Post on 18-Dec-2015
Aim to discuss
• The EORTC trials in anal cancer
• US and UK trials
• What we have learnt so far
• Where do we go from here?
Randomised trials • UKCCR ACT 1 CRT vs RT• EORTC 22861 CRT vs RT
• RTOG 8704/ECOG Role of MMC
• RTOG 98-11 Role of NACT/cisplat • ACCORD-03 Role of NACT cisplat/ RT dose • CRUK ACT 2 Role of cisplat vs MMC + maintenance 5FU/cisplat• EORTC Role of 5FU vs CDDP/MMC 22011-40014 not extended to phase III
UKCCCR Anal Cancer Trial (ACT 1)
CMT – 45Gy + Mitomycin C 5FU
RT alone 45Gy
Boost25Gy implant or15Gy in 6F
Boost25Gy implant or15Gy in 6F
6 weeks
6 weeks
ACT I :Time to first local relapse
75
50
25
0
Per
cent
age
of p
atie
nts
havi
ng a
loca
l rel
apse
(%
)
0 2 4 6 8 10 12 14 16 18 20Time since randomisation (years)
RT aloneCMTHR 0.46, p<0.001
Effect of CD34 - RFS
Follow-up (years)
543210
Pro
gre
ssio
n-f
ree
ra
te (
%)
100
80
60
40
20
0
Follow-up (years)
543210P
rog
ress
ion
-fre
e r
ate
(%
)
100
80
60
40
20
0
RT armP=0.002
CRT armP=0.86
Mawdsley et al. (2004 GI ASCO)
1
234
ACT II Factorial DesignChemoradiation Comparison
MMC 5FU CRT No
maintenance
CisP 5FU CRT No
maintenance MMC 5FU CRT
+Maintenance
CisP 5FU CRT
+Maintenance
MMCN=472
CisPN=468
versus
MMC 5FU CRT No maintenance
CisP 5FU CRT No maintenance
MMC 5FU CRT Maintenance
CisP 5FU CRT Maintenance
No MaintN=446
Maint N=448
versus
ACT II Factorial DesignMaintenance Comparison
Chemoradiation Regimens
1 2 3 4 5RT week
5FU
MMC
1 2 3 4 5RT week
5FU
CisP
1000mg/m2 d1-4 & 29-3224 hour continuous iv infusion
12mg/m2 d1 onlyiv bolus, max single dose 20 mg
60mg/m2 d1 & 29 iv infusion
1000mg/m2 d1-4 & 29-3224 hour continuous iv infusion
6
6
ACT II EndpointsChemoradiation (CRT) comparison
Primary Endpoints • Complete response rate at 6
months• Acute Toxicity (CTC Grade 3 & 4)
Maintenance comparison Primary Endpoint• Recurrence Free Survival
Both comparisons Secondary Endpoints• Colostomy Rate• Cause-specific & Overall survival
50.4 Gy in 28 fractions over 5 ½ weeks
(no gap)Phase I
30.6 Gy in 17 fractions
Parallel opposed
3cm below inf. tumour (or margin)
Anal bolus
Phase II GTV + 3cm
19.8Gy in 11 fractions
N0 groins
Planned volume (canal)
Direct field (margin only)
N+ groins all GTV +3cm
Anal bolus
Mean Doses Received• PTV primary 51.37Gy ± 0.84 (95% CI) • PTV inguinal nodes 51.41Gy ± 1.54
• Uninvolved inguinal 36.53Gy ± 3.38 • Uninvolved external iliac 34.28Gy + 5.63
• Femoral heads 47.32Gy ± 3.45
Aggarwal A, et al., Radiother Oncol. 2012 Jun;103(3):341-6
Tumour Stage
MMC(472)
CisP(468)
T stageT1 T2 49% (232) 54% (254)T3 T4 48% (225) 44% (205)TX 15 13
N StageNode negative 63% (297) 62% (290)Node positive 32% (150) 33% (155)NX 25 23
Response at 26 weeksPatients with response data
(863)
MMC(432/472)
CisP(431/468)
CR primary 90% 90%
CR N0 83% (358)
84% (362)
CR N+ 3% (15) 3% (12)
CR Nx 4% (18) 3% (12)
PR 3% (14) 6% (24)
SD 1% (5) 1% (6)
PD 5% (22) 3% (15)
P=0.66
ACT II Compliance & Toxicity
• Radiotherapy – 92% MMC vs 90% CisP - total dose 50.4Gy– ~3% >7 days interruptions
• Chemotherapy - weeks 1 & 5 – 75% MMC vs 72% CisP full dose weeks 1 & 5
• Acute toxicity – 58% MMC vs 60% CisP Grade 3 – 13% MMC vs 12% CisP Grade 4 – 71% MMC vs 72% CisP combined Grade 3/4
CR at 26 weeks
Difference (95% CI)
P value
MMC CisP83%
(358/432)84%
(362/431)+1% (-3.8 to 6.1) p =0.66
No Maint
Maint
82%(337/409)
85% (348/410)
+3% (-2.6 to 7.5)p = 0.34
ACT II – Conclusions
• Excellent CR rate at 6 months - 83% v 84% - no difference MMC/Cisp
• No difference in colostomy rate• No difference in PFS• 60% of pts not in CR at 11 weeks
achieved CR at 26 weeks.• We recommend assessment at 26
weeks in future trials
Maintenance Comparison- Recurrence Free Survival
Event is progression, recurrence or death
0
20
40
60
80
100
Re
curr
en
ce-f
ree
surv
iva
l (%
)
Maint 468 345 251 183 132 61 16 1472 346 263 183 116 67 19 4No Maint
No. at risk
0 1 2 3 4 5 6 7 8Time from randomisation (years)
No Maint - 103 events
Maint - 100 events
HR: 0.94, 95% CI: 0.72 to 1.24, P=0.67
75%
75%
0
20
40
60
80
100
Ove
rall
surv
ival
(%
)
448 361 278 203 138 71 22 3Maint446 369 278 198 125 67 19 4No Maint
No. at risk
0 1 2 3 4 5 6 7 8Time from randomisation (years)
HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21
84%
85%
No Maint - 74 events
Maint - 60 events
Maintenance Comparison - Overall Survival
HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21
ACT II – Conclusions 2Maintenance comparison• Preliminary data shown 2009• Median follow-up now 5 years• No evidence of any difference in
PFS, cause specific survival or overall survival
Site of relapse
Number % total relapses
PELVIC NO METS 133 64%
PELVIC WITH METS 30 14%
DISTANT METS ONLY 46 22%
TOTAL CRUDE PF (WITH OR WITHOUT METS)
163 78%
TOTAL RELAPSES 209
The pattern was similar for PF only and PF + mets (data not shown)
ACCORD- 03
• Locally advanced >4cm or N1 anal canal
• Therapeutic intensification – Induction chemotherapy– High dose radiotherapy
• Primary endpoint: colostomy-free-survival(CFS).
• Secondary endpoint : QoL, local control (LC), overall survival (OS), and cancer-specific survival.
ACCORD 03
low boost15 Gy
45 GyCDDP 5 FU 2 cycles
CTCDDP 5FU 2 cycles
high boost20-25 Gy
45 GyCDDP 5 FU 2 cycles
CTCDDP 5FU 2 cycles
low boost15 Gy
45 GyCDDP 5 FU 2 cycles
No CT
high boost20-25 Gy
45 GyCDDP 5 FU 2 cycles
No CT
R
70% 82% 77% 73%
5 years CFS
Thoughts• No longer feasible to think that one size fits
all in anal cancer
• We improved
overall 3 year DFS from 54% (ACT I)
to 74% (ACT II)
• We took 7 years to do ACT II
• We probably need international collaboration for next studies
Radiotherapy strategies which need exploring• (1) Optimization of radiotherapy (optimal
dose/fractionation/concomitant boost/brachytherapy)
• (2) Optimal field sizes
• (3) Evaluation of new radiosensitization protocols (oxaliplatin, irinotecan, taxanes).
• (4) Optimization of radiotherapy techniques (IMRT/VMAT/Brachytherapy)