act ii: the second uk phase iii anal cancer trial
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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 - PowerPoint PPT PresentationTRANSCRIPT
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.
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
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
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
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
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
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
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
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
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
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
Accrual
• 940 patients
• Jun 2000 – Dec 2008
• 59 sites
• Multi centre & National collaboration
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
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
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%
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%
CRT ComparisonComplete Response at 6 months
0
20%
40%
60%
80%
100%
MMC CisP
P=0.53
94.5% 95.4%
MMC
CisP
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%
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%
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
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%
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
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
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
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
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