick James
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RTOG 6 month toxicity outcomes
n= 291, 145 RT only, 146 chemo-radiotherapy
0
10
20
30
40
50
60
70
80
Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Unknown
Chemo RT
RT only
Presented by: Nick James
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Loco-regional disease free survival in
chemotherapy randomisation
N at risk (events)
HR (95% CI) = 0.68 (0.48-0.96)
Stratified logrank p= 0.03
0 . 0
0
0 . 2
5
0 . 5
0
0 . 7
5
1 . 0
0
178 96(54) 69(16) 58(4) 44(1) 35(0) 18(1)RT182 108(35) 76(14) 66(3) 56(1) 46(1) 25(1)Chemo-RT
0 12 24 36 48 60 72Months since randomization
N at risk (events)
HR (95% CI) = 0.57 (0.37-0.90)
Stratified logrank p= 0.01
0 . 0
0
0 . 2
5
0 . 5
0
0 . 7
5
1 . 0
0
178 109(37) 85(11) 74(2) 52(2) 39(0) 20(0)RT182 121(20) 93(7) 79(3) 66(0) 54(0) 32(1)Chemo-RT
0 12 24 36 48 60 72Months since randomization
Loco-regional control
(invasive and non-invasive)Invasive loco-regional control
James et al, Radiotherapy with or without chemotherapy for invasive bladder cancer.
NEJM 2012 366, 1477-1488
Presented by: Nick James
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rtrandgp1
rtrandgp2
rtrandgp3
rtdosestratum1
rtdosestratum2
NeoCT1
NeoCT2
Primary
rtrandgp1
rtrandgp2
rtrandgp3
rtdosestratum1
rtdosestratum2
NeoCT1
NeoCT2
Primary
Favours CT Favours no CT1.2 .5 1 2
LRDFS - consistency across subgroupsHazard ratio (95% CI)
Randomised sRT 63 0.63
Randomised RHDV 58
Elect sRT 239
RT dose 55Gy/20F 140 0.73
RT dose 64Gy/32F 212
Neoadjuvant CT 118 0.60
No neoadjuvant CT 242
N P-value
Primary analysis 360
0.77 (0.33, 1.75)
0.97 (0.35, 2.69)
0.59 (0.38, 0.92)
0.72 (0.39, 1.32)
0.63 (0.40, 0.98)
0.58 (0.31, 1.09)
0.72 (0.46, 1.11)
0.66 (0.46, 0.94)
0.77 (0.33, 1.75)
0.97 (0.35, 2.69)
0.59 (0.38, 0.92)
0.72 (0.39, 1.32)
0.63 (0.40, 0.98)
0.58 (0.31, 1.09)
0.72 (0.46, 1.11)
0.66 (0.46, 0.94)
Presented by: Nick James
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Patterns of recurrence after chemoRT
Any recurrence
93/182 pts
Loco-regionalrecurrence
53
Non-muscle
invasive25
Muscle invasive18
Pelvic nodes6
Distantrecurrence or
second primary
40
Metastasis29
Second primary11
Presented by: Nick James
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MARKERS FOR OUTCOME
Presented by: Nick James
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Baseline indicators of poor
outcome with (chemo)RT
• Poor bladder function• Highly symptomatic bladders
•Extensive CIS
• Prior pelvic RT
• Inflammatory bowel disease
• Certain genetic disorders
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Can we select good responders?
• Select patients for radiotherapy on
basis of initial response to therapy
– Rationale for Boston Trimodality
Approach
• Biological markers
Presented by: Nick James
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Biopsy proven muscle invasive bladder cancer
Induction chemoradiotherapy 3 weeks
Cystectomy
Salvage cystectomy Adjuvant
chemotherapy in
selected cases
Maximal transurethral resection of tumor
Cystoscopy and biopsy week 7 Residual disease or
new T1+ T0 or non-invasive
disease only Consolidation chemoradiotherapy weeks 8-9
Cystoscopy and biopsy week 17 T1+ disease Ta or Tis disease
Intravesical therapy T0
Surveillance
Trimodality
therapy
Presented by: Nick James
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Results – Boston approach
348 patients
Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality
therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012;61:705-11
60 (17%)
Immediate
cystectomy42 (12%)
delayedcystectomy
246 (71%)
retained
bladder
Presented by: Nick James
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MRE11 hypothesis
1. Low tumor expression of DNA DSBsignaling proteins would be associated with
better outcome following radical radiotherapy
in bladder cancer due to decreased DNArepair
2. Would not expect it to be related to
outcome following surgery, as not mediatedvia DNA damage mechanisms
Presented by: Nick James
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Choudhury A, Nelson LD, Teo MT, et al. MRE11 expression is predictive of cause-specific survival followingradical radiotherapy for muscle-invasive bladder cancer. Cancer Res 2010;70:7017-26
MRE11 hypothesis
Presented by: Nick James
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Conclusions
• No convincing evidence surgery superior toprimary bladder preservation with salvage surgery
• Neoadjuvant chemotherapy improves overall
survival
• Synchronous chemo-radiation is safe and
improves pelvic control and hence is
complementary to neoadjuvant treatment
• Markers are emerging which now needprospective evaluation
P t d b Ni k J
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