Radio-chemotherapy: for whom and when?

Nick James University of Birmingham

@Prof_Nick_James #NJBladderCancer

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

Presented

Background
Bladder cancer outcomes have not significantly improved for 30 years

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

If you keep doing the same thing you get the same results
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

IS SURVIVAL BETTER AFTER SURGERY?

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

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.

Bladder preservation UHB Data

Male:Female 110:45 Mean Age 74yrs 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Zarkar, A, Mead S. Unpublished internal audit data

Radiotherapy Survival
100

Percent survival

Male Female

50

12

24

36

48

Survival (Mo)

Zarkar, A, Mead S. Unpublished internal audit data

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+

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Data on 14,693 Cystectomies UK 2001-2012 Prashant Patel, unpublished data

Mortality Rates From Breast Cancer US and the UK

Presented

NEOADJUVANT CHEMOTHERAPY AND SURVIVAL

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.

Presented

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.

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

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

RADIO-CHEMOTHERAPY: FOR WHOM AND WHEN?

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

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

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