Bladder preservation in muscle

invasive disease
Nick James
University of Warwick and
University Hospitals Birmingham

@Prof_Nick_James
#NJBladderCancer

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)

BC2001: Trial design

Patients with muscle invasive
bladder cancer
RANDOMISE

CT

No
CT

Standard volume RT
+ synchronous chemotherapy

Reduced high
dose volume RT
+ synchronous chemotherapy

Standard volume RT

Reduced high
dose volume RT

sRT

RHDV RT

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

0
7

Target volume tumour + bladder + 1.5-2cm

Chemotherapy via peripherally inserted central
line as outpatient therapy

Patient demographics
Performance status

Male = 289/360 (80%)

50

50

100

100

150

150

200

200

250

Age at randomisation

<60

60-69

70-79

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%

% of non-missing

80%
70%

60%

50%

40%

30%

20%
10%
0%
1

CT

No CT

RTOG 6 month toxicity outcomes

80
70
60
50
C h em o R T
R T o n ly

40
30
20
10
0
G ra d e 0

G ra d e 1

G ra d e 2

G ra d e 3

G ra d e 4

U n kn ow n

n= 291, 145 RT only, 146 chemo-radiotherapy

12

N at risk (events)
Chemo-RT 182 (35) 108 (14)
RT 178 (54) 96 (16)

24
36
48
Months since randomization
76
69

(3)
(4)

66
58

(1)
(1)

56
44

60
(1)
(0)

46
35

72
(1)
(1)

25
18

1.00
0.75
0.50
0.25

Stratified logrank p= 0.03

HR (95% CI) = 0.57 (0.37-0.90)

Stratified logrank p= 0.01

0.00

Proportion invasive locoregional disease-free

0.75
0.50
0.25

HR (95% CI) = 0.68 (0.48-0.96)

0.00

Proportion locoregional disease-free

1.00

Loco-regional disease free survival in

chemotherapy randomisation

12

N at risk (events)
Chemo-RT 182 (20) 121 (7)
RT 178 (37) 109 (11)

24
36
48
Months since randomization
93
85

(3)
(2)

79
74

(0)
(2)

66
52

60
(0)
(0)

54
39

72
(1)
(0)

32
20

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

EGFR
Overexpression correlates with poor
prognosis
Some evidence RT responses worse in
EGFR+ tumours
In vitro, EGFR targeting radio-sensitises

Cetuximab
IgG1 Mab targeting the EGFR
Proven role as radiosensistiser in head and
neck cancer
Targets immune cells to the tumour
Possible anti-angiogenic role

TUXEDO
Multi-stage trial
Phase I: can we combine Cetximab with
chemo-RT?
Phase IIa single arm: expanded safety and
efficacy with phase I regimen
Phase IIb: randomise ChemoRT vs. CRT+
Cetuximab

TUXEDO
Multi-stage trial
Phase I: can we combine Cetximab with
chemo-RT?
Phase IIa single arm: expanded safety and
efficacy with phase I regimen
Phase IIb: randomise ChemoRT vs. CRT+
Cetuximab

Phase I regimen

Phase 1 patients
No. of patients 7
Sex 7 male, 0 female
Median age 70 yrs (range 60-75)
Tumour stage T2a: 2; T2b: 2; T3b: 3
Reduced dosage 1 pt had reduced dosage of cetuximab (missed wks 3 and 4 of
treatment due to skin toxicity)
Withdrawals 1 pt withdrew from RT due to relocation
Dose intensity:
Cetuximab 99%
Mitomycin C 98.3%
5-FU 100%

Phase 1 toxicity

TUXEDO summary

7/7 phase 1 pts had CR at 3m

Delivery of core chemoRT excellent
Delivery of cetuximab near 100%
Protocol amended to make neoAd chemo
optional
DMC approved progression to phase IIa
Open to new centres