Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard?

Adjuvante therapie van het coloncarcinoom anno 2004-2005:

is 5FU/LV nog steeds de standaard?

Prof.dr. C.J.A. Puntafd. Medische Oncologie

UMC St. RadboudNijmegen

Adjuvant therapy for colon cancerhot topics 2004

•FOLFOX

•Capecitabine

•Stage II

•Primary endpoint in randomised studies

Adjuvant therapy for stage III colon cancer - history

• 1990: 12 months 5FU/levamisole (absolute reduction of mortality = 13%)

• 1990: NIH consensus

• 1996: 6 months 5FU/LV is equivalent

• 2001: comparable benefit in elderly patients (>70 yrs)

•No preference for 5FU/LV schedule

Adjuvant therapy for colon cancer - new developments in 1990s

• Locoregional chemotherapy: no benefit

•Different schedules of 5FU/LV: no benefit

(3 months infusional 5FU 6 months 5FU/LV Mayo Clinic, Ann Oncol, in press)

•New modulators of 5FU (IFN!): no benefit

New drugs for adjuvant therapy in colon cancer since 1998

• Irinotecan

•Oxaliplatin

•Edrecolomab

• IFN

•Raltitrexed

•Capecitabine

•UFT/LV

•COX-2 inhibitors

•Signal transduction inhibitors (EGF-R,VEGF)

Irinotecan as adjuvant therapy in stage III colon cancer

•Bolus 5FU regimen with irinotecan (IFL) versus weekly 5FU/LV, n = 1254

•No benefit in DFS or OS

Data are accumulating that irinotecan should be combined with infusional and not bolus 5FU

Saltz et al. ASCO 2004

Primary endpoint in randomised adjuvant studies

Overall survival as primary endpoint in adjuvant studies

• considered as gold standard until 2004

Disadvantages:

• long duration of studies

• poor compliance of investigators

• slow implementation of promising new therapies

•with inconsistent use of more effective drugs after recurrence, effect of adjuvant Rx difficult to assess

Disease-free survival as endpoint of adjuvant studies in colon cancer

•Pooled analysis of > 17.000 patients enrolled in 17 phase III adjuvant 5FU studies 1978 – 1996

• 34% stage II, 65% stage III

• 74% of recurrences < 3 years

•Excellent correlation between 3-yr DFS and 5-yr OS

Sargent et al. ASCO 2004

3-yrs disease-free survival as endpoint of adjuvant studies in colon cancer

Cautions:

•Proportion of stage II patients is increasing: overall prognosis will be better

•Meta-analysis restricted to 5FU. With new effective drugs available, median survival after recurrence will be longer, DFS in adjuvant setting may be prolonged

•DFS at 3 years may not remain the gold standard !!

Adjuvant treatment in stage II colon cancer

Problems in studies with adjuvant therapy in stage II colon cancer

Large studies needed:

• at this stage relatively few events

• elderly population with relatively high incidence of non-cancer related deaths

• accrual in 90’s compromised by relatively low incidence of stage II disease

5FU/LV as adjuvant therapy for stage II colon cancer - history

result on survival

• IMPACT 6 studies n = 1100 negative

•NSABP 4 studies1 n = >2000 positive

•Mayo ’95 n = 318 negative

•CKVO ’012 n = 1029 positive

•QUASAR ’04 n = 3239 positive

1 2 studies without observation arm2 stage II and stage III colon+rectal

Adjuvant treatment in stage II colorectal cancer – QUASAR study

Gray et al. ASCO 2004

observation 5FU schedule

n 1617 1622

5-yr OS 77.4% 80.3% (p.02)

• Adjuvant treatment results in absolute 3% overall survival benefit in stage II colorectal cancer• No significant benefit in pts > 70 yrs

Adjuvant treatment in stage II colon cancer

•Data are accumulating that adjuvant treatment may be effective

•Absolute survival benefit for fluoropyrimidine treatment is approx. 3 – 4%

Oral fluoropyrimidines as adjuvant treatment

for colon cancer

UFT/LV versus 5FU/LV (Roswell Park schedule) in stage II + III colon cancer

Wolmark et al. ASCO 2004

5FU/LV UFT/LV

n 777 784

5-yr DFS 68.3% 66.9%

5-yr OS 78.7% 78.7%

UFT/LV has equivalent efficacy and toxicity to 5FU/LV

X-ACT trial in adjuvant treatment of stage III colon cancer

• 1° endpoint: DFS

• 2° endpoints

• OS

• tolerability

• pharmacoeconomics

• QoL

Stage IIIresection <8 weeks

Capecitabine1 250 mg/m2 twice daily,

d1–14, q21d n=1 004

Bolus 5-FU/LV5-FU 425 mg/m2 plus

LV 20 mg/m2, d1–5, q28dn=983

24 weeks

X-ACT powered to establish at least equivalence of capecitabine to 5-FU/LV

• Primary endpoint DFS80% power for at least equivalence primary endpoint met if upper limit 95% CI HR <1.25

• Secondary analysestests for superiorityRFS, OSmultivariate and subgroup analyses

• All analyses shown were prospectively planned

X-ACT treatment arms were well balanced

Capecitabine (n=1 004) (%)

Bolus 5-FU/LV (n=983) (%)

Age, median (range) 62 (25–80) 63 (22–82)

ECOG 0/1 85 / 15 85 / 15

Male/female 54 / 46 54 / 46

CEA: normal / >ULN 83 / 9 84 / 7

T1–2 T3/T4

10 76 / 14

10 76 / 14

Nodal status: N1/2 70 / 30 71 / 29

Tumour differentiation Well/moderate Poor/anaplastic

9 / 65 16 / 1

10 / 63 19 / 1

Cassidy et al. ASCO 2004

DFS: primary endpoint achieved (ITT)

HR = 0.87 (95% CI: 0.75–1.00)

Capecitabine (n=1 004)

5-FU/LV (n=983)

Estimated probability

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

Years

Capecitabine showed trend to superior DFS (ITT)


0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

Absolute differenceat 3 years: 3.6%

p=0.0528

3-year DFS

Capecitabine (n=1 004) 64.2%

5-FU/LV (n=983) 60.6%

Years

Capecitabine showed trend to improved OS (ITT)


0 1 2 3 4 5 6

Years

Absolute difference at 3 years: 3.7%

1.0

0.8

0.6

0.4

3-year OS

Capecitabine (n=1 004) 81.3%

5-FU/LV (n=983) 77.6%

HR = 0.84 (95% CI: 0.69–1.01)p=0.0706

Capecitabine consistent benefit in subgroup analysis for DFS

Hazard ratio and 95% CI

capecitabine better Bolus 5-FU/LV better

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

ITT population

MaleFemale

<40 40–69 years old≥70

N1 (1–3 nodes)N2 (4 nodes)

Baseline CEA <ULNBaseline CEA >ULN

1 987

1 074 912

76 1 543 396

1 389 593

1 672 155

n

1.0

0.8

0.6

0.4

0.2

0

Estimated probability of grade 3/4 adverse event

0 1 2 3 4 5 6 7 8Months

5-FU/LVcapecitabine

Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia

p<0.001

Fewer key grade 3/4 toxicities and later onset with capecitabine

Adjuvant chemotherapy needs active management

Patients (%)

Capecitabine (n=995)

Bolus 5-FU/LV(n=974)

Completed full course of treatment

84 88

Needed dose reduction 42 44

Needed interruption 15 5

Needed delay 46 29

Needed dose reduction, interruption or delay

57 52

Cassidy et al. ASCO 2004

Capecitabine as adjuvant treatment in stage III colon cancer

Compared to 5FU/LV, capecitabine has:

• trend towards better DFS

• trend towards better OS

• improved safety (but is still cytotoxic treatment!)

Capecitabine should replace 5FU/LV as adjuvant treatment in stage III colon cancer

FOLFOX as adjuvant treatment

for colon cancer

MOSAIC: Study Designstage II + III colon cancer

R

LV5FU2

FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²

Primary: – Disease-Free Survival (DFS)

Secondary:– Safety (including long-term)– Overall Survival (OS)

Endpoints

MOSAIC Rationale 1:MOSAIC Rationale 1:LV5FU2 in LV5FU2 in metastaticmetastatic colon cancer colon cancer

de Gramont et al. J Clin Oncol, 1997

5-FU infusion5-FU infusion 5-FU infusion5-FU infusion

D1D1 5-FU bolus5-FU bolus D2D2

LV LV

5-FU bolus5-FU bolus

Compared to monthly bolus 5-FU/LV: improved progression-free survival decreased toxicity

MOSAIC Rationale 2:MOSAIC Rationale 2:LV5FU2 in LV5FU2 in adjuvantadjuvant colon cancer colon cancer

André et al. J Clin Oncol, 2003



LV LV


Compared to monthly bolus 5-FU/LV: same efficacy: 73% 3-year DFS decreased toxicity



LV LV


OXA

MOSAIC Rationale 3:MOSAIC Rationale 3:FOLFOX4 in FOLFOX4 in metastaticmetastatic coloreactal cancer coloreactal cancer

Improved PFS compared to:

LV5FU2 de Gramont et al. J Clin Oncol 2000

IFL Goldberg et al. J Clin Oncol 2004

LV

OXA

R

MOSAIC: Treatment arms

*ambulatory infusion

LV5FU2

FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²

Every 2 weeks, 6 months of treatment (12 cycles)

D1D1 5-FU bolus5-FU bolus D2D2 5-FU bolus5-FU bolus

LV LV5-FU infusion* 5-FU infusion*

D1D1 5-FU bolus5-FU bolus D2D2 5-FU bolus5-FU bolus

LV LV5-FU infusion* 5-FU infusion*

MOSAIC: Patient characteristics

FOLFOX4 LV5FU2 (n=1123) (n=1123)

Median age, years 61 60

Male/Female % 56 /44 52 /48

KPS 80-100 % 86.2 87.6

Stage II/ III % 40 /60 40 /60

Bowel obstruction % 18 19

Perforation % 7 7Stratification for TNM stage, bowel obstruction/perforation, center

Median time surgery – start chemo: 5.7 wks (range 1.1 – 17)

DFS by treatment arm (ITT)

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 months

Probability

Hazard ratio: 0.76 [0.64 – 0.89] p =0.0008

24% risk reduction in the FOLFOX4 arm

3-year DFS

FOLFOX4 (n=1123) 78.7%LV5FU2 (n=1123) 73.3%

abs. difference = 5.4%

Disease-Free Survival Stage III patients

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

Probability

months

25% risk reduction for stage III patients

Hazard ratio: 0.75 [0.62-0.90] p=0.002Hazard ratio: 0.75 [0.62-0.90] p=0.002

3-year DFS

FOLFOX4 (n=672) 72.8%LV5FU2 (n=675) 65.8%


Disease-Free Survival Stage II patients

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

Hazard ratio: 0.79 [0.57-1.09] p=0.151Hazard ratio: 0.79 [0.57-1.09] p=0.151

Probability

months

21% risk reduction for stage II patients

3-year DFS

FOLFOX4 (n=451) 87.4%LV5FU2 (n=448) 84.3%


DFS analysis according to prognostic factors

ITT population

MaleFemale> 65 years old< 65 years oldT4T1,T2,T3N2N0,N1Stage IIIStage IIBowel obstructionNo obstructionTumour perforationNo perforationBaseline CEA > 5Baseline CEA < 5Well/moderately differentiatedPoorly differentiatedVenous invasionNo venous invasion

FOLFOX better LV5FU2 better

MOSAIC: Safety results, toxicity per patient

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

Thrombocytopenia 1.7 0.4

Neutropenia 41.1 (Gr 4: 12.2) 4.7

Febrile neutropenia 0.7 0.1

Neutropenic sepsis 1.1 0.1

Diarrhoea 10.8 6.7

Stomatitis 2.7 2.2

Vomiting 5.9 1.4

Allergy 3.0 0.2

Alopecia (Gr 2) 5.0 5.0

All cause mortality 0.5 0.5

MOSAIC:Peripheral sensory neuropathy

Paresthesias FOLFOX4 arm

Per patient One year(n=1108) after

Grade 0 8 % 70 %

Grade 1 48.1 % 24 %

Grade 2 31.5 % 5 %

Grade 3 12.4 % 1 %

Overall 82% 30%

(NCI version 1)

High-risk stage II colon cancer

Either of the following characteristics:

•Stage T4

• < 10 regional lymphnodes examined

•Bowel obstruction

• Tumor perforation

•Poorly differentiated histology

•Venous invasion

MOSAIC study in stage II/III colon cancer

Patients (n) 5FU/LV FOLFOX

total 1123 1123

Stage III 675 (60%) 672 (60%)

Stage II 448 (40%) 451 (40%)

High-risk stage II 290 (26%) 286 (25%)

Hickish et al. ASCO/ESMO 2004

0 6 12 18 24 30 36 42 48

3-year DFSFOLFOX4 (n=286) 84.9%LV5FU2 (n=290) 79.8%

abs. difference 5.1%

28% risk reduction in the FOLFOX4 arm

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

months

Probability

Disease-Free Survival High-risk stage II patients

Disease-Free Survival High-risk stage II patients

Hazard ratio 0.72 [0.48-1.08] N.S.

MOSAIC study in subgroups of colon cancer

Hazard ratio for relapse (95% CI)

Decrease in relative risk

of recurrence

Absolute difference in

3-yr DFS

Overall

n = 2246

0.76

(0.64-0.89) p.0008

24% 5.4% #

Stage III

n = 1247

0.76

(0.62-0.92) p.002

25% 7.0%

Stage II

n = 899

0.80

(0.56-1.15) NS

21% 3.1%

High-risk stage II

n = 576

0.72

(0.48-1.08) NS

28% 5.1%

# 4-yr DFS 75.9% vs. 69.1%, abs. diff. 6.8%

FOLFOX as adjuvant treatment in colon cancer

•Significant DFS benefit overall (stage II + III)

•MOSAIC study not designed for stage II – III subgroups

•Significant benefit in stage III, overall increasing after longer follow-up (DFS 3yrs. 5.4% 4-yrs. 6.8%)

•With so many effective drugs available, overall survival as endpoint becomes less reliable

FOLFOX as adjuvant treatment in stage II colon cancer

•Benefit in stage II is small, non-significant

•Benefit in high-risk stage II seems comparable to stage III but non-significant (underpowered)

•Prospective studies in high-risk stage II will probably never be performed

FOLFOX as adjuvant treatment in stage II colon cancer

•Relapse rate in stage II 20%

•Absolute benefit of 5FU/LV 4%

To cure 1 patient, 25 patients have to be treated

•Additional benefit of FOLFOX 3% (extrapolation!)

To cure 1 patient, 14 patients have to be treated

One out of 25 overall will not relapse if treated by FOLFOX instead of 5FU/LV

New standards for adjuvant treatment in stage II and III

colon cancer

Proposal for new standard adjuvant treatment in stage III colon cancer

• FOLFOX 12 cycles q 2 weeks

• For patients refusing or ineligible for FOLFOX: capecitabine 8 cycles q 3 weeks

•Capecitabine + oxaliplatin should not be administered outside adjuvant trials (ongoing)

Proposal for new standard adjuvant treatment in stage II colon cancer

Stage II overall

• capecitabine 8 cycles q 3 weeks, or observation ?

Stage II high-risk:

• FOLFOX or capecitabine ?

Adjuvant treatment in colon cancer:which option is best for our patients?

• patients must be informed about:

the reality of treatment

the associated risks/benefits

• Information should be provided by a physician with experience in chemotherapy

Documents

Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard?