nuf bladder cancer talk aug 2013 v3

7/27/2019 NUF Bladder Cancer Talk Aug 2013 v3

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Bladder preservation in muscleinvasive disease

Nick James

University of Birmingham

@Prof_Nick_James#NJBladderCancer

1


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Overview

Evidence base for bladder preservation

as alternative to surgery

Chemoradiotherapy compared toradiotherapy alone

Biomarker data

Presented


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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


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Age standardised 5 year survival rates in UK

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


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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


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Breast cancer therapy

timelines

1880 1900 1920 1940

1960 1980 2000 2020

Radical

mastectomy -

Halstead

Adjuvant RT

Adjuvant

hormone

therapy

Adjuvant

chemotherapy

Adjuvant

HER2

targeting

Adjuvantaromatase

inhibitors

Breast cancer


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Mortality Rates From Breast

Cancer US and the UK


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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

US Intergroup Trial BA06 EORTC 30894
http://content.nejm.org/content/vol349/issue9/images/large/07f1.jpeg


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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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IS SURVIVAL BETTER AFTERSURGERY?


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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.


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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


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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 restrictedto operable muscle-invasivedisease, 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


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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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Choice of treatment

Surgery and radiotherapy data relate to

different segments of the population

Neoadjuvant therapy data also mainlyrelate to younger patients

Hence age/fitness is important factor in

treatment decisions


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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 Poor bladder function

Highly symptomatic bladders

Extensive CIS

Prior pelvic RT

Inflammatory bowel disease

Certain genetic disorders


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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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BCON: Aim and endpoints

To determine if thehypoxia-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


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BCON Results

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-freesurvival(%)

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


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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 RT

RT 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

.50

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

.50

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

invasive25

Muscle invasive18

Pelvic nodes6

Distantrecurrence or

second primary

40

Metastasis29

Second primary11


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MARKERS FOR OUTCOME


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Can we select good responders?

Select patients for radiotherapy on

basis of initial response to therapy

Rationale for Boston TrimodalityApproach

Biological markers


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Biopsy proven muscle invasive bladder cancer

Induction chemoradiotherapy 3 weeks

Cystectomy

Salvage cystectomyAdjuvant

chemotherapy in

selected cases

Maximal transurethral resection of tumor

Cystoscopy and biopsy week 7

Residual disease or

new T1+

T0 or non-invasive

disease only

Consolidation chemoradiotherapy weeks 8-9

Cystoscopy and biopsy week 17

T1+ diseaseTa or Tis disease

Intravesical therapy

T0

Surveillance

Trimodality

therapy


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Results Boston approach

348 patients

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

60 (17%)

Immediate

cystectomy42 (12%)

delayedcystectomy

246 (71%)

retained

bladder


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MRE11 hypothesis

1. Low tumor expression of DNA strand

break signaling proteins would be

associated with better outcome followingradical radiotherapy in bladder cancer due

to decreased DNA repair

2. Would not expect it to be related tooutcome following surgery, as not

mediated via DNA damage mechanisms


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ChoudhuryA, Nelson LD, Teo MT, et al. MRE11 expression is predictive of cause-specific survival followingradical radiotherapy for muscle-invasive bladder cancer. Cancer Res 2010;70:7017-26

MRE11 hypothesis


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Conclusions

No convincing evidence surgery superior to

primary bladder preservation with salvage

surgery

Neoadjuvant chemotherapy improves overallsurvival

Synchronous chemo-radiation is safe and

improves pelvic control and hence iscomplementary to neoadjuvant treatment

Markers are emerging which now need

prospective evaluation

nuf bladder cancer talk aug 2013 v3

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