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