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ACT II: The SecondUK Phase III Anal Cancer Trial
Professor Roger James on behalf of the NCRI ACT II Trial Management Group and Investigators
ASCO, Florida, May 2009. Abstract ID: LBA 4009 (30894)Cancer Research UK grant number: C444/A628
ISRCTN number: 26715889
SponsorFunder
A randomised trial of chemoradiation using mitomycin of cisplatin, with or without maintenance cisplatin/5-
FU in squamous cell carcinoma of the anus.
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Background
Standard treatment - RT + 5-FU + MMC• UKCCCR ACT 1 • EORTC 22861• RTOG 87-04/ECOG 1289
Research questions1. Concurrent chemoradiotherapy • Different chemotherapy – RTOG 98-11 / ACT II /EORTC• Increase RT dose – ACCORD 3
2. Additional therapy• Neoadjuvant chemotherapy – RTOG 98-11 & ACCORD 3• Maintenance chemotherapy – ACT II
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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
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Factorial Design1. Chemoradiation Comparison
MMC 5FU CRT No maintenance
CisP 5FU CRT No maintenance
MMC 5FU CRT Maintenance
CisP 5FU CRT Maintenance
N=471 N=469
versusMMCMMC CisPCisP
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MMC 5FU CRT No
maintenance
CisP 5FU CRT No
maintenance
MMC 5FU CRT Maintenance
CisP 5FU CRT Maintenance
N=446
N=448
No maintenanceNo maintenance
versus
MaintenanceMaintenance
Factorial Design2. Maintenance Comparison
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Statistical Methods
Sample Size• Target sample size ~950 patients
CRT Comparison• 5% increase of CR rate from 90% to 95% - CisP armMaintenance 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
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Primary 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
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Entry Criteria
Histologically confirmed No evidence of metastases Fit for all possible treatments and consent
– Minimum GFR > 50 ml/minGFR <60 confirmed by EDTA clearance /other isotopic
method
– Normal blood counts, LTF’s– Adequate Cardiac function– No contraindications to treatment
X Known HIV positive patients not eligible
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Radiotherapy50.4 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
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Chemoradiation Treatment
1 2 3 4 65RT week
5FU
MMC
1 2 3 4 65RT 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
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Maintenance Treatment
Week
5FU
CisP
Starts 4 wks after end of primary CRT
1000mg/m2 d1-4 & 29-3224 hour continuous iv infusion
60mg/m2 d1 & 29 iv infusion
1 2 3 4
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Accrual
• 940 patients
• Jun 2000 – Dec 2008
• 59 sites
• Multi centre & National collaboration
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Patient Demographics - 1
MMCNo maint
n=246
CisPNo maint
n=246
MMC Maintn=226
CisPMaintn=222
*GenderMale
Female
38%62%
38%62%
38%62%
37%63%
*Age<65 65
75%25%
75%25%
73%27%
74%26%
*GFR <60 60
4%
96%
4%
96%
4%
96%
4%
96%
Pre Rx-colostomy No
YesN/K
81%7%
12%
76%11%13%
71%14%15%
80%9%
12%
* Stratification factor
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Patient Demographics - 2
MMCNo maint
n=246
CisPNo maint
n=246
MMC Maintn=226
CisPMaintn=222
*Site Canal Margin N/K
80%16%4%
81%15%4%
83%14%4%
81%14%4%
* T1 T2 T3 T4 N/K
11%41%29%13%6%
11%41%29%13%6%
10%39%31%14%7%
10%39%30%14%7%
*Node +veNode -veN/K
29%63%8%
29%63%8%
31%61%8%
30%61%9%
* Stratification factor
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Results: Grade 3 & 4 Acute Toxicity During Chemoradiation
0
20%
40%
60%
80%
100%
Haematological Non-haematological
MMC
CisPP<0.001
P=0.17
2 treatment related deaths
24.7% 13.4% 60.2% 64.6%
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P=0.38
Prior MMC
Prior CisP
Results: Grade 3 & 4 Acute Toxicity During Maintenance by Prior Chemoradiation
0%
20%
40%
60%
80%
100%
Haematological Non Haematological
3.3% 2.9%
P=0.819.1% 11.7%
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CRT ComparisonComplete Response at 6 months
0
20%
40%
60%
80%
100%
MMC CisP
P=0.53
94.5% 95.4%
MMC
CisP
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CRT ComparisonColostomy rate at 3 years
P=0.26
Includes colostomies for toxicity and pre treatment colostomies not reversed
0
20
40
60
80
100
MMC CisP
13.7% 11.3%
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Results: Maintenance Comparison
Recurrence Free SurvivalEvent is progression, recurrence or death
0
20
40
60
80
100
Re
curr
en
ce-f
ree
surv
iva
l (%
)
468 345 251 183 132 61 16 1Maint472 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%
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Results: Sites of First Recurrence
MMCn=472
CisPn=468
NoMaintn=446
Maintn=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
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Results : Maintenance Comparison Overall Survival
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 risk0 1 2 3 4 5 6 7 8
Time from randomisation (years)
HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21
No Maint - 74 events
Maint - 60 events
84%
85%
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Results: Maintenance Comparison Causes of death
No Maintn=446
Maintn=448
Anal cancer 52 44
All treatment-related* 3 2
New cancer 5 3
Other 11 8
Unknown 3 3
Total 74 60
* Chemoradiation: 3, 2 Chemotherapy, 1 Radiotherapy. Salvage surgery: 2
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Results: Maintenance Comparison
Cause Specific Survival
0
20
40
60
80
100
Ca
use
Spe
cific
Su
rviv
al (
%)
448 361 278 203 138 71 22 3Maint446 369 278 198 125 67 19 4No Maint
No. at risk0 1 2 3 4 5 6 7 8
Time from randomisation (years)
No Maint - 52 eventsMaint - 44 events
HR: 0.84, 95% CI: 0.57 to 1.26, P=0.41
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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
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NCRI ACT II Trial – Conclusions
Overall• Largest ever trial in anal cancer • Changed UK standard of care• Comparable (or better) results to others
– Dose - 50.4Gy, no gap– Single dose of MMC– low frequency of grade 3/4 haematological and
non-haematological toxicity
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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