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7/27/2019 Bladder Cancer Talk RSM Winter Meeting Jan2014
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Bladder preservation in muscleinvasive disease
Nick James
University of Warwick
@Prof_Nick_James
#NJBladderCancer1
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Overview
Evidence base for bladder preservation
as alternative to surgery
Chemoradiotherapy compared toradiotherapy alone
Biomarker data
Presented
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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
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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
chemotherapy
Adjuvant
HER2
targeting
Adjuvantaromatase
inhibitors
Breast cancer
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Mortality Rates From Breast
Cancer US and the UK
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NEOADJUVANTCHEMOTHERAPY AND
SURVIVAL
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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
US Intergroup Trial BA06 EORTC 30894
http://content.nejm.org/content/vol349/issue9/images/large/07f1.jpeg7/27/2019 Bladder Cancer Talk RSM Winter Meeting Jan2014
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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
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IS SURVIVAL BETTER AFTERSURGERY?
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Survival from UK Registry data
453 UK pts,
1993-1996
Ratio
RT:cystectomy3:1
10 year survival
RT 22% Surgery24%
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.
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Canadian Registry Data
Bladder Cancer Variations in the use of total cystectomy and
in 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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Survival surgery vs
radiotherapy Stein et al: 1054 cystectomy patients 5- and 10-YS 60%
and 43%
Rdel et al: 415 RT patients 5- and 10-YS 51% and 31%
However, cystectomy series:
included 213 T0, Ta, Tis patients
excluded 112 inoperable patients
If comparison is restrictedto operable muscle-invasivedisease, 5-YS:
radical cystectomy 47%
Conservative therapy 45%
Rdel C, et al: J Clin Oncol 20: 3061-3071, 2002
Stein JP et al JCOFeb 1 2001: 666-675
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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 to
different segments of the population
Neoadjuvant therapy data also mainlyrelate to younger patients
Hence age/fitness is important factor in
treatment decisions
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OUTCOMES AFTER
NEOADJUVANTCHEMOTHERAPY AT
HEARTLANDS HOSPITAL
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Study aims
To examine the survival outcome in patientswith muscle-invasive bladder cancer
Retrospective data collection
To compare radical cystectomy with radicalradiotherapy in this group following neo-adjuvant platinum-based combination
chemotherapy Study based on Heart of England Trust
patients (BHH and GHH)
S Meade and A Zarkar, unpublished data
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Study Design
Patients included: Received neo-adjuvant platinum-gemcitabine chemotherapy
(3 cycles) Patients diagnosed between September 2004-2011
Data collection: Histology Chemotherapy regimen Method of definitive local treatment (cystectomy/RRT)
Analysis: OS calculated from time of diagnosis to date of last followup or death
S Meade and A Zarkar, unpublished data
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ResultsCystectomy patients Radiotherapy patients
Number of pts 42 27
Mean age (yrs) 64.5 (48-79) 69.5 (60-82)
Males (%) 79 74
Mean follow up (months)
To death/Feb 2013
40 (6-91) 47.4 (6-101)
Median survival (months) 47 50
% alive at 3 years 43 63
% alive at 4 years 35 52
S Meade and A Zarkar, unpublished data
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Overall survival
Radiotherapy
Cystectomy
S Meade and A Zarkar, unpublished data
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Patients unsuitable for surgery
Elderly
Severe cardiovascular or chest
problems
Obese
Diabetes
Patients reluctant or unable to cope with
stoma
etc
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Patients unsuitable for
(chemo)RT Poor bladder function
Highly symptomatic bladders
Extensive CIS
Prior pelvic RT
Inflammatory bowel disease
Certain genetic disorders
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CHEMORADIATION VSRADIOTHERAPY ALONE
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Synchronous Chemo-
radiotherapy Numerous phase I/II studies showing
feasibility and safety
Three phase III studies RT vs RT + Cisplatinum (NCIC)
RT vs RT + nicotinamide/carbogen
(BCON) RT vs RT + 5FU/MMC (BC2001)
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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
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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
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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
Relapse-freesurvival(%)
Time from randomization (months)
RT + CON
RT alone
164 128 109 82 62 31
161 111 84 62 50 21
Logrankp= 0.06
HR 0.86 (0.74-1.0) p=0.06 at 3 years
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
+ synchronous chemotherapy
Reduced high
dose volume RT
Standard volume RT
+ synchronous chemotherapy
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
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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
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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
50
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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
fnon-missing
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
fnon-missing
4
3
2
1
0
Worst grade of on-treatment toxicity by week
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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
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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
.50
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
.50
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
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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)
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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
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MARKERS FOR OUTCOME
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Can we select good responders?
Select patients for radiotherapy on
basis of initial response to therapy
Rationale for Boston TrimodalityApproach
Biological markers
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Biopsy proven muscle invasive bladder cancer
Induction chemoradiotherapy 3 weeks
Cystectomy
Salvage cystectomyAdjuvant
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+ diseaseTa or Tis disease
Intravesical therapy
T0
Surveillance
Trimodality
therapy
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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
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MRE11 hypothesis
1. Low tumor expression of DNA strand
break signaling proteins would be
associated with better outcome followingradical radiotherapy in bladder cancer due
to decreased DNA repair
2. Would not expect it to be related tooutcome following surgery, as not
mediated via DNA damage mechanisms
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ChoudhuryA, 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
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Conclusions
No convincing evidence surgery superior to
primary bladder preservation with salvage
surgery
Neoadjuvant chemotherapy improves overallsurvival
Synchronous chemo-radiation is safe and
improves pelvic control and hence iscomplementary to neoadjuvant treatment
Markers are emerging which now need
prospective evaluation