standard of care for anal squamous cancer...esmo preceptorship program comparison 1 versus 2 doses...
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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
ESMO PRECEPTORSHIP PROGRAM
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)
ESMO PRECEPTORSHIP PROGRAM
Squamous cell carcinoma of the Anus
Predominantly loco-regional disease
Unless primary uncontrolled or recurrent
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
2 Trials
No advantage to induction chemotherapy
prior to CRT
(actually worse in RTOG 9811)
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
The 5 R's Of Radiobiology/
Fractionation
Repair
Redistribution
Reoxygenation
Repopulation
Radiosensitivity
ESMO PRECEPTORSHIP PROGRAM
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%
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
Conclusions
1. MMC/cisplatin no difference in any indicators
2. Maintenance chemotherapy no benefit
3. Need a 6th R (reinvigoration of immune system
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
Question 1
Do you need 2 doses of MMC?
ie 10mg/m2 X 2
Or 12mg/m2 X 1 (max 20mg)
03/01/13
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
Impact of day 29 Chemo Compliance on PFS (n=862)
HR 1.63 (95% CI: 1.23 to 2.17 ) p=0.001
ESMO PRECEPTORSHIP PROGRAM
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
825 mg/mradiation days
Goodman 2014 Retrospective
50-54 Gy Mitomycin 10 mg/m2 day 1,29
825 mg/mradiation days
Oliveira 2016 phase II 54 -59Gy mitomycin15 mg/m2 IV day 1
825 mg/mradiation days
Peixoto 2016 50-54 Gy Mitomycin 10 mg/m2 day 1,29
825 mg/mradiation days
Goodman 2017*IMRT
50-56 Gy Mitomycin 10 mg/m2 day 1,29
825 mg/mradiation days
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
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
ESMO PRECEPTORSHIP PROGRAM
Thank you
03/01/13
ESMO PRECEPTORSHIP PROGRAM
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
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