Xeloda versus 5-FU/LV in adjuvant colon cancer: whats your conclusion? David Kerr University of Oxford Oxford, UK.

Xeloda versus 5-FU/LV in adjuvant colon cancer: what’s your conclusion?

David Kerr University of Oxford

Oxford, UK

Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer?

Against: Axel GrotheyFor: Jim Cassidy

Against

Axel GrotheyMayo Clinic

Rochester, Minnesota, USA

Large body of evidence for 5-FU in adjuvant treatment of colon cancer

5-FU/LV (Mayo Clinic regimen) versus observation

Mayo Clinic regimen versus Roswell Park regimen

Bolus 5-FU/LV versus continuous infusion 5-FU/LV (LV5FU2)

IFL vs Roswell Park (CALGB89803)

FOLFIRI versus infused 5-FU/LV (PETACC-3, ACCORD-2)

FLOX versus bolus 5-FU/LV (NSABP C-07)

FOLFOX versus LV5FU2 (MOSAIC)

Bolus 5-FU/LV evolved as standardof care for stage III colon cancer

1O’Connell MJ et al. J Clin Oncol 1997;15:246–50 2IMPACT investigators. Lancet 1995;345:939–443Wolmark N et al. J Clin Oncol 1993;11:1879–87 MOF = lomustine (MeCCNU), vincristine, 5-FU

5-year DFS 5-year OS

(%) p value (%) p value

5-FU/LV vs observation1

(NCCTG) 74 vs 58 0.004 74 vs 63 0.02

5-FU/LV vs observation2 (IMPACT)

71 vs 62 <0.0001 83 vs 78 0.03

5-FU/LV vs MOF3

(NSABP C-03) 73 vs 64 0.0004 84 vs 77 0.003

Continuous infusion versus bolus 5-FU/LV:

similar efficacy, improved safety

LV5FU2 (n=452)

Bolus 5-FU/LV (n=453)

DFS (HR [95% CI]) 1.270 (0.87–1.86) p=0.21

OS (HR [95% CI]) 1.025 (0.78–1.35) p=0.86

Grade 3 / 4 adverse events (% of patients)

Neutropenia 7 16

Diarrhea 4 9

Mucositis 2 7

Nausea / vomiting* 1 3

All toxicities 11 26

André T et al. J Clin Oncol 2003;21:2896–903*Not significant

Landmark trials: recent evidence for 5-FU-based combinations

DFS Hazard ratio

(95% CI)

p value

OS Hazard ratio

(95% CI)

p value

FOLFOX vs LV5FU21

(MOSAIC) 0.77

(0.65–0.90) <0.001 0.91

(0.75–1.11) Not

reported

FLOX vs bolus 5-FU/LV2 (NSABP C-07)

0.79 (0.67–0.93)

<0.004 Not reported

Not reported

IFL vs bolus 5-FU/LV3

(CALGB89803) Not

reported 0.84 Not

reported 0.88

FOLFIRI vs LV5FU24 (PETACC-3)

0.89 (0.77–1.11)

0.091 Not reported

Not reported

1de Gramont A et al. Proc ASCO 2005 (Abst 3501)2Wolmark N et al. Proc ASCO 2005 (Abst LBA3500)

3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500)4Van Cutsem E et al. Proc ASCO 2005 (Abst LBA8)

Patient management with 5-FU/LV

Regular visits to hospital/clinic with i.v. regimens ensures

– greater opportunity for face-to-face interaction with clinicians and nurses

– reduced risk of over and under compliance

Critical points on Xeloda

Xeloda monotherapy has always been compared with the Mayo Clinic regimen in the adjuvant and palliative settings

– the most toxic way to give 5-FU/LV

More appropriate comparators

– in the USA: Roswell Park regimen

– in Europe: LV5FU2

Question of appropriate dosing of Xeloda

5-FU/LV: the evidence

Large body of clinical trial data for 5-FU/LV and 5-FU-based combination regimens

In the 1990s, bolus 5-FU/LV became the standard of care in the adjuvant setting

Infusional 5-FU/LV has similar efficacy and an improved safety profile compared with bolus 5-FU/LV

Xeloda has not been tested against infusional 5-FU/LV

5-FU-based combinations with oxaliplatin have evolved as standard of care

For

Jim CassidyBeatson Oncology Centre

Glasgow, UK

Evidence for Xeloda comes from two phase III trials: X-ACT and XELOXA (n=3 848)

1° endpoint: DFS

Stage III,resection 8 weeks

Xeloda(n=1 004)

Bolus 5-FU/LV(n=983)

24 weeks

Stage III colon cancer

XELOX(n=937)

24 weeks

Bolus 5-FU/LV (Mayo Clinic or Roswell Park)

(n=924)24 or 32 weeks

1° endpoint: DFS

X-ACT

XELOXA

Continuous infusion 5-FU/LV or Xeloda?

Mayo Clinic regimen was the standard of care

Superiority of infused vs bolus 5-FU/LV not shown1

Xeloda has a significantly improved safety profilevs bolus 5-FU/LV (p<0.001)2

In a meta-analysis in MCRC, Xeloda offers at least equivalent efficacy with superior safety vs continuous infusion 5-FU3

1André T et al. J Clin Oncol 2003;21:2896–9032Cassidy J et al. Ann Oncol 2002;13:566–75

3Cole S et al. Proc ASCO 2005 (Abst 3591)

Trend to superior DFS with Xeloda (ITT)

Estimated probability

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

Absolute differenceat 3 years: 3.6%

Test for superiorityp=0.0528

3-year DFS

Xeloda (n=1 004) 64.2%

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

Years

HR=0.87 (95% CI: 0.75–1.00)Compared to HR upper limit 1.20, p<0.0001

Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

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

1.0

0.8

0.6

0.4

0.2

0.0

Estimated probability of agrade 3 / 4 adverse event

0 1 2 3 4 5 6 7 8Months

5-FU/LVXeloda

p<0.001

Fewer and later onset of key grade 3 / 4 adverse events with Xeloda versus 5-FU/LV

Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

Oral Xeloda offers freedom withouta loss of effective management

Proven compliance in clinical trials

Patients lead a more normal lifestyle with home-based treatment

Patients prefer oral chemotherapy

Patient education is a priority

– time allocated before treatment begins

– patients advised on side-effect management up-front

– telephone follow-up

Less time in hospital = more face-to-face time with family

Flexibility with Xeloda: 28 opportunities for modifying dose per cycle

Dose modification = interrupt, delay or reduce

5-FU/LV425 / 20mg/m2

(i.v. bolus)

Xeloda1 250mg/m2 twice daily

(oral)

Day

Days 1–14 Rest

1 8 15 21

Repeat cycle at day 28

ampm

28

Repeat cycle at day 21

= Administration of oral tablet at home; point at which dose modification can occur

= Visit to hospital/clinic for i.v. administration

Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV

Mean visitsper patient

Xeloda (n=995)

5-FU/LV (n=974)

3 0

2 0

1 0

0AE treatment Drug administration Total

McKendrick JJ et al. J Clin Oncol Proc ASCO 2004;23:265 (Abst 3578; poster update)

Calculated time per administration (minutes)

AIO de Gramont Xeloda

Leucovorin 120 120–240 –

5-FU bolus – 5 –

Prolonged infusion (set-up)

30 30–60

–

Xeloda – – –

Replacing infused 5-FU/LV withXeloda: less time per patient

Total ‘chair’ time 150 155–305 30*

*Upfront patient education

-1864

1450

-3004

-57 -259

7

Net costs per patient versus 5-FU/LV (£)

4 000

2 000

0

–2 000

–4 000

Xeloda is a uniquely ‘dominant’ treatmentin cancer chemotherapy: UK perspective

Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl. 3):iii73 (Abst 274PD)

Total Drugs Administration Hospital Medications Consultations

(€2 721) use

Xeloda versus Mayo Clinic regimen in adjuvant treatment

Benefits

At least equivalent efficacy

Trend to improved DFS + OS

Improved RFS

toxicity

Convenience

Cost savings

Risks

hand-foot syndrome

Xeloda is an ideal combination partner in the adjuvant setting

XELOXA1 MOSAIC2 NSABP C-073 Grade 3/4 toxicities XELOX 5-FU/LV FOLFOX LV5FU2 FLOX 5-FU/LV

Diarrhea 19 20 12 7 36 32

Stomatits <1 8 3 2 NR NR

Nausea 5 4 5 2 15 10

Vomiting 6 3 6 1 12 12

Neurosensory 11 0 12 0 8 1

HFS 5 <1 2 2 NR NR

Neutropenia 8 15 41 5 5 2

Febrile neutropenia <1 4 2 <1 NR NR

1Schmoll H-J et al. Proc ASCO 2005 (Abst 3523)

2André T et al. N Engl J Med 2004;350:2343–513Smith R et al. Proc Am Soc Clin Oncol 2003;22 (Abst 1181; poster update)

Xeloda: the evidence

At least as effective as 5-FU/LV for stage III colon cancer

– strong trend to superior DFS, superior RFS and trend to superior OS

Fewer grade 3/4 toxicities than 5-FU/LV

Dosing flexibility improves side effect management

Convenience of oral administration allows patients to lead a more normal lifestyle

Cost effective

Effective, safe and convenient combination partner, simplifying combination treatment

The fluoropyrimidine of choice in the adjuvant treatmentof colon cancer

Debate summary

David KerrUniversity of Oxford

Oxford, UK

The need for improved adjuvant treatment for colon cancer

Adjuvant 5-FU/LV has benefits, but

– considerable discrepancy between consensus recommendations and use1

– 40–50% of elderly patients (>69 years) with stage III disease do not receive adjuvant chemotherapy2

Need for more effective and convenient regimens

1Grothey A et al. Med Klin 2002;97:270–7 2Hensley-Alford S et al. Proc Am Soc Clin Oncol 2003;23:748 (Abst 3008)

Adjuvant Xeloda: a favorable benefit/risk ratio

Single-agent Xeloda is at least as effective as, and better tolerated than, 5-FU/LV– proven role in stage III– should also be considered for stage II patients– efficacy and safety benefits maintained in older

patients– cost savings with improved outcomes and

lifestyle

Xeloda can replace 5-FU/LV as it offers the best balance of efficacy, safety and convenience for patients

Authorities have approved Xeloda as adjuvant treatment for colon cancer

EMEA approved Xeloda (31 March 2005)

. . . Xeloda is indicated for the adjuvant treatmentof patients following surgery for stage III (Dukes’ stage C) colon cancer

FDA approved 15 June 2005

Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer?