management of early rectal cancer: any role for adjuvant ... · surgery and adjuvant ct in mri...
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Management of early rectal cancer:Any role for adjuvant chemotherapy?
Andrés CervantesProfessor of Medicine
DISCLOSURE SLIDE
Employment: None; Stock Ownership: None
Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas.
Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD
Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. Grant support: Merck Serono, Roche.
Others: Executive Board member of ESMO, Chair of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.
ESMO PRECEPTORSHIP PROGRAM
� TME surgery
� Optimal staging by MRI
� Pathological assessment of the quality of surgery
� Preoperative radiation or chemoradiation
� Integration of knowledge in a multidisciplinary team approach
� Selective approach for preoperative treatment
� Non surgical approach for patient with complete remision
CURRENTS CONCEPTS IN RECTAL CANCERDIAGNOSIS AND THERAPY
ESMO PRECEPTORSHIP PROGRAM
IMPROVEMENT IN RECTAL CANCER TREATMENT
OUTCOMES IN NORWAY
Local Recurrence Distant Metastases
Distant metastases 4x greater risk than local recurrence
Guren MG, et al Acta Oncol 2015; 54:1714-1722.
ADJUVANT THERAPY FOR LOCALIZED RECTAL CANCER
Ann Oncol 2017; 28(suppl 4):iv22-iv40.
ESMO PRECEPTORSHIP PROGRAM 7
� MRI Staging
� MDT discussion
� Preoperative treatment if indicated
� TME Surgical resection
� Pathology assessment and estimation of risk
� Postoperative chemotherapy if indicated
CURRENT APPROACH TO RECTAL CANCER
8
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally
advanced disease?
ESMO PRECEPTORSHIP PROGRAM
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE IN THE PRE-TME PRE-
RT/CHRT PREOPERATIVE ERA?
� American Intergroup
� Quasar
� Japanese Society of Colon and Rectal Meta-analysis on individual data
� Cochrane Meta-analysis on individual data
ESMO PRECEPTORSHIP PROGRAM
THE ROLE OF SYSTEMIC CHEMOTHERAPY IN LOCALISED RECTAL CANCER:
Gunderson et al. J Clin Oncol 2004
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED
RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
The American Intergroup* Pooled Analysis
* NSABP, NCCTG and US-GI Intergroup
THE ROLE OF SYSTEMIC CHEMOTHERAPY IN LOCALISED RECTAL CANCER:
The QUASAR Collaborative Group. Lancet 2007; 370:2020.
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED
RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
The QUASAR TRIAL
UK QUASAR uncertain indication trial Approx 30% rectal.
5yr survival 5 yr recurrence
Chemo No chemo
P-value
Chemo No chemo
P-value
Whole cohort 80.3% 77.4% 0.02 22.2% 26.2%, 0.001
Rectal subgroup p=0.05 19.6% 26.8%, 0.005
The QUASAR Collaborative Group. Lancet 2007; 370:2020.
WHAT IS THE EVIDENCE WE HAVE?
The Quasar trial
Sakamoto et al. Br J Cancer 2007
WHAT IS THE EVIDENCE WE HAVE?
The Japanese Society of Cancer of Colon
and Rectum Meta-analysis on UFT trials
2012
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED
RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
The Cochrane Meta-analysis
Petersen et al, Cochrane Data Base of Systenatic Rev 2012; CD004078
Petersen et al, Cochrane Data Base of Systenatic Rev 2012; CD004078
17
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally
advanced disease?
18
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE IN THE TME/PREOPERATIVE RT OR CHRTERA?
• Chronicle trial • Proctor/script trial • Meta-analysis by Breugomon
individual data from 4 trials and 1200 pts
• Adore trial• CAO/ARO/AIO -04 trial
CHRONICLE TRIAL: ASSESSING THE VALUE OF ADJUVANT CHEMOTHERAPY IN THE TREATMENT OF RECTAL CANCER AFTE R
PREOPERATIVE CHEMORADIATION
Glynne Jones et al. Ann Oncol 2014; 25:1356
Glynne Jones et al. Ann Oncol 2014; 25:1356
� Target population 800 pts
� Primary end point: DFS at 3 years (HR:0.75)
� Accrued nr. Patients 113
� Underpowered to detect any potential benefit of Chemotherapy
� HR for DFS: 0.80 (95%CI: 0.38-1.69; p:0.56)
� HR for OS: 1.18 (95%CI: 0.43-3.26; p:0.75)
WHAT IS THE EVIDENCE WE HAVE?
The Chronicle trial
Breugom et al, Ann Oncol 2015; 26:696-701
PROCTOR/SCRIPT TRIAL: ASSESSING THE VALUE OF ADJUVANT CHEMOTHERAPY IN THE TREATMENT OF
RECTAL CANCER AFTER PREOPERATIVE CHEMORADIATION OR 5X5 RADIATION
� Target population 840 pts� Primary end point: OS at 5 years improved from60 to 70%� Accrued nr. Patients 437 over 14 years� Underpowered to detect any potential benefit of
Chemotherapy� 5 year OS for observation: 79.2%� 5 year OS for adj therapy: 80.4%
� HR for DFS: 0.80 (95%CI: 0.60-1.07; p:0.13)� HR for OS: 0.93 (95%CI: 0.61-1.29; p:0.73)
22
Breugom et al. Lancet Oncol 2015; 16:200-207.
WHAT IS THE EVIDENCE WE HAVE?
The Breugom’s Meta-analysis
Adding Oxaliplatin to 5-FU based adjuvant therapy in localised colon/rectal cancer
Trial N Control Exp. Stag
e
DFS HR
P value
OS HR
P value
Absolute
Gain in OS
G3
Neur
o
Tox
MOSAIC1 2246 FULV2 FOLFOX4 II/III 0.80
0.003
0.84
0.046
4,2% at 6 y
stage III
12%
NSABP-C072 2407 FULV
Roswell
FLOX II/III 0.80
0.0034
0.82
0.002
2,7 at 5 y
Stage III
8,2%
XELOXA3 1886 FULV
Mayo
CAPEOX III 0.80
0.0038
0.83
0.04
6 % at 7 y 11%
1André T, et al. J Clin Oncol 2007; 27:3109-3116. 2Kuebler JP, et al. J Clin Oncol 2007; 25:2198-2204.3Schmoll HJ et al. J Clin Oncol 2015; 33:3733-3740.
Adding Oxaliplatin to 5-FU based adjuvant therapy in localised colon/rectal cancer
Trial N Control Exp. Stag
e
DFS HR
P value
OS HR
P value
Absolute
Gain in OS
G3
Neur
o
Tox
MOSAIC1 224
6
FULV2 FOLFOX4 II/III 0.80
0.003
0.84
0.046
4,2% at 6 y
stage III
12%
NSABP-C072 240
7
FULV
Roswell
FLOX II/III 0.80
0.0034
0.82
0.002
2,7 at 5 y
Stage III
8,2%
XELOXA3 188
6
FULV
Mayo
CAPEOX III 0.80
0.0038
0.83
0.04
6 % at 7 y 11%
AIO044 123
3
FU mFOLFOX
6
II/III 0.79
0.030
0.96
NS
0.7 at 3 y 9%
NSABP R045 128
4
FU/Cap
e
+ Oxali II/III 0.94
NS
0.94
NS
NR 6%
PETACC66 898 Cape + Oxali II/III 1.04
NS
NR NR 8%1André T, et al. J Clin Oncol 2007; 27:3109-3116. 2Kuebler JP, et al. J Clin Oncol 2007; 25:2198-2204.3Schmoll HJ et al. J Clin Oncol 2015; 33:3733-3740. 4Roedel C et al. Lancet Oncol 2015; 16:979-989. 5Allegra CJ et al. J Natl Cancer Inst 2015; 107: pii: djv248.
Hong YS et al. Lancet Oncol 2014; 15:1245-1253.
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED
RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
THE ADORE TRIAL
BOLUS 5FU-LV
Mayo Clinic Schedule
FOLFOX
Rectal Cancer
patients who
completed
preoperative
Long course
chemoradiation
and Surgery with
free margins
ypT3-4N0
or
anyTN1-2
1:1 Randomization
Hong YS et al. Lancet Oncol 2014; 15:1245-1253.
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED
RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
THE ADORE TRIAL
� No observational arm
� Randomised phase II trial 80% Power
� Unilateral hypothesis
� Target population 320 pts
� Primary end point: DFS at 3 years improved by8% from 70 to 78%
� Accrued nr. Patients 322 over 3.5 years
ADORE TRIAL: ADJUVANT CHEMOTHERAPY IN STAGE II/III RECTAL
CANCER AFTER PREOPERATIVE CHEMORADIATION
DISEASE FREE AND OVERALL SURVIVAL
Hong YS et al. Lancet Oncol 2014; 15:1245-1253.
28
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: WHAT IS THE EVIDENCE WE HAVE?
• The pre-TME/preoperative RT or ChRT data• The TME/preoperative RT or ChRT data• How to integrate ChT in patients with locally
advanced disease?
ESMO Rectal Cancer Guidelines: Staging
SoC
TME alone
AVOID RT
TME alone if
high quality or
plus
SCPRT/CRT
SCPRT
or
CRT
Then TME
CRT or
SCPRT +
FOLFOX
then TME
Key
Messages
cT1-2; cT3a/b if
middle or high cN0
(cN1 ig high) MRF
clear; no EMVI
cT3a/b very low
levators clear. MRF
clear, cT3a/b in mid or
high rectum, cN1-2 (not
extranodal), no EMVI
cT3c/d or very low,
levators not threatened,
MRF clear. cT3c/d mid
rectum, cN1-N2
(extranodal), EMVI +ve
cT3 with MRF involved
cT4b,
levators threatened,
lateral node +ve
Glynne Jones, R et al. Ann Oncol 1017;28 (Supplement 4): iv22–iv40.
George TG , et al. Curr Colorectal Cancer Rep 2015; 11:275-280
DOWNSTAGING AFTER NEOADJUVANTTREATMENT : NEOADJUVANT RECTAL SCORE
NEOADJUVANT RECTAL SCOREA SERIES OF 158 LOCALLY ADVANCED RECTAL CANCER
PATIENTS TREATED WITH CT-RT
Log Rang Test p: 0.004
(Mantel Cox)
Roselló S, et al. Clin Colorectal Cancer 2018; 17:104-112
NEOADJUVANT RECTAL SCORE IN CAO/ARO/AIO04 TRIAL
Fokas E, et al, Ann Oncol 2018; 29:1521-1527
NEOADJUVANT CT PLUS CT-RT VERSUS CT-RT FOLLOWED BY SURGERY AND ADJUVANT CT IN MRI DEFINED HIGH RISK RE CTAL
CANCER: THE PHASE II RADOMIZED VALENCIAN EXPERIENCE
Fernández-Martos et al. Ann Oncol 2015; 26: 1722-1728
Concurrent CRT with
CAPOX
CAPOX x 4
MRI defined
Locally advanced
Rectal Cancer
patients
N=108
1:1 Randomization
S Adjuvant
CAPOX
Concurrent CRT with
CAPOXS
POLISH PHASE III TRIAL CRT VS 5X5 AND FOLFOX
S
5x5 FOLFOX 4 x 3
S
RT+5FU LV wk1,5
Ox weekly
34
Primary end point R0 resectionLocally advanced
Unresectable
Locally recurrent
• MRI defined 66%
• Oxaliplatin became
optional
• Short duration FOLFOX
• Weekly Ox single agent
wk 2,3,4
Bujko et al Ann Oncol. 2016;27:834-842.
Primary end point R0 resection
Bujko K, et al. Ann Oncol 2016; 27:834-842
POLISH TRIAL: OVERALL SURVIVAL FAVORS PREOPERATIVE
SCPRT + CHRT VERSUS PREOPERATIVE CHEMORADIATION IN
LOCALLY ADVANCED RECTAL CANCER
HR: 0.73 p: 0.046
THE WAY FORWARD: THE PHASE III RADOMIZED RAPIDO TRI AL
PI: Prof. C. van de Velde
CRT with
CAPECITABINE
Week 1-6
5x5 RT
Week 1
MRI defined
Locally advanced
Rectal Cancer
patients
N=920
1:1 Randomization
SURGERY
Week12
Adjuvant
CT
OPTIONAL
Neoadjuvant XELOX x6
Week 3-16SURGERY
Week 24-28
DFS at 3 years improved by 10% from 50 to 60%
ESMO PRECEPTORSHIP PROGRAM
THE ROLE OF ADJUVANT CHEMOTHERAPY IN LOCALISED RECTAL CANCER: CONCLUSIONS
� Adjuvant Chemotherapy is not standard of care for all localized
rectal cancer patients
� Adjuvant Chemotherapy should be considered for patients at risk after direct surgery without neoadjuvant therapy
� Adjuvant Chemotherapy should be also considered after neoadjuvant Chemoradiation for patients with stage ypIII and high risk stage ypII. LoE: II GoR: C
� The decision on postoperative Chemotherapy (FU alone or combined with oxaliplatin) should be risk balanced, taking into account both the predicted toxicity for a particular patient and the risk of relapse, and should be made jointly by the individual and the clinician
ESMO PRECEPTORSHIP PROGRAM
Thank you