1. ACT II: The Second UK Phase III Anal Cancer Trial
A randomised trial of chemoradiation using mitomycin of cisplatin, with or without maintenance cisplatin/5-FU in squamous cell carcinoma of the anus.
Professor Roger James
on behalf of the NCRI ACT II Trial Management Group and Investigators
ASCO, Florida, May Abstract ID: LBA 4009 (30894)
Cancer Research UK grant number: C444/A628 ISRCTN number:
Sponsor
Funder

2. Background Standard treatment - RT + 5-FU + MMC Research questions
UKCCCR ACT 1
EORTC 22861
RTOG 87-04/ECOG 1289
Research questions
1. Concurrent chemoradiotherapy
Different chemotherapy – RTOG / ACT II /EORTC
Increase RT dose – ACCORD 3
2. Additional therapy
Neoadjuvant chemotherapy – RTOG & ACCORD 3
Maintenance chemotherapy – ACT II
Do think you need to set the scene first

3. Objectives To evaluate in a factorial design
Whether chemoradiation using Cisplatin or Mitomycin produces a higher complete response rate
Whether maintenance therapy will improve local control or prolong survival 3

4. Factorial Design 1. Chemoradiation Comparison
MMC 5FU CRT No maintenance
CisP 5FU CRT No maintenance
MMC
versus
CisP
MMC 5FU CRT Maintenance
CisP 5FU CRT Maintenance
N=471
N=469

5. Factorial Design 2. Maintenance Comparison
No maintenance
N=446
MMC 5FU CRT No maintenance
CisP 5FU CRT No maintenance
versus
Maintenance
N=448
MMC 5FU CRT Maintenance
CisP 5FU CRT Maintenance

6. Statistical Methods Sample Size Analysis
Target sample size ~950 patients
CRT Comparison
5% increase of CR rate from 90% to 95% - CisP arm
Maintenance Comparison
decrease of recurrence from 25% to 17.5% - maintenance arm
Each with 80% power, p<0.05
Analysis
905/940 patients evaluable
Median follow-up 3 yrs
Intention to Treat 6

7. Primary Endpoints Chemoradiation (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 7

8. Entry Criteria Histologically confirmed No evidence of metastases
Fit for all possible treatments and consent
Minimum GFR > 50 ml/min
GFR <60 confirmed by EDTA clearance /other isotopic method
Normal blood counts, LTF’s
Adequate Cardiac function
No contraindications to treatment
Known HIV positive patients not eligible 8

9. Radiotherapy 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

10. Chemoradiation Treatment1 2 3 4 5 6
RT week
1000mg/m2 d1-4 & 29-32
24 hour continuous iv infusion
5FU
12mg/m2 d1 only
iv bolus, max single dose 20 mg
MMC 1 2 3 4 5 6
RT week
1000mg/m2 d1-4 & 29-32
24 hour continuous iv infusion
5FU
60mg/m2 d1 & 29
iv infusion
CisP 10

11. Maintenance Treatment
Starts 4 wks after end of primary CRT 1 2 3 4
Week
1000mg/m2 d1-4 & 29-32
24 hour continuous iv infusion
5FU
60mg/m2 d1 & 29
iv infusion
CisP 11

12. Accrual 940 patients Jun 2000 – Dec 2008 59 sites
Multi centre & National collaboration
We do need this slide in – only one with no of pts entered and duration of accrual 12

13. Patient Demographics - 1
* Stratification factor
MMC
No maint
n=246
CisP
Maint
n=226
n=222
*Gender
Male
Female
38%
62%
37%
63%
*Age
<65
65
75%
25%
73%
27%
74%
26%
*GFR
<60
60 4%
96%
Pre Rx-colostomy No
Yes
N/K
81% 7%
12%
76%
11%
13%
71%
14%
15%
80% 9%
Pre treatment colos not stratification factor
could delete row and add info to colos at 3 yrs slide - 10% of pts had pre treatment colostomies

14. Patient Demographics - 2
* Stratification factor
MMC
No maint
n=246
CisP
Maint
n=226
n=222
*Site Canal
Margin
N/K
80%
16% 4%
81%
15%
83%
14%
* T1 T2 T3 T4
11%
41%
29%
13% 6%
10%
39%
31% 7%
30% *
Node +ve
Node -ve
63% 8%
61% 9%

15. Results: Grade 3 & 4 Acute Toxicity During Chemoradiation
100%
P=0.17
80%
60%
P<0.001
MMC
CisP
40%
1 cardiac 5-FU death
1 neutropaenic sepsis – not picked up and acted on in time – subject of internal enquiry – cross sites
20%
24.7%
13.4%
60.2%
64.6%
Haematological
Non-haematological
2 treatment related deaths

16. Results: Grade 3 & 4 Acute Toxicity During Maintenance by Prior Chemoradiation
100%
80%
60%
Prior MMC
P=0.38
Prior CisP
40%
P=0.81
11.7%
9.1%
3.3%
2.9%
20% 0%
Haematological
Non Haematological

17. CRT Comparison Complete Response at 6 months
100%
94.5%
95.4%
80%
MMC
CisP
60%
40%
20%
MMC
CisP

18. CRT Comparison Colostomy rate at 3 years
100 80 60
P=0.26 40 20
13.7%
11.3%
MMC
CisP
Includes colostomies for toxicity and pre treatment colostomies not reversed

19. Results: Maintenance Comparison Recurrence Free Survival
Event is progression, recurrence or death
100
HR: 0.94, 95% CI: 0.72 to 1.24, P=0.67
75% 80
75% 60
Recurrence-free survival (%) 40
No Maint events 20
Maint events 1 2 3 4 5 6 7 8
Time from randomisation (years)
No. at risk
No Maint
472
346
263
183
116 67 19 4
Maint
468
345
251
183
132 61 16 1

20. Results: Sites of First Recurrence
MMC
n=472
CisP
n=468 No
Maint
n=446
Maint
n=448
Local only
21 (4%)
28 (6%)
24 (5%)
23 (5%)
Loco-regional
18 (4%)
25 (5%)
24 (5%)
19 (4%)
Loco-regional & distant
11 (3%)
8 (2%)
7 (2%)
11 (3%)
Any loco-regional
50 (11%)
61 (13%)
55 (12%)
53 (12%)
Extra-pelvic only
21 (4%)
10 (2%)
16 (4%)
14 (3%)
Missing
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
Total recurrences 72 72 72 68

21. Results : Maintenance Comparison Overall Survival
100
85%
HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21 80
84% 60
Overall survival (%) 40
No Maint events 20
Maint events 1 2 3 4 5 6 7 8
No. at risk
Time from randomisation (years)
No Maint
446
369
278
198
125 67 19 4
Maint
448
361
278
203
138 71 22 3

22. Results: Maintenance Comparison Causes of death
No Maint
n=446
Maint
n=448
Anal cancer 52 44
All treatment-related* 3 2
New cancer 5
Other 11 8
Unknown
Total 74 60
* Chemoradiation: 3, 2 Chemotherapy, 1 Radiotherapy. Salvage surgery: 2

23. Results: Maintenance Comparison Cause Specific Survival
100
HR: 0.84, 95% CI: 0.57 to 1.26, P=0.41 80 60
Cause Specific Survival (%) 40
No Maint events 20
Maint events 1 2 3 4 5 6 7 8
No. at risk
Time from randomisation (years)
No Maint
446
369
278
198
125 67 19 4
Maint
448
361
278
203
138 71 22 3

24. NCRI ACT II Trial – Conclusions
CRT comparison
No evidence for superior CR rate with cisplatin
Increased haematological toxicity in MMC pts
No statistically significant difference in colostomy rate
Maintenance comparison
Preliminary data - follow-up ongoing
No statistically significant difference in RFS, OS or cause specific survival
Compared with other trials
ACT I
Comparable patients
Better disease control and survival – less toxicity
Lower RT dose, No gap, no second MMC & lower CisP dose
RTOG 98-11
Comparable patients but no T1’s
Less grade 3/4 toxicity
Disease control and survival using CisP better 24

25. NCRI ACT II Trial – Conclusions
Overall
Largest ever trial in anal cancer
Changed UK standard of care
Comparable (or better) results to others
Dose Gy, no gap
Single dose of MMC
low frequency of grade 3/4 haematological and non-haematological toxicity
Would leave this in have deleted sentence comparing with ACT 1
Info for comparison with other trials
ACT I
Comparable patients
Better disease control and survival – less toxicity
Lower RT dose, No gap, no second MMC & lower CisP dose
RTOG 98-11
Comparable patients but no T1’s
Less grade 3/4 toxicity
Disease control and survival using CisP better 25

26. Acknowledgements To all patients participating in the trial
To all site staff at the 59 UK sites
To coordinating centre staff at the Cancer Research UK & UCL Cancer Trials Centre
To members of the
Data Monitoring Committee
Trial Steering Committee
Again leave in for acknowledgements 26