Anal Cancer

Rob Glynne-Jones Mount Vernon Cancer Centre on behalf of NCRI anal cancer subgroup

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

Colostomy-free survival

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

PFS -free survivalMMC vs CisP comparison

73%

74%

Overall Survival CR vs Not CR week 26

93%

61%

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

ACT II Timing of pelvic recurrences(93% in years 1-3)

Year 1

Year 2

Year 3

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

RTOG 9811 Time to Colostomy

Cisplat

MMC

RTOG 9811 Ajani JA et al JAMA 2008

MMC

Cisplatin

RTOG 9811 Ajani JA et al JAMA 2008

RTOG 9811 Disease Free Survival

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)