7/28/2019 Bladder Preservation for muscle invasive disease

1/22

Bladder preservation in muscleinvasive disease

Nick James

University of Birmingham

1

7/28/2019 Bladder Preservation for muscle invasive disease

2/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

3/22

Age standardised 5 year survival rates in UK

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

7/28/2019 Bladder Preservation for muscle invasive disease

4/22

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Prashant Patel, unpublished data

7/28/2019 Bladder Preservation for muscle invasive disease

5/22

Mortality Rates From Breast

Cancer US and the UK

7/28/2019 Bladder Preservation for muscle invasive disease

6/22

IS SURVIVAL BETTER AFTERSURGERY?

7/28/2019 Bladder Preservation for muscle invasive disease

7/22

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.

7/28/2019 Bladder Preservation for muscle invasive disease

8/22

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 in

BC2001 and BCON

Median age in

USC series

7/28/2019 Bladder Preservation for muscle invasive disease

9/22

Choice of treatment

Surgery and radiotherapy data relate to

different segments of the population

Hence age/fitness is important factor intreatment decisions

7/28/2019 Bladder Preservation for muscle invasive disease

10/22

Patients unsuitable for surgery

Elderly

Severe cardiovascular or chest

problems

Obese

Diabetes

Patients reluctant or unable to cope with

stoma

7/28/2019 Bladder Preservation for muscle invasive disease

11/22

Patients unsuitable for

(chemo)RT Poor bladder function

Extensive CIS

Prior pelvic RT

Inflammatory bowel disease

7/28/2019 Bladder Preservation for muscle invasive disease

12/22

CHEMORADIATION VSRADIOTHERAPY ALONE

7/28/2019 Bladder Preservation for muscle invasive disease

13/22

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)

7/28/2019 Bladder Preservation for muscle invasive disease

14/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

15/22

BCON: RT vs RT + carbogen/nicotinamide

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-frees

urvival(%)

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

7/28/2019 Bladder Preservation for muscle invasive disease

16/22

BC2001

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

NoCT

sRT RHDV RT

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

7/28/2019 Bladder Preservation for muscle invasive disease

17/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

18/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

19/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

20/22

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)RT

182 121(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

7/28/2019 Bladder Preservation for muscle invasive disease

21/22

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

7/28/2019 Bladder Preservation for muscle invasive disease

22/22

Conclusions

No convincing evidence surgery superior to

primary bladder preservation with salvage

surgery

Synchronous chemo-radiation is safe and

improves pelvic control

Long term toxicity outcomes good

Suitable for older patients