Adyuvancia en cáncer colorectal. Nuevos Horizontes€¦ · (5-FU still favoured by EBM) Characterization of High risk CRC stage II For treatment option (5FULV2) MSS Stage II Summary.

Ramon Salazar

Catalan Institue of Oncology.

IDIBELL. Spain

Tertulias Oncológicas

Adyuvancia en cáncer colorectal.Nuevos Horizontes

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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


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)


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


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


Stage III – NSABP-C07

Yothers G et al. J Clin Oncol 2011;29:3768-74

DFS OS


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.


DFS Comparison by Regimen, cont.


DFS Comparison by Risk Group and Regimen


Interaction p: 0.11

DFS Comparison by Risk Group and Regimen, cont.


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


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



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

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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

Adyuvancia en cáncer colorectal. Nuevos Horizontes€¦ · (5-FU still favoured by EBM) Characterization of High risk CRC stage II For treatment option (5FULV2) MSS Stage II Summary.

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