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8/14/2019 SAMO Workshop - radio-chemotherapy for whom and when.ppt
1/30
Radio-chemotherapy: for whom andwhen?
Nick James
University of Birmingham
@Prof_Nick_James
#NJBladderCancer1
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Overview
Evidence base for bladder preservation
as alternative to surgery
Chemoradiotherapy compared toradiotherapy alone
Presented
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Background Bladder cancer outcomes have not
significantly improved for 30 years
Prepared by Cancer Research UK- http://info.cancerresearchuk.org/cancerstats/
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If you keep doing the same thing
you get the same resultsZehnder P, Studer UE, Skinner EC, Thalmann
GN, Miranda G, Roth B, Cai J, Birkhauser
FD, Mitra AP, Burkhard FC, Dorin RP,Daneshmand S, Skinner DG, Gill IS.
Unaltered oncological outcomes of radical
cystectomy with extended lymphadenectomyover three decades. BJU Int 2013;112:E51-8
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IS SURVIVAL BETTER AFTERSURGERY?
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Survival is better after
surgery? Variations in the use of total cystectomy and
in the use of pelvic RT among the regions ofOntario 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 from UK Registry data
453 UK pts,
1993-1996
Ratio
RT:cystectomy
3:1
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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Bladder preservationUHB Data
Male:Female 110:45
Mean Age74yrs male, 77.6 yrs female
38% > 80 years Mean Age for Cystectomy
64.1 years (UHB)
65.1 years (National)
Nationally 6% > 80 years
Rad to Cyst ratio 1.4:1
Zarkar, A, Mead S. Unpublished internal audit data
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Radiotherapy Survival
0 12 24 36 480
50
100
Survival (Mo)
Percentsu
rvival
Male
Female
Zarkar, A, Mead S. Unpublished internal audit data
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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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Bladder cancer is a systemic
disease No plateau in
survival curves
Local control
Surgery or RT
Metastases
Systemic
therapy
Data on 14,693 Cystectomies UK 2001-2012
Prashant Patel, unpublished data
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Mortality Rates From Breast
Cancer US and the UK
Presented
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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
Presented
http://content.nejm.org/content/vol349/issue9/images/large/07f1.jpeg8/14/2019 SAMO Workshop - radio-chemotherapy for whom and when.ppt
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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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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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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
%
of
non-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 RTRT 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
0.5
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
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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
invasive
25
Muscle invasive18
Pelvic nodes6
Distantrecurrence or
second primary
40
Metastasis29
Second primary11
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RADIO-CHEMOTHERAPY:FOR WHOM AND WHEN?
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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 Highly symptomatic bladders
Extensive CIS
Prior pelvic RT
Inflammatory bowel disease
Certain genetic disorders
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Conclusions
No convincing evidence surgery superior to
primary bladder preservation with salvage
surgery
Neoadjuvant chemotherapy improves overall
survival
Synchronous chemo-radiation is safe and
improves pelvic control and hence iscomplementary to neoadjuvant treatment