ADJUVANT THERAPY FOR COLON CANCER...Adding Oxaliplatin to 5-FU based adjuvant therapy in localised...
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ESMO Preceptorship Programme Prof. Andrés Cervantes ADJUVANT THERAPY FOR COLON CANCER GASTROINTESTINAL CANCER–Singapore – 19-21/11/2019
Transcript of ADJUVANT THERAPY FOR COLON CANCER...Adding Oxaliplatin to 5-FU based adjuvant therapy in localised...
ESMO Preceptorship Programme
Prof. Andrés Cervantes
ADJUVANT THERAPY FOR COLON CANCER
GASTROINTESTINAL CANCER–Singapore – 19-21/11/2019
CONFLICT OF INTEREST DISCLOSURE
Employment: None; Stock Ownership: None
Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Pierre Fabre, 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, Director of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.
Current approach to localised colon cancer
• Clinical Staging
• Surgical resection
• Pathology assessment and estimation of risk
• Treatment based upon TNM stage
• Postoperative chemotherapy for 6 months: standard of care in stage III
• Postoperative chemotherapy of value for some stage II colon cancers
Historical landmarks in localised colon cancer• 5-FU + Levamisol 12 months in 1990
Moertel C et al. N Eng J Med 1990; 322:352-358
Historical landmarks in localised colon cancer
5-FU + Levamisol in 1990
Moertel C et al. N Eng J Med 1990; 322:352-358
DFS HR: 0.55 p:0.0001OS HR:67 p:0.006
Absolute increase in OS at 3,5 years: 16%
ESMO MAGNITUDE OF THE CLINICAL BENEFIT SCALE
• 5-FU + Levamisol in 1990 DFS HR. 0.55 OS HR:67 p:0.006
• Absolute increase in OS at 3,5 years: 16%
Cheny NI et al. Ann Oncol 2015; 27:1547-1573
X
X
Historical landmarks in stage III colon cancer
1990 12 months 5-FU + Levamisol
1996 6 months 5-FU+Folinic acid
2004 6 months FOLFOX4 is better than LV5FU2
Capecitabine at least as active as IV 5-FU/FA
UFT/LV similar activity compared to IV 5-FU/FA
2006 Bolus 5-FU/FA/oxaliplatin better than bolus 5-FU/FA
2008 CAPOX better than bolus 5FULVCapecitabine/oxaliplatin better than bolus 5-FU/FA2018 3 months as good as 6 for low risk stage III colon ca.
5FU-based adjuvant therapy increases survival in CRC
Sargent D, et al. J Clin Oncol 2009; 29:872-877
Adjuvant therapy increases the chance of survival:
Evidence in 13,793 stage III colon cancer patients
Sargent D, et al. J Clin Oncol 2009; 29:872-877
Absolute increase at 8 years 10.3%
Adding Oxaliplatin to 5-FU based adjuvant
therapy in localised colon cancer
Trial N Control Exp. Stage DFS HR
P value
OS HR
P value
Absolute
Gain in OS
G3
Neuro
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; 25:2198-22043Schmoll HJ et al. J Clin Oncol 2015; 33:3733-3740
ESMO MAGNITUDE OF THE CLINICAL BENEFIT SCALE
• MOSAIC No Grade A
• NSABP C07 No Grade A
• XELOXA Grade A in OS over 5%
Cherny NI et al. Ann Oncol 2015; 27:1547-1573
Current approach to localised colon cancer
MUST DO
• Postoperative chemotherapy standard of care in stage III
– Oxaliplatin–based treatment for 6 months
• FOLFOX4, CAPOX, FLOX
– In patients without comorbidities and younger than 70 yo.
– Pay attention to sensory peripheral neurotoxicity during treatment
André T, et al. J Clin Oncol 2007; 27:3109-3116.
Adding Oxaliplatin to 5-FU based adjuvant therapy in
localised colon cancer in MOSAIC: Stage II vs III
André T, et al. J Clin Oncol 2015; 33:4176-4187.
Adding Oxaliplatin to 5-FU based adjuvant therapy in
localised colon cancer in MOSAIC: Stage III N1 vs III N2
Current questions to adjuvant therapy colon cancer
• Should we check for Microsatellite instability
(MIS)?
• How to select stage II colon cancer patients for
adjuvant therapy?
• Duration of treatment: 3 versus 6 months?
• Any role for Precision Medicine?
Hutching G et al. J Clin Oncol 2011; 29:1271-1270
MSI is strongly
prognostic,
... but
not clearly
predictive
Characterization of high risk stage II colon cancer
Risk factors
– Perforation
– Occlusion
– pT4
– Less than 12 LN
– Poorly differentiated tumors
– Vascular invasion
– Lymphatic invasion
– Perineural invasion
– High CEA
• In MSS cancers
• Adjuvant-FU based CT to be discussed with patients
Adjuvant therapy increases the chance of survival:
Evidence in 7,105 stage II colon cancer patients
Sargent D, et al. J Clin Oncol 2009; 29:872-877
Absolute increase at 8 years 5.4%
Current approach to localised colon cancer
MUST DO
• Postoperative chemotherapy standard of care in stage II
– 5FU vs Oral Fluoropyrinidines–based treatment for 6 months
• FU-LV, Capecitabine, UFT
Current approach to localised colon cancer
MUST NEVER DO• Postoperative chemotherapy stage II or III
– Irinotecan-BASED
– Adding Bevacizumab or other anti-angiogenics
– Adding Cetuximab or other anti-EGFR antibodies
Current approach to localised colon cancer
MUST NEVER DO
• Postoperative chemotherapy stage II or III
– Irinotecan-BASED
– Adding Bevacizumab or other anti-angiogenics
– Adding Cetuximab or other anti-EGFR antibodies
Study Schema
IDEA Trials Summary
Non-inferiority Hypothesis Testing
Primary DFS Analysis (mITT)
Primary DFS Analysis (mITT), cont.
DFS Comparison by Risk Groups, cont.
Summary
[1] Tie, Sci Transl Med 2016; [2] Reinert, JAMA Oncol 2019
Stage II
post-surgery (4-10 weeks)
Stage I-III (mostly stage III)
post-surgery (30 days)
(N= 84)
(N= 10)
78% of ctDNA+ relapse
10% of ctDNA- relapse
70% of ctDNA+ relapse
12% of ctDNA- relapse
ctDNA as a major prognostic factor in resected
stage II and III colon cancer patients
Post-operative (week 6-8, N=69)
Can ctDNA be used to (1) detect minimal residual disease (2) predictive of recurrence ?
Mutation tracking (serial plasma samples; N = 94)
Increase predictive accuracy
20%
57% of ctDNA+ relapse
10% of ctDNA- relapse87% of ctDNA+ relapse
5% of ctDNA- relapse
35%
Corcoran RB, and Chabner BA. N Eng J Med 2018; 379:1754-1765.
Corcoran RB, and Chabner BA. N Eng J Med 2018; 379:1754-1765.
Dienstmann R, et al. Nat Rev Cancer 2017; 17:79-92
Schematic representation of colo-rectal
cancer subtypes
Thanks
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