ASCO Bladder Cancer Talk Jun 2013 v2

A Multidisciplinary Approach in MuscleInvasive Disease - Novel Chemotherapy Combinations and Targets in Chemoradiation
Nick James University of Birmingham
Conflicts of interest
Honoraria from Pierre Fabre
Presented by: Nick James
Learning objectives
To describe the past and current evidence supporting chemoradiation as a bladdersparing approach and how to incorporate molecular biomarkers and therapies
Overview
Evidence base for bladder preservation as alternative to surgery Chemoradiotherapy compared to radiotherapy alone Biomarker data
Background
Bladder cancer outcomes have not significantly improved for 30 years
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
Breast cancer therapy timelines

Adjuvant HER2 Adjuvant targeting chemotherap
y Radical mastectomy - Halstead Adjuvant hormone therapy Adjuvant aromatase inhibitors
Adjuvant RT
Breast cancer
1880
1900
1920
1940
1960
1980
2000
2020
Mortality Rates From Breast Cancer US and the UK
NEOADJUVANT CHEMOTHERAPY AND SURVIVAL

Presented by:
Neoadjuvant chemotherapy
Surgery +/- MVAC chemotherapy
Surgery or RT +/- CMV 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.
MRC/EORTC Trial - Loco-regional and metastatic control
Locoregional control
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.
IS SURVIVAL BETTER AFTER SURGERY?

Presented by:
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.
Survival is better after surgery?

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
Age at diagnosis
1600
Median age in BC2001 and BCON Median age in USC series
1400
1200
1000
800
Median age in
Male cases Female cases
BA06 & SWOG 8710

600 400
200
0 0-4 5-9 1014 1519 2024 2529 3034 3539 4044 4549 5054 5559 6064 6569 7074 7579 8084 85+
Choice of treatment
Surgery and radiotherapy data relate to different segments of the population Neoadjuvant therapy data also mainly relate to younger patients Hence age/fitness is important factor in treatment decisions
Presented by:
CHEMORADIATION VS RADIOTHERAPY ALONE

Synchronous Chemoradiotherapy
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)
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
BCON: Aim and endpoints

To determine if the hypoxia-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
BCON Results
100
Carbogen + Nicotinamide
Relapse-free survival (%)
80
HR 0.86 (0.74-1.0) p=0.06 at 3 years
HR 0.85 (0.73-0.99) p=0.04
60
Control arm
40
Log rank p = 0.06 RT + CON 164 RT alone 161 111 84 62 50 21 128 109 82 62 31
20
0 0 12 24 36 48 Time from randomization (months) 60
Relapse free survival
Overall survival
Hoskin PJ, Rojas AM, Bentzen SM, et al: Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol 28:4912-8, 2010
BC2001: Trial design

Patients with muscle invasive bladder cancer
RANDOMISE
CT
Standard volume RT + synchronous chemotherapy Standard volume RT sRT
Reduced high dose volume RT + synchronous chemotherapy Reduced high dose volume RT RHDV RT
No CT
Pragmatic design: Centres could offer double or either single randomisation Patients ineligible for one randomisation could participate in other
Chemotherapy regimen
MMC 12mg/m2 5FU 500mg/m2/d RT 55 Gy/20 f or 64 Gy/32 f Weeks
Target volume tumour + bladder + 1.5-2cm Chemotherapy via peripherally inserted central line as outpatient therapy
Patient demographics
Performance status
250 200
Age at randomisation
150 200
150
100
50
50
100
<60
60-69
70-79
80+
Male = 289/360 (80%)
Mean (SD) 70.5 (8.2) years Median (IQR) 71.9 (64.1 - 76.2) years Older than patients in previously published trials including SWOG 87101(median 63 y) and BA062 (median 64 y)
1. Grossman et al NEJM 2003 Volume 349:859-866 2. Lancet 1999; 354: 533-40
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 Worst grade of on-treatment toxicity by week
RT 55Gy/20F
100% 90% 80%
% of non-missing
RT 64Gy/32F
100% 90% 80%
70% 60% 50% 40% 30% 20% 10% 0% 1 2 3 4 1 2 3 4
4 3 2 1 0
% of non-missing
70% 60% 50% 40% 30% 20% 10% 0% 1 2 3 4 5 6 7 1 2 3 4 5 6 7
4 3 2 1 0
CT
No CT
CT
No CT
RTOG 6 month toxicity outcomes

80 70 60 50 40 30 20 10 0 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Unknown Chemo RT RT only
n= 291, 145 RT only, 146 chemo-radiotherapy
Loco-regional disease free survival in chemotherapy randomisation

1.00
Proportion invasive locoregional disease-free
Proportion locoregional disease-free
0.75
0.50
0.25
Stratified logrank p= 0.03
0.25
HR (95% CI) = 0.68 (0.48-0.96)
0.50
0.75
1.00
HR (95% CI) = 0.57 (0.37-0.90) Stratified logrank p= 0.01
0.00
12
24 36 48 Months since randomization 76 69 (3) (4) 66 58 (1) (1) 56 44 (1) (0)
60 46 35 (1) (1)
72 25 18
0.00
0
12
24 36 48 Months since randomization 93 85 (3) (2) 79 74 (0) (2) 66 52 (0) (0)
60 54 39 (1) (0)
72 32 20
N at risk (events) Chemo-RT 182 (35) 108 (14) RT 178 (54) 96 (16)
N at risk (events) Chemo-RT 182 (20) 121 (7) RT 178 (37) 109 (11)
Loco-regional control Invasive loco-regional control (invasive and non-invasive) James et al, Radiotherapy with or without chemotherapy for invasive bladder cancer. NEJM 2012 366, 1477-1488
Study Study Study
LRDFS - consistency across subgroups ID HR (95% CI) ID ID HR (95% CI) HR (95% C

N
rtrandgp1 rtrandgp1 rtrandgp1 Randomised sRT 63
rtrandgp2 rtrandgp2 rtrandgp2 Randomised RHDV 58
P-value
Hazard ratio (95% CI)
0.63
0.77 (0.33, 1.75) 0.77 (0.33, 1.75) 0.77 (0.33,
0.97 (0.35, 2.69) 0.97 (0.35, 0.97 (0.35, 2.69)
Elect sRTrtrandgp3 rtrandgp3 rtrandgp3 239

rtdosestratum1 rtdosestratum1 RT rtdosestratum1 dose 55Gy/20F 140
0.59 (0.38, 0.92) 0.59 (0.38, 0.59 (0.38, 0.92)
0.73
0.72 (0.39, 1.32) 0.72 (0.39, 0.72 (0.39, 1.32)
RT rtdosestratum2 dose 64Gy/32F 212 rtdosestratum2 rtdosestratum2

NeoCT1 NeoCT1 118 NeoCT1 Neoadjuvant CT NeoCT2 NeoCT2 NoNeoCT2 neoadjuvant CT 242 Primary PrimaryPrimary Primary analysis
0.63 (0.40, 0.98) 0.63 (0.40, 0.63 (0.40, 0.98)
0.60
0.58 (0.31, 1.09) 0.58 (0.31, 0.58 (0.31, 1.09)
0.72 (0.46, 1.11) 0.72 (0.46, 0.72 (0.46, 1.11)
360
0.66 (0.46, 0.94) 0.66 (0.46, 0.66 (0.46, 0.94)
.2
.5.2 1 2 2 .2 .5 1 .5 1 2 FavoursFavours CT Favours Favours CT no CT Favours CT Favours no CT no CT
Patterns of recurrence after chemoRT
Any recurrence 93/182 pts
Loco-regional recurrence 53
Distant recurrence or second primary 40
Non-muscle invasive 25
Muscle invasive 18
Pelvic nodes 6
Metastasis 29
Second primary 11
MARKERS FOR OUTCOME
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
Can we select good responders?

Select patients for radiotherapy on basis of initial response to therapy
Rationale for Boston Trimodality Approach
Biological markers
Biopsy proven muscle invasive bladder cancer
Trimodality therapy
Maximal transurethral resection of tumor Induction chemoradiotherapy 3 weeks Cystoscopy and biopsy week 7 T0 or non-invasive disease only Residual disease or new T1+ Cystectomy
Consolidation chemoradiotherapy weeks 8-9 Cystoscopy and biopsy week 17 T0 Ta or Tis disease Intravesical therapy Surveillance
T1+ disease Salvage cystectomy
Adjuvant chemotherapy in selected cases
Results Boston approach

348 patients
60 (17%) Immediate cystectomy
42 (12%) delayed cystectomy
246 (71%) retained bladder
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 Presented by: Nick James
MRE11 hypothesis
1. Low tumor expression of DNA DSB signaling proteins would be associated with better outcome following radical radiotherapy in bladder cancer due to decreased DNA repair 2. Would not expect it to be related to outcome following surgery, as not mediated via DNA damage mechanisms
MRE11 hypothesis
Choudhury A, Nelson LD, Teo MT, et al. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res 2010;70:7017-26
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 is complementary to neoadjuvant treatment Markers are emerging which now need prospective evaluation

ASCO Bladder Cancer Talk Jun 2013 v2

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A Multidisciplinary Approach in MuscleInvasive Disease - Novel Chemotherapy Combinations and Targets in Chemoradiation

Nick James University of Birmingham

Presented by: Nick James

Presented by: Nick James

Presented by: Nick James

Presented by: Nick James

Bladder cancer is a systemic disease

Breast cancer therapy timelines

Presented by: Nick James

Mortality Rates From Breast Cancer US and the UK

Presented by: Nick James

NEOADJUVANT CHEMOTHERAPY AND SURVIVAL

Surgery +/- MVAC chemotherapy

Surgery or RT +/- CMV chemotherapy

Presented by: Nick James

MRC/EORTC Trial - Loco-regional and metastatic control

IS SURVIVAL BETTER AFTER SURGERY?

Survival from UK Registry data

Presented by: Nick James

Survival is better after surgery?

Median age in BC2001 and BCON Median age in USC series

Male cases Female cases

BA06 & SWOG 8710

CHEMORADIATION VS RADIOTHERAPY ALONE

Presented by: Nick James

Cisplatinum and RT +/- surgery

BCON: Aim and endpoints

Relapse-free survival (%)

HR 0.86 (0.74-1.0) p=0.06 at 3 years

HR 0.85 (0.73-0.99) p=0.04

0 0 12 24 36 48 Time from randomization (months) 60

Relapse free survival

BC2001: Trial design

Standard volume RT + synchronous chemotherapy Standard volume RT sRT

MMC 12mg/m2 5FU 500mg/m2/d RT 55 Gy/20 f or 64 Gy/32 f Weeks

Male = 289/360 (80%)

Presented by: Nick James

70% 60% 50% 40% 30% 20% 10% 0% 1 2 3 4 1 2 3 4

70% 60% 50% 40% 30% 20% 10% 0% 1 2 3 4 5 6 7 1 2 3 4 5 6 7

Presented by: Nick James

RTOG 6 month toxicity outcomes

Presented by: Nick James

n= 291, 145 RT only, 146 chemo-radiotherapy

Loco-regional disease free survival in chemotherapy randomisation

Proportion invasive locoregional disease-free

Proportion locoregional disease-free

Stratified logrank p= 0.03

HR (95% CI) = 0.68 (0.48-0.96)

HR (95% CI) = 0.57 (0.37-0.90) Stratified logrank p= 0.01

24 36 48 Months since randomization 76 69 (3) (4) 66 58 (1) (1) 56 44 (1) (0)

24 36 48 Months since randomization 93 85 (3) (2) 79 74 (0) (2) 66 52 (0) (0)

Study Study Study

LRDFS - consistency across subgroups ID HR (95% CI) ID ID HR (95% CI) HR (95% C

Hazard ratio (95% CI)

0.77 (0.33, 1.75) 0.77 (0.33, 1.75) 0.77 (0.33,

0.97 (0.35, 2.69) 0.97 (0.35, 0.97 (0.35, 2.69)

Elect sRTrtrandgp3 rtrandgp3 rtrandgp3 239

0.59 (0.38, 0.92) 0.59 (0.38, 0.59 (0.38, 0.92)

0.72 (0.39, 1.32) 0.72 (0.39, 0.72 (0.39, 1.32)

RT rtdosestratum2 dose 64Gy/32F 212 rtdosestratum2 rtdosestratum2

0.63 (0.40, 0.98) 0.63 (0.40, 0.63 (0.40, 0.98)

0.58 (0.31, 1.09) 0.58 (0.31, 0.58 (0.31, 1.09)

0.72 (0.46, 1.11) 0.72 (0.46, 0.72 (0.46, 1.11)

0.66 (0.46, 0.94) 0.66 (0.46, 0.66 (0.46, 0.94)