act ii: the second uk phase iii anal cancer trial

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