ASCO Bladder Cancer Talk Jun 2013 v2

7/16/2019 ASCO Bladder Cancer Talk Jun 2013 v2

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A Multidisciplinary Approach in Muscle-

Invasive Disease - Novel ChemotherapyCombinations 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 evidencesupporting chemoradiation as a bladder-

sparing approach and how to incorporate

molecular biomarkers and therapies




Overview

• Evidence base for bladder preservation asalternative to surgery

• Chemoradiotherapy compared to

radiotherapy alone• Biomarker data




Background

• Bladder cancer outcomes have notsignificantly 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

1880 1900 1920 1940 1960 1980 2000 2020

Radical

mastectomy

- Halstead

Adjuvant RT

Adjuvant

hormone

therapy

Adjuvant

chemotherap

y

Adjuvant

HER2

targeting

Adjuvantaromatase

inhibitors

Breast cancer




Mortality Rates From Breast

Cancer US and the UK




NEOADJUVANTCHEMOTHERAPY AND SURVIVAL

Presented by:



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


http://content.nejm.org/content/vol349/issue9/images/large/07f1.jpeg



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




IS SURVIVAL BETTER AFTERSURGERY?

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 andin 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

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



Choice of treatment

• Surgery and radiotherapy data relate todifferent 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 VSRADIOTHERAPY ALONE




Synchronous Chemo-

radiotherapy

• Numerous phase I/II studies showingfeasibility 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 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




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

R e l a p s

e - f r e e s u r v i v a l ( % )

Time from randomization (months)

RT + CON

RT alone

164 128 109 82 62 31

161 111 84 62 50 21

LogŠrankp = 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



BC2001: Trial design

Reduced high

dose volume RT

+ synchronouschemotherapy

Reduced high

dose volume RT†

Standard volume RT†

+ synchronouschemotherapy

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

Patients ineligible for one randomisation could participate in other




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




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

5 0

<60 60-69 70-79 80+

0

5 0

0 1 2




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

% o f

n o n - m i s s i n g

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

f n o n - m i s s i n g

4

3

2

1

0

Worst grade of on-treatment toxicity by week




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




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)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




rtrandgp1

rtrandgp2

rtrandgp3

rtdosestratum1

rtdosestratum2

NeoCT1

NeoCT2

Primary

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)




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




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

Induction chemoradiotherapy 3 weeks

Cystectomy

Salvage cystectomy Adjuvant

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+ disease Ta or Tis disease

Intravesical therapy T0

Surveillance

Trimodality

therapy




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




MRE11 hypothesis

1. Low tumor expression of DNA DSBsignaling proteins would be associated with

better outcome following radical radiotherapy

in bladder cancer due to decreased DNArepair

2. Would not expect it to be related to

outcome following surgery, as not mediatedvia DNA damage mechanisms




Choudhury A, 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




Conclusions

• No convincing evidence surgery superior toprimary 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 needprospective evaluation

P t d b Ni k J

ASCO Bladder Cancer Talk Jun 2013 v2

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