Adjuvant treatment for stage II and III Colon Cancer · 2017. 10. 26. · Cada 2 semanas, 6 meses de tratamiento (12 ciclos) D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2 LV 200 mg/m2

Adjuvant treatment for stageII and III Colon Cancer

Ramon Salazar

Catalan Institute of Oncology

DisclosuresR. Salazar has served in a consultant or advisory role for Amgen, Merck

Serono, Taihoo, MSD, Lylli, BMS, Roche Dx and enjoyed research funding for Roche Dx, Roche Pharma and Merck Serono

Outline

• History (recent…)

• Key Trials

• Stage II

• 3 vs 6 months (Stage III)

• Elderly

5-FU/Lev better than surgery alone(Moertel et al)1990

The evolution of treatmentof early colon cancer


5-FU/LV better than surgery alone

(IMPACT)1994




(IMPACT)1994

HDLV = LDLV

5-FU/LV better than 5-FU/Lev6mo = 12mo

Lev unnecessaryWeekly = monthly

1998




(IMPACT)1994

HDLV = LDLV



1998

LV5FU2 = monthly bolus(André et al)

2002




(IMPACT)1994

HDLV = LDLV



1998

LV5FU2 = monthly bolus(André et al)

2002

FOLFOX better than LV5FU2 (MOSAIC)

FLOX better than 5-FU/LV (NSABP C-07)

2004/2005




(IMPACT)1994

HDLV = LDLV



1998

5FULV2 = monthly bolus(André et al)

2002

FOLFOX better than LV5FU2 (MOSAIC)

FLOX better than 5-FU/LV (NSABP C-07)

2004/2005


Xeloda ≥ 5-FU/LV (X-ACT)

2008XelOx better than 5-FU/LV

(NO16968)2009

Adjuvant therapy increases the chance of survival: evidence in 20,898 CC patients (ACCENT 18 trials 5FU based)

Stage II CC Stage III CC

Sargent, et al. JCO 2009

1.0

0.8

0.6

0.4

0.2

0

OS

est

imat

e

p=0.026

0 1 2 3 4 5 6 7 8

Follow-up time (years)

Surgery alone8-year OS rate (95% CI): 66.8%(63.7% to 70.0%)

Surgery + FU-based chemotherapy

8-year OS rate (95% CI): 72.2%(69.3% to 75.2%)

p<0.0001

Surgery alone8-year OS rate (95% CI): 42.7%(39.9% to 45.7%)

Surgery + FU-based chemotherapy

8-year OS rate (95% CI): 53.0%(50.2% to 55.9%)

0 1 2 3 4 5 6 7 8

Follow-up time (years)

CC=colon cancerOS=overall survival

OS

est

imat

e

1.0

0.8

0.6

0.4

0.2

0

Early DFS predicts long-term survival after adjuvant therapy

• 2- and 3-year DFS predicts 5- and 6-year overall survival

• Correlation stronger in patients with stage III disease

Correlation

coefficient

Overall survival

(all patients)

Overall survival

(stage III disease)

DFS 5-year 6-year 5-year 6-year

2-year 0.59 0.77 0.91 0.91

3-year 0.62 0.77 0.93 0.89

1.0 = perfect correlation

Sargent et al. ASCO 2009

Key trials in the 21st century• X-ACT Xeloda vs 5FU bolo (Mayo)

• MOSAIC FOLFOX4 vs LV5FU2 infusion

• NSABP C-07 FLOX vs 5FULV bolus

• NO16968 XELOX vs 5FULV bolus (500 mg/m2 weekly x6/8 wk RPark)

• CALGB 89803, ACCORD 2, PETACC-3 5FU vs FOLFIRI

• NSABP C-08 mFOLFOX6 vs mFOLFOX6 + Bevacizumab

• AVANT FOLFOX4 vs FOLFOX4 + Avastin vs XELOX + Bevacizumab

• QUASAR-2 Capecitabine ± bevacizumab

• PETACC 8 Cetuximab + Folfox vs Folfox

• NCCTG (North Central Cancer Treatment Group) N0147 trial. Cetuximab + FLOX vs FLOX

Fully resected Stage III colon cancer < 8 weeks prior to study entry

Ability to be followed > 5 years after the last patient is randomized

Phase III Capecitabine vs bolus IV 5-FU/LV in adjuvant colon cancer

(randomized) (X-ACT) M66001

Capecitabinetwice-daily 1250 mg/m2, D1-14 Q3W

RANDO MIZATION

Primary endpoint: Non-Inferiority in Disease-Free Survival

Planned sample size: 1956 pts

Leucovorin20 mg/m2 IV, D1-5 Q4W

5-FU425 mg/m2 IV bolus, D1-5 Q4W

0.4

non- inferiority proven & trend to superior DFS with Capecitabine

Years

0.6

0.8

1.0

1 2 3 4 5 6 7 8

Absolute difference

at 5 years: 4.1%

0

ITT population

HR=0.88 (95% CI: 0.77–1.01)

p=0.0682

Twelves et al. ASCO GI 2008

Estimated probability

Xeloda (n=1004)

5-FU/LV (n=983)

5-year DFS (%)

60.8

56.7

trend to superior OS with Capecitabine

Years1 2 3 4 5 6 7 80

0.4

0.6

0.8

1.0

Absolute difference

at 5 years: 3.0%

HR=0.86 (95% CI: 0.74–1.01)

p=0.0600

Xeloda (n=1004)

5-FU/LV (n=983)

5-year overall survival (%)

71.4

68.4

ITT population Twelves et al. ASCO GI 2008

Estimated probability

Patients (%)

Scheithauer et al. Ann Oncol 2003

* * * *

*p<0.001

Xeloda (n=993)

5-FU/LV (n=974)

Grade 3/4 AEs

X-ACT: safety

0

10

20

30

Capecitabine is more toxic than infusional LV5FU

Seymour et al.

3 Adjuvant Trials with 5FU + Oxaliplatin

Trial N Pts Treatment Data

MOSAIC(NEJM 2004, ASCO 2005,

ASCO 2007)

Stage II/III

2246FOLFOX-4 x 6 mos

LV5FU2 x 6 mos

5-y DFS

6-y OS

NSABP C-07(JCO 2007)

Stage II/III

2407FLOX x 6 mos

Bolus 5FULV w x 6 mos

6-y DFS

6-y OS

NO16968 (JCO

2007, ECCO-ESMO 2009)

Stage III1886

XELOX x 6 mos

Bolus 5FULV w/q4w x 6 mos

5-y-DFS(DFS 4-y

ECCO-ESMO 2009)

OXA

R

MOSAIC: Treatment arms

LV5FU2

FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²

Cada 2 semanas, 6 meses de tratamiento (12 ciclos)

D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2

LV 200 mg/m2 5-FU 22h 600 mg/m2 5-FU 22h 600 mg/m2

D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2

5-FU 22h 600 mg/m2 5-FU 22h 600 mg/m2LV 200 mg/m2 LV 200 mg/m2

LV 200 mg/m2

stage II/III colon cancer

MOSAIC: treatment administration

FOLFOX4 LV5FU2

Pacientes aleatorizados 1123 1123

Pacientes tratados 1108 1111

Número total de ciclos 11829 12506

Media/Mediana 10.7 11.3

12 ciclos 74.7% 86.5%

Intensidad de dosis relativa mediana %

Oxaliplatino 81 NA

5-FU 85 98

PFS (ITT)

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

Probabilidad

HR: 0.77 [0.65 – 0.92] p < 0.01

FOLFOX4 (n=1123) 77.8%

LV5FU2 (n=1123) 72.9%

3-años

André et al. NEJM 350;23

2004

PFS Stage III

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

Probabilidad

HR: 0.76 [0.62-0.92]

FOLFOX4 (n=672) 71.8%

LV5FU2 (n=675) 65.5%

3-años

André et al. NEJM 350;23

2004

MOSAIC and NSABP C-07 Stage II and III (ITT)OS updated results with longer f-up

André et al., JCO 2015; Yothers et al., JCO 2011

DFS: 61.7 vs 67.5 HR = 0.82 (95% CI, 0.71 – 0.95) DFS: 64.2 vs 69.4 HR = 0.82 (95% CI, 0.72 – 0.93)

MOSAIC: safety

NCI Gr 3 % FOLFOX4 LV5FU2(n=1108) (n=1111)

Trombocitopenia 1.6 0.4

Neutropenia 41.0 ( Gr 4: 12.2) 4.7

Neutropenia Febril 0.7 0.1

Sepsis Neutropénica 1.1 0.1

Diarrea 10.8 6.7

Estomatitis 2.7 2.2

Vómitos 5.9 1.4

Alergia 3.0 0.2

Alopecia (Gr2) 5.0 5.0

Neurosensory 12.4 0.3

Mortalidad por cualquier causa 0.5 0.5

Chemo/radiotherapy-naive

stage III colon ≤8 weeks since resection

N=1886

Primary endpoint: superiority of DFS

Secondary endpoints: RFS, OS, tolerability

n=944

n=942

RANDO MISATION

Adjuvant XELOX vs 5-FU/LV:NO16968 (XELOXA) Phase III trial

Bolus 5-FU/LV (6 months)

Mayo Clinic [n=664]or

Roswell Park [n=278]

XELOX (6 months)

capecitabine 1000mg/m2 bid d1–14oxaliplatin130mg/m2 d1

q3w8 cycles

Haller et al. ECCO-ESMO 2009

5-year DFS:benefit with XELOX maintained and increased over time

XELOX

5-FU/LV 1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

ITT population

Δ at 4 years: 6.1% Δ at 5 years: 6.3%

Δ at 3 years: 4.5%

70.9% 68.4%

3-year

DFS

66.5% 62.3%

4-year

DFS

5-year

DFS

59.8%

66.1%

HR=0.80 (95% CI: 0.69–0.93)p=0.0045

Trend to improved OS with XELOX

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX

5-FU/LV

Δ at 5 years: 3.4%

HR=0.87 (95% CI: 0.72–1.05)p=0.1486

Years

77.6%

5-year

OS

74.2%

1.0

0.6

0.8

1. André et al. JCO 2009

1 2 3 4 5 6 7 8

Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease

Years

XELOX (n=944)

FOLFOX4 (n=672) –

5-yr OS 6-yr OS

72.9%

77.6%

NO16968 (XELOXA)*

MOSAIC1**

–

*Median observation time: 57.0 months**Median follow-up: 81.9 monthsITT population

0.4

0

Safety

Grade 3/4 AEs (%)

XELOX

n=938

5-FU/LV

n=926

Febrile neutropenia 0.4 4.2

Neutropenia 8.8 15.9

Diarrhoea 19.4 20.2

Stomatitis 0.6 8.9

Nausea 5.2 4.5

Vomiting 6.2 3.3

HFS 5.4 0.6


Schmoll et al. JCO 2007

Cross-trial comparison with MOSAIC

Schmoll et al. JCO 2007

*MOSAIC trial: André et al. NEJM 2004

Grade 3/4 AEs (%)

XELOX

n=938

FOLFOX4

(MOSAIC)*

n=1108

Febrile neutropenia 0.4 1.8

Neutropenia 8.8 41.1

Diarrhoea 19.4 10.8

Stomatitis 0.6 2.7

Nausea 5.2 5.1

Vomiting 6.2 5.8

HFS 5.4 2.0


Stage II testing

• Les meves de ESMO I ESMO GI 2016

• Les de la sessio ESMO 2017 del pavo angles

QUASAR

Gill et al., JCO 2004; Quasar Col Group, Lancet 2007;

Introducción

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

NIH

pT4, 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 de pacientes concáncer de colon estadio II de alto riesgo

T4MSI

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)

• Addition of OXL is not supported in Stage II (MOSAIC and NSABP C-07)

André et al., JCO 2015; Yothers et al., JCO 2011

DFS: 73.6 vs 75.2 HR = 0.89 (95% CI, 0.68 – 1.16)

DFS: 80.1 vs 82.1 HR = 1.04 (95% CI, 0.72 – 1.50)

What´s the question in Stage III

IDEA: adjuvant 3 vs 6 months Folfox/Xelox

IDEA Trials Summary

Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

Non-inferiority Hypothesis Testing


Results: RFS/DFS Overall Population


Primary Efficacy Analysis


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


DFS Comparison by Risk Group and Regimen, cont.


CÁNCER COLORRECTAL

Grothey A, et al. LBA21. ESMO 2017

What about the elderly population

• Do they need or deserve the same ”treat”• Sharper Balance toxicity-efficacy and life expectancy

Sargent et al, 2001

ACCENT DATABASE 5FU CHX

Upper limit75y as per inclusioncriteria

female patients 70–75 years had the same oxaliplatin benefit as younger patients

DFS and OS benefits in patients 70–75 years were similar to those of younger patientsfor the first 3 years of follow-up, but were lost later on due to deaths from other causes.

Oral capecitabine improved outcomeswhen compared with bolus 5-FU/LV in the X-ACT trial in patients ≥70 years

Summary of the evidence

• LV5FU2 vs bolus 5FULV vs capecitabine• LV5FU2 infusion non-inferior and better safety

• Capecitabine non-inferior (maybe better) than bolus 5FULV, better safety thanbolus, but worse than LV5FU2 Oxaliplatin Folfox/Xelox adds both efficacy and toxicity in stage III

• Stage II high risk (T4MSS): 5FULV2 (or capecitabine)

• 3 months Xelox is an option in low risk stage III (T3N1)

• Elderly• Balance between life expectancy, efficacy and safety

• Geriatric assesment

Questions?

Questions?

75 y-old female T4N1No comorbidities, good surgical recoveryPS 0How would you treat her

Questions?

75 y-old male T4N0No comorbiditiesPS 0How would you treat him

Questions?

75 y-old male T4N0No comorbiditiesPS 0How would you treat him

If MSI?

Prognostic signatures in early-stage CRC <br />are not predictive of chemotherapy benefit

Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting

Prognosis in early-stage CRC is dictated by microenvironment features


Slide 29


Documents

Adjuvant treatment for stage II and III Colon Cancer · 2017. 10. 26. · Cada 2 semanas, 6 meses de tratamiento (12 ciclos) D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2 LV 200 mg/m2