samo workshop - radio-chemotherapy for whom and when.ppt

8/14/2019 SAMO Workshop - radio-chemotherapy for whom and when.ppt

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Radio-chemotherapy: for whom andwhen?

Nick James

University of Birmingham

@Prof_Nick_James

#NJBladderCancer1


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Overview

Evidence base for bladder preservation

as alternative to surgery

Chemoradiotherapy compared toradiotherapy alone

Presented


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Background Bladder cancer outcomes have not

significantly improved for 30 years

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


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If you keep doing the same thing

you get the same resultsZehnder 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 lymphadenectomyover three decades. BJU Int 2013;112:E51-8


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IS SURVIVAL BETTER AFTERSURGERY?


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Survival is better after

surgery? Variations in the use of total cystectomy and

in the use of pelvic RT among the regions ofOntario 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 from UK Registry data

453 UK pts,

1993-1996

Ratio

RT:cystectomy

3:1

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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Bladder preservationUHB Data

Male:Female 110:45

Mean Age74yrs 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Zarkar, A, Mead S. Unpublished internal audit data


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Radiotherapy Survival

0 12 24 36 480

50

100

Survival (Mo)

Percentsu

rvival

Male

Female

Zarkar, A, Mead S. Unpublished internal audit data


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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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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


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Mortality Rates From Breast

Cancer US and the UK

Presented


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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

Presented
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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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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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 RTRT 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

0.5

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


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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

invasive

25

Muscle invasive18

Pelvic nodes6

Distantrecurrence or

second primary

40

Metastasis29

Second primary11


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RADIO-CHEMOTHERAPY:FOR WHOM AND WHEN?


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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 Highly symptomatic bladders

Extensive CIS

Prior pelvic RT

Inflammatory bowel disease

Certain genetic disorders


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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 iscomplementary to neoadjuvant treatment

samo workshop - radio-chemotherapy for whom and when.ppt

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