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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/Lev better than surgery alone(Moertel et al)1990
5-FU/LV better than surgery alone
(IMPACT)1994
The evolution of treatmentof early colon cancer
5-FU/Lev better than surgery alone(Moertel et al)1990
5-FU/LV better than surgery alone
(IMPACT)1994
HDLV = LDLV
5-FU/LV better than 5-FU/Lev6mo = 12mo
Lev unnecessaryWeekly = monthly
1998
The evolution of treatmentof early colon cancer
5-FU/Lev better than surgery alone(Moertel et al)1990
5-FU/LV better than surgery alone
(IMPACT)1994
HDLV = LDLV
5-FU/LV better than 5-FU/Lev6mo = 12mo
Lev unnecessaryWeekly = monthly
1998
LV5FU2 = monthly bolus(André et al)
2002
The evolution of treatmentof early colon cancer
5-FU/Lev better than surgery alone(Moertel et al)1990
5-FU/LV better than surgery alone
(IMPACT)1994
HDLV = LDLV
5-FU/LV better than 5-FU/Lev6mo = 12mo
Lev unnecessaryWeekly = monthly
1998
LV5FU2 = monthly bolus(André et al)
2002
FOLFOX better than LV5FU2 (MOSAIC)
FLOX better than 5-FU/LV (NSABP C-07)
2004/2005
The evolution of treatmentof early colon cancer
5-FU/Lev better than surgery alone(Moertel et al)1990
5-FU/LV better than surgery alone
(IMPACT)1994
HDLV = LDLV
5-FU/LV better than 5-FU/Lev6mo = 12mo
Lev unnecessaryWeekly = monthly
1998
5FULV2 = monthly bolus(André et al)
2002
FOLFOX better than LV5FU2 (MOSAIC)
FLOX better than 5-FU/LV (NSABP C-07)
2004/2005
The evolution of treatmentof early colon cancer
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
Neurosensory 11.4 0.1
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
Neurosensory 11.4 12.4
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
Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting
Results: RFS/DFS Overall Population
Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting
Primary Efficacy Analysis
Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting
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
DFS Comparison by Risk Group and Regimen, cont.
Presented By Qian Shi at 2017 ASCO Annual Meeting
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
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
Slide 29
Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting
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