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Ramon Salazar
Catalan Institue of Oncology.
IDIBELL. Spain
Tertulias Oncológicas
Adyuvancia en cáncer colorectal.Nuevos Horizontes
Disclosure Information
• Scientific Advisory Boards & IDMC (last 5 years):
• Bio-Techs: VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer
• Pharma: Amgen, Pfizer, Novartis, Ipsen, Merck, Roche Farma, Tayhoo, Lylli, MSD
• Speaker (last 5 years):
• Pharma: Amgen, Pfizer, Novartis, Ipsen, Merck, Roche Farma, Lylli, MSD,AZD, Celgene.
• Owner of Scientific Blog: www.tertuliasoncologicas.com
www.tertalk.com
http://www.tertuliasoncologicas.com/http://www.tertalk.com/
Outline
• Stage II
• Stage III
• Elderly
• Future avenues
– Key concepts & trials in the 21st century• Quasar, Mosaic, NSABP C-07, X-
Act, NO16968 (Xeloxa)
• IDEA
– 3 vs 6 months
– ctDNA & microenvironment
Medical Oncology Department
Stage II – QUASAR study
QUASAR Collaborative Group. Lancet 2007; 370:2020-29
•n=3239 (91% stage II, 9% stage III, 77% colon cancer, 23% rectal cancer)
•5FU-based chemotherapy
•median follow-up 5.5 years → absolut benefit 3.6% in survival
non-significant benefit
Aprox. 64% of patients had fewer than 12 nodes
assess risk-benefit ratio
RR recurrence 0.82RR death 0.84
All patients
Stage II patients
Factores clínico-patológicos en estadío II de alto riesgo
Benson et al., JCO 2004; Compton et al., Cancer 2000; Labianca et al.,Ann Oncol 2010; JAMA
1990
Factores de mal pronóstico
ASCO pT4, alto grado histológico, perforación, ganglios analizados < 13
AJCCpT4, alto grado histológico, invasión vascular, linfática o perineural, CEA preoperatorio
elevado, margen radial afectado
ESMOpT4, alto grado histológico, obstrucción o perforación, ganglios analizados < 12,
invasión vascular, linfática o perineural
NIHpT4, alto grado histológico o diferenciación coloide o en anillo de sello, CEA
preoperatorio elevado, aneuploidía, delección de 17p o 18q, fase S proliferación elevada
Mayor beneficio, pero limitado, en el grupo depacientes con cáncer de colon estadio II de altoriesgo
Stage II – prognosis factors
Medical Oncology Department
Stage II – Additional prognosis factors
1 Ribic CM et al. N Eng J Med 2003;349:247-2572 Sargent DJ et al. J Clin Oncol 2010;28:3219-3226
- Microsatellite instability / Mismatch repair deficiency:• Prognostic factor (good)
• Predictive value (heterogeneity of data) → controversial results about benefit of 5FU-based CT
- Retrospective studies(1,2) → lack of benefit of 5FU based CT (detrimental)
- Analysis of large studies• PETTAC3, QUASAR, CALGB 9581 and CALGB 89803
→Confirmed its prognostic value
→5-FU lack of benefit but not detrimental
dMMR dMMR
T4-MSI?
Roth et al., J Natl Cancer Inst 2012
Variable HR (95%, CI)
T stage (T4 vs T3) 1.73 (1.38 – 2.17)
No of LN examined 0.79 (0.60 – 0.90)
MSI (MSI-H vs MS-L/S) 0.54 (0.37 – 0.81)
BRAF 1.17 (0.79 – 1.73)
KRAS 1.05 (0.85 – 1.30)
Variable HR (95%, CI)
T stage (T4 vs T3) 1.94 (1.50 – 2.52)
No of LN examined 0.73 (0.63 – 0.96)
MSI (MSI-H vs MS-L/S) 0.43 (0.27 – 0.70)
BRAF 1.56 (1.02 – 2.39)
KRAS 1.10 (0.86 – 1.42)
Medical Oncology Department
Stage II – MOSAIC exploratory analysis
- High risk stage II patients:•T4 (stage IIB, stage IIC)
•Inadequately sampled nodes (< 10 nodes)
•Poorly differentiated (grade 3) *except for MSI-H tumors
•Venous invasion
•Bowel obstruction or perforation (urgent surgery)
Andre T et al . J Clin Oncol 2009;27:3109-3116
• Perforation
• Occlusion
• pT4• Lymph node < 12
• Poorly differenciated tumour
• Venous/lymphatic/Perineuralinvasion
Adjuvant chemotherapy: to be discussed
(5-FU still favoured by EBM)
Characterization of High risk CRC stage IIFor treatment option (5FULV2)
MSS
Stage II Summary
Medical Oncology Department
Stage III – MOSAIC
Andre T et al. J Clin Oncol 2009;33:4176-4187
DFS
DFS 58.9 vs 66.4%
HR 0.78, p=0.005
OS 68.7 vs 72.9%
HR 0.8, p=0.023
Medical Oncology Department
Stage III – NSABP-C07
Yothers G et al. J Clin Oncol 2011;29:3768-74
DFS OS
Medical Oncology Department
Stage III – NO16968 (XELOXA)
Schmoll HJ et al. J Clin Oncol 2015;33:3733-40
RFS
OS
Characterization of agressive stage III CRC
MSSKRAS mut.BRAF mut. ctDNA residualdisease?
*Taieb et al JAMA Oncol 2016
Stratification by TN risk groups & molecular types in clinical trialsIntensified or de- intensified chemotherapy according to risk factors?
Stage III– Prognosis
Primary Efficacy Analysis
Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting
IDEA stage III
Primary DFS Analysis (mITT), cont.
Presented By Qian Shi at 2017 ASCO Annual Meeting
DFS Comparison by Risk Groups, cont.
Presented By Qian Shi at 2017 ASCO Annual Meeting
DFS Comparison by Regimen, cont.
Presented By Qian Shi at 2017 ASCO Annual Meeting
DFS Comparison by Risk Group and Regimen
Presented By Qian Shi at 2017 ASCO Annual Meeting
Interaction p: 0.11
DFS Comparison by Risk Group and Regimen, cont.
Presented By Qian Shi at 2017 ASCO Annual Meeting
Interaction p: 0.11
Definition of High Risk Stage II Disease
Presented By Timothy Iveson at 2019 ASCO Annual Meeting
IDEA stage II high risk
Results: DFS Comparison by Regimen
Presented By Timothy Iveson at 2019 ASCO Annual Meeting
IDEA stage II high risk
Medical Oncology Department
Elderly patients – efficacy (Median age at Dx 68!!!)
Sargent DJ et al. N Eng J Med 2001;345:1091-7 Goldberg RM et al. J Clin Oncol 2006;24:4085-91
< 70y
≥70y
Elderly patients – efficacy:
Age interaction not confirmed for Xelox
• IDEA results:– Fofox 6 months remains the standard
– Capox 3 = 6 months (also in st 3 high risk subgroup)
• Geriatric assesment– Balance between life expectancy, efficacy and safety
• Capecitabine alone is a good compromise in many cases– If OXA is added, 3 months > 6
Idea & Elderly patients - Summary
Minimal residual disease detection
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Future of adjuvant therapy in high risk stage II/III CRC
Prognosis in early-stage CRC is dictated by microenvironment features
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Future of adjuvant therapy in high risk stage II/III CRC
Slide 27
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Future of adjuvant therapy in high risk stage II/III CRC
Slide 28
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Slide 29
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Foxy-5 = synthetic hexapeptide derived from Wnt-5a protein
Decrease migration of cancer cells / metastases
Lower recurrence rate
Better overall survival
Wnt-5a / Foxy-5
Wnt-5a keeps the tumor cells in check
Wnt-5a expression
Kaplan-Meier curves showing cumulative and recurrence-free survival in cancer patients stratified by Wnt-5a expression
Dejmek et al., Cancer Research, 2005c Jönsson et al., Cancer Research, 2002
BREASTCOLON
Foxy-5
Canesin et al., PLOS One, 2017
Foxy-5 significantly reduces the metastatic burden
..but, has no effect on primary tumour volume or weight
53
Protocol – study overview
Foxy-5 (1.8 mg/kg)
Min 9 doses
wnt-5a
3wFU
additional Tx*
Co
ntro
lTx
Arm
3/w
3/w
3/w
SUR
GER
Y
SOC only
3/w
3/w
3/w
3/w
etc3/w
Ad
juvan
tth
erapy
39 doses (total) or start of adjuvant Tx
SOC only
n=180 1:1
Recruitment target:- Randomized at least n=60 with low/no Wnt-5a- N=30 randomized to Control arm
ctDNAFU
Muchas [email protected]
Tertulias Oncológicas
www.tertuliasoncologicas.comwww.tertalk.com
mailto:[email protected]://www.tertuliasoncologicas.com/http://www.tertalk.com/
La plataforma de divulgación científica especializada en oncología Tertulias
Oncológicas con el objetivo de divulgar información sobre oncología, objetiva,
accesible y contrastada científicamente.
Se distingue de los demás medios de comunicación por incorporar en su oferta
informativa un formato innovador: las tertulias. Además, la plataforma publica
diariamente en formato artículo las últimas novedades en oncología.
Satisfacer las necesidades informativas de los profesionales y los afectados por la
patología, ya sean pacientes o familiares, es la meta prioritaria del medio.
www.tertuliasoncologicas.com
www.tertalk.com
Tertulias Oncológicas
http://www.tertuliasoncologicas.com/
La plataforma de divulgación científica especializada en oncología Tertulias
Oncológicas con el objetivo de divulgar información sobre oncología, objetiva,
accesible y contrastada científicamente.
Se distingue de los demás medios de comunicación por incorporar en su oferta
informativa un formato innovador: las tertulias. Además, la plataforma publica
diariamente en formato artículo las últimas novedades en oncología.
Satisfacer las necesidades informativas de los profesionales y los afectados por la
patología, ya sean pacientes o familiares, es la meta prioritaria del medio.
www.tertuliasoncologicas.com
www.tertalk.com
Tertulias Oncológicas
http://www.tertuliasoncologicas.com/
Therapeutic algorithm of localized colorectal cancer
Primary tumor resection
Stage O Stage 1 Stage 2 Stage 3 Stage 4
Screening program
(SEE ParagpraphXXx)
Follow up(see algorithm for
follow up)
Low Risk High Risk*
Adjuvant therapy:XELOX 3 months
FOLFOX 6 months
(See guidelines for mCRC)
Adjuvant therapy:De Gramont 6
months
XELOX 6 months
FOLFOX 6 months
Complete resection achieved
Non complete resection achieved
Follow up (see algorithm for follow up)
Therapeutic algorithm of localized colorectal cancer
Primary tumor resection
Stage O Stage 1 Stage 2 Stage 3 Stage 4
Screening program
(SEE ParagpraphXXx)
Follow up(see algorithm for
follow up)
Low Risk High Risk*
Adjuvant therapy:XELOX 3 months
FOLFOX 6 months
(See guidelines for mCRC)
Adjuvant therapy:De Gramont 6
months
XELOX 6 months
FOLFOX 6 months
Complete resection achieved
Non complete resection achieved
Follow up (see algorithm for follow up)
* MSS T4