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Bladder preservation in muscle invasive disease

Nick James University of Birmingham @Prof_Nick_James #NJBladderCancer


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Overview
Evidence base for bladder preservation as alternative to surgery Chemoradiotherapy compared to radiotherapy alone Biomarker data

Presented

Background
Bladder cancer outcomes have not significantly improved for 30 years

Zehnder 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 lymphadenectomy over three decades. BJU Int 2013;112:E51-8

Presented by: Nick James

Age standardised 5 year survival rates in UK

Prepared by Cancer Research UK - http://info.cancerresearchuk.org/cancerstats/

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 RT

Breast cancer
Radical mastectomy Halstead

Adjuvant HER2 Adjuvant targeting chemotherapy


Adjuvant aromatase inhibitors

Adjuvant hormone therapy

1880

1900

1920

1940

1960

1980

2000

2020

Mortality Rates From Breast Cancer US and the UK

NEOADJUVANT CHEMOTHERAPY AND SURVIVAL

Neoadjuvant chemotherapy
US Intergroup Trial BA06 EORTC 30894

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?

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.

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

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 restricted to operable muscle-invasive disease, 5-YS: radical cystectomy 47% Conservative therapy 45%
Rdel C, et al: J Clin Oncol 20: 3061-3071, 2002 Stein JP et al JCO Feb 1 2001: 666-675

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

Patients unsuitable for surgery


Elderly Severe cardiovascular or chest problems Obese Diabetes Patients reluctant or unable to cope with stoma etc

Patients unsuitable for (chemo)RT


Poor bladder function Highly symptomatic bladders Extensive CIS Prior pelvic RT Inflammatory bowel disease Certain genetic disorders

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

Reduced high dose volume RT + synchronous chemotherapy Reduced high dose volume RT
RHDV RT

No CT

Standard volume RT
sRT

Pragmatic design: Centres could offer double or either single randomisation

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

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


N
rtrandgp1 rtrandgp1 63 Randomised sRT
rtrandgp2 58 rtrandgp2 Randomised RHDV

P-value 0.63

Hazard ratio (95% CI)

0.77 (0.33, 1.75) 0.77 (0.33,

0.97 (0.35, 0.97 (0.35, 2.69)

Elect sRTrtrandgp3 rtrandgp3 239


rtdosestratum1 rtdosestratum1 RT dose 55Gy/20F 140

0.59 (0.38, 0.59 (0.38, 0.92)

0.73

0.72 (0.39, 0.72 (0.39, 1.32)

RT dose 64Gy/32F 212 rtdosestratum2 rtdosestratum2


NeoCT1 118 NeoCT1 Neoadjuvant CT NeoCT2 NeoCT2 No neoadjuvant CT 242

0.63 (0.40, 0.63 (0.40, 0.98)

0.60

0.58 (0.31, 0.58 (0.31, 1.09)

0.72 (0.46, 0.72 (0.46, 1.11)

PrimaryPrimary Primary analysis

360

0.66 (0.46, 0.66 (0.46, 0.94)

.2

.2 .5 1 .5 CT FavoursFavours CT

1 2 2 FavoursFavours 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

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

MRE11 hypothesis
1. Low tumor expression of DNA strand break 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