ADJUVANT TREATMENT OF COLON CANCER · Stage III colon cancer • No previous CT • Resection ≤ 8...

ADJUVANT TREATMENT OF COLON CANCER

NameMichel DUCREUX

Gustave Roussy Cancer Campus, Grand Paris, FRANCE

DISCLOSURE SLIDE

My wife is the Head of The Oncology Business Unit in Sandoz Company (French Affiliate)

Participation to advisory boards:ROCHEMERCK SERONOAMGENNOVARTISSANOFIBAYERSIRTEXLILLYSERVIERIPSEN

2

Speaker in symposiums:ROCHEMERCK SERONONOVARTISIPSENLILLYAMGEN

Research funding:ROCHEMERCK SERONOPFIZER

ESMO PRECEPTORSHIP PROGRAM

Adjuvant chemotherapy is indicated for stage III (N+) FOLFOX / CapeOx ; 3 months vs 6 months Capecitabine or (inf.) FU/LV as an option for some patients FOLFOX / CapeOx for patients < 70y, use with caution for pts > 70y

Antibodies (EGFR, VEGF) are not indicated The decision for an adjuvant treatment should balance the risk of

cancer mortality and that of comorbidities Specific problems

Stage II The future…..

Aims of the talk

STAGE III (N+)…


Sargent D, J Clin Oncol 2009Moertel et al NEJM 1990

10.3%

First positive study: 5FU + levamisole…


X’Act trial (Capecitabine vs FuFol Mayo) Overall survival

Twelves C, N Engl J Med 2005

Non infériority < 0,001Superiority 0,05

Stage III colon

(n= 1987)


2004 combination chemotherapy!

FOLFOX new standard stage III


MOSAIC studyMain endpoint: Disease-Free Survival (3-years)Secondary endpoint: tolerance, overall survival (6-years)

n=2246Inclusion:Oct 1998–Jan 2001 (146 centres; 20 countries)• Colon cancer, complete resection• Stage II, 40%; Stage III, 60%• Age 18–75 years• KPS ≥60• No previous CT

RLV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123)

(n=1123)

A. de Gramont et al., ASCO 2003 / T. André et al. NEJM 2004

ESMO PRECEPTORSHIP PROGRAMA. de Gramont et al., ASCO 2007 / T. André et al. JCO 2009

Data cut-off: January 2007 months

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.84 [0.71–1.00]

p=0.046

2,5%

FOLFOX4LV5FU2

MOSAIC: Long-term resultsOverall survival ITT


Long-term Tolerance

(% patients)FOLFOX

5.5LV5FU2

6.1

0

10

20

30

40

50

60

PendantTx

6 mois 1-an 2-ans 3-ans 4-ans

Grade 1Grade 2Grade 3

Evaluable patientsn=976 4-yearGrade 0 85.5%Grade 1 12.0%Grade 2 2.8%Grade 3 0.7%

Data cut-off: January 2007

Second cancer

Peripheral Neuropathy

ESMO PRECEPTORSHIP PROGRAMA. de Gramont et al., ASCO 2007 / T. André et al. JCO 2009Data cut-off: January 2007

FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III

Months

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stade II 1.00 [0.70–1.41]

Stade III 0.80 [0.65–0.97]

0.1%

4.2%

p=0.986

p=0.023

Overall survival Stage II / III


Stage III colon cancer

•No previous CT• Resection ≤ 8 weeks

n=1886

n=944

n=942

RANDO MISATION

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

Bolus 5-FU/LV (6 months) Mayo Clinic [n=664]*oruRoswell Park [n=278]**

XELOX (6 months) Capecitabin 1000mg/m2

BID D1 to 14(1 week rest)

+ oxaliplatin 130 mg/m2 IV D1 every 3 weeks

8 cycles

Main endpointBetter DFS


1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

HR=0.87 (IC 95% : 0.72–1.05)p= 0.1486

Years

78 %

74 %

XELOX n=9445-FU/LV n=942

Mean follow-up : 59 months

Surv

ie g

loba

le

ITT population

Overall survival Xelox vs Fufol

Schmoll et al. J Clin Oncol 2015;33:3733-40Confirmed with longer follow-up: 73 vs 67%


64%CapecitabineX-ACT, 200565%LV5FU2MOSAIC 200461%LV5FU2André, 200366%FUFOL ou RPMIXELOXA, 201063%FUFOLINT0089, 200562%FUFOLIMPACT 199444%SurveillanceIMPACT 199352%SurveillanceMoertel 19903-y DFSTreatmentStudy

Monotherapy

73%71%

FOLFOX4XELOX

MOSAIC 2004XELOXA, 2010

Poly CT

The last 15 years

A LITTLE BIT MORE COMPLICATED…


Fluoropyrimidine ± Oxaliplatin Stage III HR for

DFS P value DFS ∆ (%) HR for OS P valueOS ∆ (%)

MOSAIC (FOLFOX)

0.78CI, 0.65-0.93

@ 5 year

0.005∆ 7.5%

58.9% vs 66.4%@ 5 year

0.80CI, 0.65-0.97

@ 6 year

0.023∆ 4.2%

68.7% vs 72.9%@ 6 year

NSABP C-07(FLOX)

0.78CI, 0.68-0.90

@ 5 year

0.0007 ∆ 6.6 %57.8% vs 64.4%

@ 5 year

0.85CI, 0.72-1.00

@ 5 year

0.052∆ 2.7%

73.8% vs 76.5%@ 5 year

XELOXA(XELOX)

0.80CI, 0.69-0.93

@ 5 year

0.004∆ 5 %

62% vs 67%@ 3 year

0.83CI, 0.70-0.99

@ 5 year

0.04∆ 3.0%74% vs. 77%

(@ 5y)

X-ACTFU/FA bolus vs.

Capecitabine

0.87CI, 0.75-1.00

@ 3y

0.0528∆ 3.6%

60.6% vs. 64.2%@ 3y

0.84 CI: 0.69–1.01

@3y

p=0.07∆ 3.7%

77.6% vs. 81.3%@3y

1 André T, J Clin Oncol. 20092 Yothers G, J Clin Oncol 20113 Haller D, J Clin Oncol 20114 S h ll HJ J Cli O l 2016


N 1-3

N > 3

Andre et al. JCO 2015

Overall survival stage III pT3-4 N+

ESMO PRECEPTORSHIP PROGRAM Shah et al. JCO 2016

Recurrence risk over time ACCENT Database N=12.233

A ROLE FOR TARGETEDTHERAPIES?


Bevacizumab

3 large negative studies (>6000 pts)

- NSABP- C08- AVANT- QUASAR 2


NSABP-C-08: bevacizumab, no effect

C. Allegra et al., ASCO 2011, A#3508

100%

viv

ants

80

60

40

20

00 1 2 3 4 5

Years

12681289

12051233

11351163

942950

204204

mFF6 1341 Pts, 224 deathsmFF6+Bev 1337 Pts, 218 deathsHR=0.96, 95% CI (0.79-1.15)p= 0.64

SG

Allegra C et al 2013;31:359-64


Cetuximab

2 large negative studies (>6000 pts)

- N0147- PETACC 8


FOLFOX4 + cetuximab 791 699 505 356 132 2 0

FOLFOX4 811 732 527 381 131 4 0

PETACC8 : PFS : Wt KRAS

Years

DFS

rate

FOLFOX4 + CetuximabN = 791

FOLFOX4N = 811

No, events 190 179

S3-year PFS[95%CI], %

75.1[71.7; 78.1]

78.0[74.8; 80.8]

HR pour SSR [95% CI]p-value (log-rank)

1.047 [0.853; 1.286]O.6562

Taieb J et al Lancet Oncol 2014;15:862-73


Meta-analysis: nothing….

3 MONTHS VERSUS 6 MONTHS… THE IDEA STORY…


IDEA Trials Summary


Global IDEA study: toxicityAdverseEvents

FOLFOX CAPOX

G0 – 1 G2 G3 – 4 p-value G0 – 1 G2 G3 - 4 p-valueGlobal


Disease-free survival: primary endpoint not met

Grothey A et al. NEJM 2018;378:1177-88


Primary DFS Analysis (mITT), cont.

Presented By Qian Shi at 2017 ASCO Annual Meeting


DFS Forrest-plot….



3-year DFS (%)HR / CT

and subgroups

CT

XELOX FOLFOX XELOX/FOLFOX combined

SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI) 3 m 6 m 3 m 6 m 3 m 6 m

Subgroups

Low risk(T1-3 N1)

~60%

High risk (T4 and / or N2)

~40%

Combined

Non-inferior Uncertain Inferior

Grothey A et al. 2018;378:1177-88



and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%


~40%

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined


Grothey A et al. 2018;378:1177-88



and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined


Grothey A et al. 2018;378:1177-88



and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined


Grothey A et al. 2018;378:1177-88



and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

85.0(83.1-86.9)

83.1(81.1-85.2)

0.85(0.71-1.01)

81.9(80.2-83.6)

83.5(81.9-85.1)

1.10(0.96-1.26)

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined




and subgroups

CT


SSR 3-year, % (95% CI) HR(95% CI)

SSR 3-year, % (95% CI) HR(95% CI)


Subgroups

Low risk(T1-3 N1)

~60%

85.0(83.1-86.9)

83.1(81.1-85.2)

0.85(0.71-1.01)

81.9(80.2-83.6)

83.5(81.9-85.1)

1.10(0.96-1.26)

83.1(81.8-84.4)

83.3(82.1-84.6)

1.01(0.90-1.12)


~40%

64.1(61.3-67.1)

64.0(61.2-67.0)

1.02(0.89-1.17)

61.5(58.9-64.1)

64.7(62.2-67.3)

1.20(1.07-1.35)

62.7(60.8-64.4)

64.4(62.6-66.4)

1.12(1.03-1.23)

Combined 75.9(74.2-77.6)

74.8(73.1-76.6)

0.95(0.85-1.06)

73.6(72.2-75.1)

76.0(74.6-77.5)

1.16(1.06-1.26)

P-value interaction test:CT: 0.0061

Risk-groups : 0.11


Grothey A et al. 2018;378:1177-88


CTXELOX FOLFOX

Riskgroups

Low-risk(T1-3 N1)

~60%3 months

High-risk(T4 et/ou N2)

~40%6 months

IDEA : Recommandations


Grothey A et al. 2018;378:1177-88


CTXELOX FOLFOX

Riskgroups

Low-risk(T1-3 N1)

~60%3 months (3-) 6 months

High-risk(T4 et/ou N2)

~40%3 (-6) months 6 months

IDEA : Recommandations


Grothey A et al. 2018;378:1177-88

STAGE II DISEASE…. !!!!


Stage II

Small benefit (3%) with 5FU

No clear improvement with FOLFOX

Is-t possible to define a subgroupthat could benefit from FOLFOX?


Some Stage II tumours with poor prognosis

0102030405060708090

100

5yr real OS (%)

Gunderson et al, JCO 2009

Stage II Stage III

Chart1

T3N0

T4aN0

T4bN0

T1-2N1a

T1-2N1b

T3N1a

T3N1b

T3N2a

T3N2b

T4N2b

5yr rel OS (%)

5yr real OS (%)

87.5

79.6

58.4

90.7

83

74.2

65.3

53.4

37.3

15.7

Sheet1

5yr rel OS (%)Column1Series 3

T3N087.52.42

T4aN079.62

T4bN058.43

T1-2N1a90.75

T1-2N1b83

T3N1a74.2

T3N1b65.3

T3N2a53.4

T3N2b37.3

T4N2b15.7


QUASAR – old study, small benefit

ESMO PRECEPTORSHIP PROGRAMTournigand C et al. J Clin Oncol 2015;33:4176-87

MOSAIC : FOLFOX vs LV5FU2, all stage II patients: no difference

ESMO PRECEPTORSHIP PROGRAMTournigand C et al. J Clin Oncol 2015;33:4176-87

Low risk High risk

MOSAIC late follow-up and Stage II disease


Overall 5-year survival 1950 colon cancer

– Groupe 1, occlusion without perforation, n=120 33%

– Groupe 2, occlusion + perforation tumour, n=35 50%

– Groupe 3, occlusion + proximal perforation, n=13 33%

– Groupe 4, no occlusion, no perforation, n=1682 51%

Do we even know how to select high risk patients?

Chen et al, 2000


Low number of lymph nodes remains not good…

134 567 pT3N0 < 12 LN analysed

– 23.3% of the patients• 46.8% in 2003 – 12,5% en 2012

– 5-year overall survival : 66.8%• 69.8% > 12 LN versus 58.7% p< 0.001

– 16.7% of adjuvant CT if less than 12 LN:• OS with CT 78.4% versus 54.7% without, p< 0.001

Wells KO et al. Dis Colon Rectum 2017


Role of perineural invasion

US National Database: 21,488 patients:– 55.2% T3, 23.1% T2, 14.4% T1, 7.3% T4 disease– 4.6% (n = 987) had PNI– 86.8% no PNI and no CT; 8.7% no PNI and CT; 3.7% (n = 785) PNI and no

CT, and 0.9% (n = 202) PNI and CT– Patients with PNI who had CT: younger, private insurance, fewer

comorbidities greater T stage– PNI and CT improved OS in T3-4 disease (P


No benefit in Stage III patients, could be even deleterious in stage II patients

Sargent DJ et al. J Clin Oncol. 2010;28:3219

MSI(n=165)

MSS(n=863)

Stage II Stage III

MSI + tumours, no benefit from 5FU based CT


Coloprint, useful to select patients??


Immunoscore: an hope

Good reproducibility

Pagès F et al. Lancet 2018;391:2128-39


Immunoscore and stage II disease: DFS

Stage II (n=1433) - High/int/low100

20

0

Sans

rech

ute

(%)

0 1 2 3 4 5 6years

7 24

375694364

p


Tumor associated macrophages (TAM)

Two types:– Good TAM M1– Bad TAM M2

Definition of a prognostic tool: – stage II colon cancer receiving or not adjuvant CT– First step: cohort of 521 patients– Validation on a cohort of 314 patients– Best tool: IHC CD206/CD68 ratio

Feng Q et al. Clin Cancer Res 2019;doi 10.1158/1076-0432


TAM: a predictive effect???

Feng Q et al. Clin Cancer Res 2019;doi 10.1158/1076-0432


Postoperative detection (6 weeksafter surgery)

N = 93ctDNA + , n=8

Post-CT detectionN = 58

ctDNA +, n = 10

N=130ctDNA samples n=829

→ Delay between ctDNA and radiological recurrence n = 14

Prognostic impact of postoperative ctDNA?

T. Reinart et al., ESMO® 2018, Abs P456PD


75

ctDNA+ ctDNAtc-

% ré

cidi

ve 25

12

88

RECURRENCE NO RECURRENCE

Prognostic impact of postoperative ctDNA? Results : prognostic impact of postoperative ctDNA (N=93)

→ Post-operative (n=93) : positive ctDNA in 8/93 (9%) • recurrence observed in 6/8 (75%) ctDNA+ vs 10/85 (12%) in ctDNA-. • PFS significatively different in ctDNA+ vs ctDNA- patients (HR 9.7, p = 0.000018)

Est

imat

ed

recu

rrenc

e fre

e pr

obab

ility

Time since surgery (months)

ctDNA +

ctDNA-

Number at riskNegative 85 79 14 9 0Positive 8 8 0 0 0

HR, 9.7 (95%CI, 3.4-27)P=0.000018

T. Reinart et al., ESMO® 2018, Abs P456PD

Chart1

1.8

Valeur Y 1

Feuil1

Valeurs des XValeur Y 1

1.8

Pour mettre à jour le graphique, entrez des données dans ce tableau. Les données sont enregistrées automatiquement dans le graphique.


Stage II colon cancer

Age < 70y Advanced age or comorbidities

pT4 pT3

pMMR / MSS dMMR / MSI-H

Consider adj. CTx No adj. CTx

Additional marker: less than 12 LN / PNI ? /

Gene signature / Immunoscore?

Algorithm of decision in stage II disease


Stage III diseaseComplete resection

Reference

Folfox4 or Xelox

pT3N1 3 monthsXELOX

PT3N2 6 monthsXELOX or FOLFOX

> 70 y:Capecitabine or

LV5FU2

Options

CI oxaliplatin: LV5FU2 or cap

DPD measurebefore tmt

Adjuvant CT has to bediscussed

NUTS…..

ADJUVANT TREATMENT OF COLON CANCERDISCLOSURE SLIDEAims of the talkSTAGE III (N+)…First positive study: 5FU + levamisole…X’Act trial (Capecitabine vs �FuFol Mayo) Overall survival2004 combination chemotherapy!MOSAIC studyMOSAIC: Long-term results�Overall survival ITTLong-term ToleranceOverall survival Stage II / IIIXeloxXELOX vs 5-FU/LV:�NO16968 (XELOXA) Phase III trial Overall survival Xelox vs FufolThe last 15 yearsA LITTLE BIT MORE COMPLICATED…Fluoropyrimidine ± Oxaliplatin Stage III Overall survival stage III pT3-4 N+Recurrence risk over time ACCENT Database N=12.233A role for targeted therapies?Bevacizumab NSABP-C-08: bevacizumab, no effectCetuximab PETACC8 : PFS : Wt KRASMeta-analysis: nothing….3 months versus 6 months… The idea story…IDEA Trials SummaryGlobal IDEA study: toxicityDisease-free survival: primary endpoint not metPrimary DFS Analysis (mITT), cont.DFS Forrest-plot….Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Stage II disease…. !!!!Stage IISome Stage II tumours with poor prognosis QUASAR – old study, small benefitMOSAIC : FOLFOX vs LV5FU2, all stage II patients: no differenceMOSAIC late follow-up and Stage II diseaseDo we even know how to select high risk patients?Low number of lymph nodes remains not good…Role of perineural invasionMSI + tumours, no benefit from 5FU based CTColoprint, useful to select patients??Immunoscore: an hopeImmunoscore and stage II disease: DFSTumor associated macrophages (TAM)TAM: a predictive effect???Slide Number 58Prognostic impact of postoperative ctDNA?Algorithm of decision in stage II diseaseStage III diseaseNuts…..

ADJUVANT TREATMENT OF COLON CANCER · Stage III colon cancer • No previous CT • Resection ≤ 8...

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