standard of care for anal squamous cancer...esmo preceptorship program comparison 1 versus 2 doses...

ESMO Preceptorship Programme

Rob Glynne-Jones

Mount Vernon Cancer Centre

Standard of care for anal squamous

cancer

Anal Cancer –Barcelona – October 2017

ESMO PRECEPTORSHIP PROGRAM

My Disclosures: last 5 years

Speaker: Roche, Merck Serono, Sanofi

Aventis, Pfizer, AIS

Advisory Boards: Roche, Merck Serono,

Sanofi Aventis, Astra Zeneca

Funding to attend meetings: Roche,

Merck Serono, Sanofi Aventis,

Research funding: Roche, Merck Serono,

Sanofi Aventis


Squamous cell carcinoma of the

Anus

1. The standard of care is chemoradiation with 5FU/capecitabine and MMC

2. Reasonable agreement on fluoropyrimidine but not MMC dose (1 or 2?)

3. Standard of care for radiation is IMRT

4. No standard of care for dose of RT (hence PLATO study in UK)


Squamous cell carcinoma of the Anus

Predominantly loco-regional disease

Unless primary uncontrolled or recurrent


Squamous cell carcinoma of the

anus

Associated with immuno-suppression

Organ transplantation

Long-term cycosporin/azothiaprin etc..

HIV infection

Reports of tumour shrinkage when immunosuppression discontinued.

03/01/13


P16INK4A

In UK 90% patients mod/strongly + for p16INK4A

(Gilbert 2013)

p16+ 37/137(27%) relapsed

P16 - 10/16 (63%) relapsed (Gilbert 2013) p=0.0076

AuthorPatients

(n)Results

Grabenbauer 38 CD3/CD4: decreased 3 years NED

Rubio 277 CD3/CD8: increased 15 years survival

Hu 40intratumoral CD8: increased DFS

peritumoral CD8: increased OS

Gilbert 153 increased relapse-free survival

Prognostic relevance of TILs

Grabenbauer G, Clin Cancer Res 2006; Rubio C, Int J Clin Exp Pathol 2008; Hu W, J Surg Oncol. 2015; Gilbert DC, Br J Cancer 2016

High levels of TILs, especially CD8(+) cells, are associated with a favourable clinical response and survival


SCC of Anus Nigro et al 1983

Preop chemoradiation to primary tumour, pelvic and inguinal nodes

Radiotherapy 2 fields 30 Gy /15/21 days

Chemotherapy 5FU 1000mg/m2

Days 1-4, 29-32

Mitomycin C 15mg/m2

Day 1

R

A

N

D

O

M

I

Z

A

T

I

O

N

45Gy in 20-25 #

45Gy in 20-25 #

CRT+ 5FU

/MMC

N = 585 patients

ACT I Trial

15Gy Boost

Reassess and ?

boost after 6 weeks

15Gy Boost

03/01/13

75

50

25

0

Perc

enta

ge o

f p

atie

nts

hav

ing

a lo

cal r

elap

se (

%)

0 2 4 6 8 10 12 14 16 18 20Time since randomisation (years)

RT aloneCMTHR 0.46, p<0.001

ACT I :Time to first local relapse

R

A

N

D

O

M

I

Z

A

T

I

O

N

46 -54Gy in 20-

25 # CRT+ 5FU

45Gy-54 Gy in

20-25 # CRT+

5FU / MMC

N = 291 patients

RTOG 87-04 Trial

9Gy Boost

Reassess with

biopsy and ? boost

after 6 weeks

9Gy Boost


RTOG 87-04

XRT+ 5 FU XRT + 5 FU-MMC p value

Completeresponse

86% 92.2% NS

Colostomy- free survival

59% 71% 0.014

Colostomy rate 22% 9% 0.002

DFS 51% 73% 0.003

OS 71% 78% 0.1


Options for chemotherapy

Induction chemotherapy prior to CRT

Different concurrent chemotherapy in CRT

Consolidation chemotherapy after CRT

R

A

N

D

O

M

I

Z

A

T

I

O

N

NACT

5FU/cisplat

45 to 59 Gy

+ 5FU /MMC

N = 644 patients

Intergroup RTOG 98-11

45 to 59 Gy RT

+ 5-FU/CDDP

T2-4 N0 N+

MMC

Cisplatin

RTOG 9811 Ajani JA et al JAMA 2008

Disease Free Survival RTOG 9811

03/01/13

RTOG 9811 Gunderson et al 2012

Long-term analysis

RTOG 9811 Gunderson et al 2012


ACCORD- 03

Therapeutic intensification

– Induction chemotherapy (CRT cisplatin)

– High dose radiotherapy (CRT cisplatin)

Primary endpoint: colostomy-free-survival(CFS).

ACCORD 03Titre du diagramme

low boost

15 Gy

45 Gy

CDDP 5 FU 2 cycles

CT

CDDP 5FU 2 cycles

high boost

20-25 Gy

45 Gy

CDDP 5 FU 2 cycles

CT

CDDP 5FU 2 cycles

low boost

15 Gy

45 Gy

CDDP 5 FU 2 cycles

No CT

high boost

20-25 Gy

45 Gy

CDDP 5 FU 2 cycles

No CT

R

70% 82% 77% 73%

5 years CFS Standard arm

307 patients

ACCORD CFS : induction versus no induction

ACCORD CFS : boost versus no boost

ACCORD -03 Peiffert 2012


2 Trials

No advantage to induction chemotherapy

prior to CRT

(actually worse in RTOG 9811)


ACT II Factorial DesignChemoradiation Comparison

MMC 5FU CRT No maintenance

CisP 5FU CRT No maintenance

MMC 5FU CRT +Maintenance

CisP 5FU CRT +Maintenance

MMC

N=472CisP

N=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


Response at 26 weeks

Patients with response data MMC(432/472)

CisP(431/468)

CR primary 90% 90%

CR N083%

(358)

84%

(362)P=0.66


The 5 R's Of Radiobiology/

Fractionation

Repair

Redistribution

Reoxygenation

Repopulation

Radiosensitivity


Best time to assess complete clinical response (cCR) after CRT in Anal-Cancer: ACT II data

Glynne-Jones et al, Lancet Oncolology 2017

• n=691 attended all three assessments

• cCR: 64%, 80% and 85% at assessments 1, 2 and 3,

respectively

• 72%: no cCR at assessment 1; cCR by assessment 3

• 5-year OS (at assessment 3): cCR=87%; non-cCR=48%


ACT II Progression free survival

Comparison

group

3-year rate, %

(95%CI)

5-year rate , %

(95% CI)

HR (95% CI), p

value

MMC 73 (69 to 77) 69 (65 to 73)

CisP 74 (69 to 77) 69 (64 to 73) 0.95 (0.75 to

1.19), p= 0.63

No-maint 73 (68 to 77) 69 (64 to 73)

Maint 74 (69 to 77) 70 (65 to 74) 0.95 (0.75 to

1.21), p=0.70


Overall survival ACT II

Comparison

group

3-year rate, %

(95%CI)

5-year rate , %

(95% CI)

HR (95% CI), p

value

MMC 84 (80 to 87) 79 (74 to 82)

CisP 84 (80 to 87) 77 (73 to 81) 1.05 (0.80to

1.38), p=0.70

No-maint 85 (81 to 88) 79 (75 to 83)

Maint 83 (79 to 86) 76 (72 to 80) 1.07 (0.81 to

1.41). p=0.65


Colostomy free survival in ACT II

Comparison

group

3-year rate, %

(95%CI)

5-year rate , %

(95% CI)

HR (95% CI), p

value

MMC 74 (69 to 78) 67 (63 to 72)

CisP 73 (69 to 78) 67 (63 to 72) 1.01 (0.80 to

1.27), p=0.94

No-maint 67 (62 to 71) 65 (61 to 70)

Maint 74 (69 to 78) 68 (63 to 73) 0.88 (0.69 to

1.11), p=0.28


Conclusions

1. MMC/cisplatin no difference in any indicators

2. Maintenance chemotherapy no benefit

3. Need a 6th R (reinvigoration of immune system


PFS

Nearly all the risk of recurrence AUC is within 2 years

03/01/13

75

50

25

0

Perc

enta

ge o

f p

atie

nts

hav

ing

a lo

cal r

elap

se (

%)

0 2 4 6 8 10 12 14 16 18 20Time since randomisation (years)

RT aloneCMTHR 0.46, p<0.001

ACT I :Time to first local relapse


Site of relapse after CRT from ACT II

(940 patients)

PrimaryInguinal/pelvic nodesMetastases/oligometastases

Number % total relapses

Pelvic - no metastases 133 64%

Pelvic - with metastases 30 14%

Distant metastases only 46 22%

Total crude pelvic failure

(with or without

metastases)

163 78%

Total relapses 209

Data from ACT II Sebag-Montefiore D et al ASCO 2012


Question 1

Do you need 2 doses of MMC?

ie 10mg/m2 X 2

Or 12mg/m2 X 1 (max 20mg)

03/01/13


Doses of Mitomycin/CisplatinTrial Day 1 Day 29 Total

ACT I MMC 12mg/m2 none MMC 12mg/m2

EORTC MMC 12mg/m2 none MMC 12mg/m2

RTOG 8704 MMC 10mg/m2 MMC 10mg/m2 MMC 20mg/m2

RTOG 9811 MMC 10mg/m2 MMC 10mg/m2 MMC 20mg/m2

Cisp 75mg/m2 Cisp75mg/m2 Cisp 150mg/m2

ACCORD-03 Cisp 80mg/m2 Cisp 80mg/m2 Cisp 160mg/m2

ACT II MMC 12mg/m2 none MMC 12mg/m2

Cisp 60mg/m2 Cisp 60mg/m2 Cisp 120mg/m2


Comparison 1 versus 2 doses

no difference

PFS (HR 0.85, 95% CI 0.37–1.92), CFS (HR 0.91, 95% CI 0.31–2.67) between the

MMC1 and MMC2 groups. Acute grade ⩾2 toxicities were worse in the MMC2

group. 3 treatment-related deaths, all in the MMC2 group

White et al Chemoradiotherapy for squamous cell carcinoma of the anal canal: Comparison of one versus two cycles mitomycin-C. Radiother Oncol 2015;117 (2):240–245


Impact of day 29 Chemo Compliance on PFS (n=862)

HR 1.63 (95% CI: 1.23 to 2.17 ) p=0.001


Capecitabine integrated into CRT in

anal cancerStudy RT MMC Capecitabine

Glynne-Jones 2008 50.4 Gy in 28 fractions in 2 phases Single dose of MMC 12mg/m2 max 20mg

825 mg/mradiation days

Deenen 2013 59.4 Gy in 33 fractions with SIB-IMRT Single dose of MMC 10mg/m2 max 15mg


Goodman 2014 Retrospective

50-54 Gy Mitomycin 10 mg/m2 day 1,29


Oliveira 2016 phase II 54 -59Gy mitomycin15 mg/m2 IV day 1


Peixoto 2016 50-54 Gy Mitomycin 10 mg/m2 day 1,29


Goodman 2017*IMRT

50-56 Gy Mitomycin 10 mg/m2 day 1,29


Capecitabine CRT 106 patients

5-Fluoro-uracil CRT 194 patients

Peixoto RD, Wan DD, Schellenberg D, Lim HJ.J Gastrointest Oncol. 2016 Aug;7(4):665-72

Goodman KA et al IJROBP 2017;5


Capecitabine and IMRT

Better tolerated (haematological tox)

Better compliance to full dose of chemo

Less interuptions to RT

Trial N of

patients

IMRT Regimen Toxicity Efficacy

Olivatto et al,

Cancer 2013

21

(stopped

DLT)

No 5-FU/CP

+RT +

cetuximab

High OK

ACCORD 16,

J Clin Oncol

2011

16

(stopped

DLT)

No 5-FU/CP

+RT +

cetuximab

High low

Norwegian

Study

(Johnsson)

Max 21

(complete)

Yes 5-FU/MMC

+RT +

cetuximab

high CR 91%

Trials with Cetuximab in anal cancer


Study Stage

I/II/III-IV

%

2 Year

LocRegional

Failure Rate

2 Year

Overall

Survival

RTOG 9811

control:

MMC + 5-FU

47/19/31 25 % 91%

RTOG 9811*:

5-FU + Cis

48/17/31 28 % 85%

ECOG 3205 11/50/39 13% 93 %

AMC 045 24/42/34 7% 89 %

Trial N of

patients

IMRT Regimen Toxicity Efficac

y

ECOG 3205 61 some 5-FU/CisP +RT +

cetuximab

32%

G4

5%

G5

The 3-

year

LRF

23%

AMC045

HIV+

45 some NACT + 5-

FU/CisP +RT +

cetuximab

26%

G4

4%

G5

LRF

16%

Trials with Cetuximab in anal cancer

Garg MK, et al., J Clin Oncol. 2017 Jan 9: [Epub ahead of print]Garg MK, et al., J Clin Oncol 34, 2016 (suppl; abstr 3522)

IRCI anal cancer metastatic trial


Phase II trial (NCT02314169)• Inclusion: previously-treated metastatic patients• Primary Endpoint: Tumor response (RECIST 1.1)

Results:• Response in 9 of 37 patients (24%; CR in n=2)• Median OS: 11.5 months; median PFS: 4.1 months• Good toxicity profile, no SAEs

Nivolumab for previously treated unresectable metastatic anal cancer

Higher immunogenicity Better response

Morris et al, Lancet Oncolology 2017


Best time to assess complete clinical response (cCR) after CRT in Anal-Ca: ACTII data

Glynne-Jones et al, Lancet Oncolology 2017

• n=691 attended all three assessments• cCR: 64%, 80% and 85% at assessments 1, 2 and 3, respectively• 72%: no cCR at assessment 1; cCR by assessment 3• 5-year OS (at assessment 3): cCR=87%; non-cCR=48%

PLATO – PERSONALISING RADIOTHERAPY

DOSE FOR ANAL CANCER

53.2Gy

28F

58.8Gy

28F

61.6Gy

28F

Stratify for Cape vs. 5-FU

50.4Gy

28F

41.4Gy

23F

ACT3 ACT4Local excision

Obs

Adverse

Standard

Ph II

Ph III

Pilot

T1,T2<4cm N0 T3/4 NO

T2N2, T3/4 N1-3

41.4Gy

23F

T1 N0

Anal margin

Phase II trial Phase II/III trial

Courtesy of David Sebag-Montefiore


Plato design

5 Different doses

41.4Gy/ 50.4Gy/ 53.2Gy/ 58.8Gy / 61.6Gy

Allows current prognostic groups

(p16+etc..)

To be validated as predictive


Thank you

03/01/13


Goodman KA et al 2017

Neutropenia G2 diarrhoea

Full prescibeddose

Treatment break

5FU 33/63 (52%) 11/63 (17%)

16/63 (25%)

41%

capecitabine 9/44 (20%) 2/44 (5%) 28/44 (70%)

14%

significance P= 0.001 p=.069 P=.006

standard of care for anal squamous cancer...esmo preceptorship program comparison 1 versus 2 doses...

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