1. 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

2. Against: Axel Grothey For: Jim Cassidy
Should Xeloda replace 5-FU/LV for the adjuvant treatment of colon cancer?
Against: Axel Grothey
For: Jim Cassidy

3. Axel Grothey Mayo Clinic Rochester, Minnesota, USA
Against
Axel Grothey
Mayo Clinic Rochester, Minnesota, USA

4. 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)
The evidence for the use of 5-FU/LV in the adjuvant setting, either alone or in combination, comes from a large body of clinical trials.
Two large trials in the adjuvant setting have compared 5-FU/LV with observation alone [1,2]. Both of these trials demonstrated improved outcomes for patients receiving 5-FU/LV compared with no treatment.
A third trial compared adjuvant treatment with the Mayo Clinic regimen or the Roswell Park regimen of bolus 5-FU/LV [3]. The Roswell Park regimen was statistically non-inferior to the Mayo Clinic regimen in terms of disease-free (DFS) and overall survival in high-risk stage II and III colon cancer. One-third of patients experienced dose-limiting grade 3/4 diarrhea.
Three clinical trials have compared bolus administration with protracted infusion 5-FU [4–6]. However, none of these trials was adequately powered to demonstrate non-inferiority and no efficacy advantage for continuous infusion 5-FU was demonstrated.
In the adjuvant setting, the irinotecan-based regimen, FOLFIRI (with infused 5-FU/LV) has not demonstrated a significant improvement in DFS versus infused 5-FU/LV [7,8]. Overall survival data for this regimen have not yet been reported. Similarly, IFL (irinotecan plus bolus 5-FU/LV) has shown no improvement in either DFS or overall survival and is not recommended for the adjuvant treatment of colon cancer [9].
The combination of oxaliplatin with either infused 5-FU/LV (FOLFOX) or bolus 5-FU/LV (FLOX) improves DFS beyond that of 5-FU/LV alone. With a median follow-up of 4 years in the MOSAIC trial, 79.5% of patients in the overall population who received FOLFOX were disease free compared with 69.1% of patients receiving LV5FU2 (p=0.0008) [10]. In the overall population, 84.3% and 82.7% of patients are still alive after 4 years in the FOLFOX and 5-FU/LV arms, respectively. Recently reported data from the NSABP C-07 trial of FLOX versus bolus 5-FU/LV also showed a significant improvement in DFS with the combination regimen versus the single agent (p<0.004) [11]. To date, no benefit in overall survival has been demonstrated with either regimen.
1. O’Connell MJ et al. J Clin Oncol 1997;15:246–50.
2. IMPACT investigators. Lancet 1995;345:939–44.
3. Haller DG et al. Proc Am Soc Clin Oncol 1998;17:256a (Abstract 982).
4. Poplin EA et al. J Clin Oncol 2005;23:1819–25.
5. Chau I et al. Ann Oncol 2005;16:549–57.
6. André T et al. J Clin Oncol 2003;21:2896–903.
7. Van Cutsem E et al. Proc ASCO 2005 (Abstract LBA8).
8. Ychou M et al. Proc Am Soc Clin Oncol 2003;22:295 (Abstract 1183).
9. Saltz LB et al. Proc Am Soc Clin Oncol 2004;23:246 (Abstract 3500).
10. de Gramont A et al. Proc ASCO 2005 (Abstract 3501).
11. Wolmark N et al. Proc ASCO 2005 (Abstract LBA3500).

5. Bolus 5-FU/LV evolved as standard of care for stage III colon cancer
Bolus 5-FU/LV evolved as the standard of care for stage III colon cancer and has remained as such.
The two most commonly used bolus regimens are Mayo Clinic and Roswell Park. The Mayo Clinic regimen demonstrated significant improvements in DFS and overall survival versus observation alone [1,2].
In one study of the Mayo Clinic regimen, 309 of 317 enrolled patients were eligible for efficacy analyses
the proportion of patients disease-free at 5 years was 0.74 for the chemotherapy group and 0.58 for those treated with surgery alone (p=0.004)
the proportion of patients alive at 5 years was 0.74 for patients who received chemotherapy and 0.63 for patients treated with surgery alone (p=0.02) [1].
A further study of 1493 patients has shown similar DFS (0.71 vs 0.62, Mayo Clinic versus observation, respectively; p<0.0001) and overall survival (0.83 vs 0.78, respectively; p=0.03) at five years [2].
An NSABP study investigated the Mayo Clinic regimen versus lomustine (MeCCNU), vincristine and 5-FU (MOF), again this study demonstrated similar DFS (0.73 vs 0.64, respectively; p=0.0004) and overall survival (0.84 vs 0.77, respectively; p=0.003) to those seen with Mayo Clinic versus observation at five years[3].
1. O’Connell MJ et al. J Clin Oncol 1997;15:246–50.
2. IMPACT investigators. Lancet 1995;345:939–44.
3.Wolmark N et al. J Clin Oncol 1993;11:1879–87.
1O’Connell MJ et al. J Clin Oncol 1997;15:246–50 2IMPACT investigators. Lancet 1995;345:939–44 3Wolmark N et al. J Clin Oncol 1993;11:1879–87
MOF = lomustine (MeCCNU), vincristine, 5-FU

6. Continuous infusion versus bolus 5-FU/LV: similar efficacy, improved safety
Two trials examining continuous infusion 5-FU/LV versus standard bolus administration as adjuvant treatment for colon cancer terminated prematurely and were consequently insufficiently powered to show equivalent efficacy [1,2]. They did, however, confirm the safety advantages of infused versus bolus 5-FU/LV.
A recently published GERCOR trial with a 2-by-2 factorial design compared a reduced-dose ‘Mayo-like’ 5-FU/LV regimen (LV 200mg/m2 plus bolus 5-FU 400mg/m2 for five days every 28 days) with the de Gramont 5-FU/LV regimen (LV5FU2: 200mg/m2 LV over 2 hours then bolus 5-FU 400mg/m2 then 22-hour infusion 5-FU 600mg/m2 days 1 and 2, every 2 weeks) as adjuvant treatment in patients with stage II and III (Dukes’ stage B2 and C) colon cancer [3]. A second randomization allocated patients to receive 24 or 36 weeks’ treatment.
Overall, 453 patients received the bolus regimen and 452 patients received LV5FU2.
43% (389 patients) had stage II disease.
LV5FU2 was not superior to the non-standard bolus 5-FU/LV regimen in terms of either DFS or overall survival. The trial was not powered to demonstrate non-inferiority in DFS (HR = 1.04; 95% CI: 0.814–1.335) or overall survival (HR=1.27; 95% CI: 0.874–1.855).
As expected, LV5FU2 demonstrated an improved safety profile versus the bolus 5-FU/LV regimen, with significantly (p<0.001) lower incidences of all grade 3/4 toxicities [1], including
grade 3/4 neutropenia
grade 3/4 diarrhea and mucositis.
Premature withdrawal rates were 23% with LV5FU2 and 19% with bolus 5-FU/LV.
1. Poplin EA et al. J Clin Oncol 2005;23:1819–25.
2. Chau I et al. Ann Oncol 2005;16:549–57.
3. André T et al. J Clin Oncol 2003;21:2896–903.
*Not significant
André T et al. J Clin Oncol 2003;21:2896–903

7. Landmark trials: recent evidence for 5-FU-based combinations
FOLFOX has shown an improvement in DFS compared with the infusional regimen LV5FU2, but as yet has not shown superior overall survival [1]. Similarly FLOX has demonstrated an improvement in DFS compared with bolus 5-FU/LV; overall survival has not yet been reported [2].
In contrast, IFL has shown no improvement in either DFS or overall survival [3]; FOLFIRI has not shown a significant improvement in DFS and overall survival has not been reported [4].
1. de Gramont A et al. Proc ASCO 2005 (Abstract 3501).
2. Wolmark N et al. Proc ASCO 2005 (Abstract LBA3500).
3. Saltz LB et al. Proc Am Soc Clin Oncol 2004;23:246 (Abstract 3500).
4. Van Cutsem E et al. Proc ASCO 2005 (Abstract LBA8).
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)

8. 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
Patients receiving intravenous regimens based on 5-FU/LV must have regular trips to the hospital or clinic to receive their treatment.
The high number of trips to hospital ensure there is a regular opportunity to interact face-to-face with clinicians and nurses, offering many chances to discuss any concerns or side effects.
The necessity of visiting hospital for treatment also ensures there is a reduced risk of over or under compliance for patients receiving i.v. therapy.

9. 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
The two main bolus 5-FU/LV regimens are the Mayo Clinic and Roswell Park regimens. The Mayo Clinic regimen demonstrated significant improvements in DFS and overall survival versus observation alone [1–2]. However, the Mayo Clinic regimen is associated with a high incidence of side effects.
The Roswell Park 5-FU/LV regimen may be seen as a more appropriate comparator in the USA; it was statistically non-inferior to the Mayo Clinic regimen in terms of DFS and overall survival in high-risk stage II and III colon cancer [3]. However, one-third of patients experienced dose-limiting grade 3/4 diarrhea and the Roswell Park regimen has never become a global standard.
Although considered by some Europeans to be the optimal mode of delivering i.v. 5-FU/LV, delivering 5-FU by continuous infusion is not a standard approach in the adjuvant treatment of colon cancer. Infused 5-FU/LV has similar efficacy and improved safety versus bolus, but is associated with increased risk of central venous access complications [4].
1. O’Connell MJ et al. J Clin Oncol 1997;15:246–50.
2. IMPACT investigators. Lancet 1995;345:939–44.
3. Haller DG et al. Proc Am Soc Clin Oncol 1998;17:256a (Abstract 982).
3. André T et al. J Clin Oncol 2003;21:2896–903.

10. 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
Bolus 5-FU/LV evolved as the standard of care for stage III colon cancer and has remained as such despite the introduction of new infusional regimens.
The two main bolus regimens are the Mayo Clinic and Roswell Park regimens. The Mayo Clinic regimen demonstrated significant improvements in DFS and overall survival versus observation alone [1–2].
To date, the studies that have evaluated bolus 5-FU/LV versus continuous infusion have not been powered to demonstrate equivalence. At best we can say the two routes of administration may have similar efficacy [3–5].
Recent evidence shows that 5-FU-based combinations with oxaliplatin are more effective than 5-FU/LV alone [6,7].
1. O’Connell MJ et al. J Clin Oncol 1997;15:246–50.
2. IMPACT investigators. Lancet 1995;345:939–44.
3. André T et al. J Clin Oncol 2003;21:2896–903.
4. Poplin EA et al. J Clin Oncol 2005;23:1819–25.
5. Chau I et al. Ann Oncol 2005;16:549–57.
6. de Gramont A et al. Proc ASCO 2005 (Abstract 3501).
7. Wolmark N et al. Proc ASCO 2005 (Abstract LBA3500).

11. Jim Cassidy Beatson Oncology Centre Glasgow, UK
For
Jim Cassidy
Beatson Oncology Centre Glasgow, UK

12. Bolus 5-FU/LV (Mayo Clinic or Roswell Park)
Evidence for Xeloda comes from two phase III trials: X-ACT and XELOXA (n=3 848)
1° endpoint: DFS
Xeloda
(n=1 004)
X-ACT
Stage III,
resection £8 weeks
24 weeks
Bolus 5-FU/LV
(n=983)
1° endpoint: DFS
XELOX (n=937)
24 weeks
Xeloda is firmly established as first-line treatment for metastatic colorectal cancer (MCRC). In MCRC two randomized, phase III trials have demonstrated superior response rates and similar time to progression and overall survival with favorable safety for Xeloda versus bolus 5-FU/LV [1,2].
An open-label, multinational, randomized phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for stage III colon cancer [3,4].
Primary endpoint: at least equivalence with Xeloda in DFS.
Secondary objectives: equivalence in relapse-free survival (RFS) and overall survival; predefined superiority and confirmatory analyses (subgroups, multivariate); safety; pharmacoeconomics.
Multivariate analyses were prospectively planned to assess the robustness of the analyses for DFS, RFS and overall survival, subgroup analysis of DFS was also planned.
A second phase III trial, XELOXA, is evaluating Xeloda in combination with oxaliplatin versus two bolus regimens of 5-FU/LV, the Mayo Clinic regimen and the Roswell Park regimen [5].
A total of 1886 patients with surgically resected, chemotherapy-naïve, stage III colon cancer have been randomized 1:1.
Patients received eight cycles of standard XELOX versus four cycles of 5-FU/LV (Roswell Park regimen; 32 weeks) or six cycles of 5-FU/LV (Mayo Clinic regimen; 24 weeks); choice of comparator regimen was preselected by each center prior to study start.
The primary objective is to show that DFS is superior with XELOX versus bolus 5-FU/LV.
Secondary endpoints include overall survival, tolerability, convenience and pharmacoeconomic outcomes; pharmacogenetic and tumor marker studies are also being performed.
1. Van Cutsem E et al. Br J Cancer 2004;90:1190–7.
2. Cassidy J et al. Ann Oncol 2002;13:566–75.
3. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
4. Cassidy J et al. J Clin Oncol 2004;22:247s (Abstract 3509).
5. Schmoll H-J et al. J Clin Oncol Proc ASCO 2005 (Abstract 3523).
Stage III colon cancer
XELOXA
Bolus 5-FU/LV (Mayo Clinic or Roswell Park)
(n=924) 24 or 32 weeks

13. 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 profile vs 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
In the mid-1990s, the Mayo Clinic regimen was considered to be the standard of care in the adjuvant setting. Phase III data have not shown superiority of infused 5-FU/LV versus bolus 5-FU/LV in this setting [1].
Adjuvant Xeloda is at least as effective as bolus 5-FU/LV with a strong trend towards superior DFS (p=0.0528) [2]. In addition, in a predefined analysis of key grade 3/4 adverse events (including diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome and neutropenia) Xeloda demonstrated a significantly superior safety profile compared with bolus 5-FU/LV (p<0.001).
Xeloda has not been directly compared with continuous infusion 5-FU/LV in the adjuvant setting. However, in the metastatic setting a recent meta-analysis has shown that Xeloda has at least equivalent efficacy with a superior safety profile compared with continuous infusion 5-FU/LV [3]. This is likely to be applicable in the adjuvant setting.
1. André T et al. J Clin Oncol 2003;21:2896–903.
2. Cassidy J et al. Ann Oncol 2002;13:566–75.
3. Cole S et al. J Clin Oncol Proc ASCO 2005 (Abstract 3591).
1André T et al. J Clin Oncol 2003;21:2896–903
2Cassidy J et al. Ann Oncol 2002;13:566–75
3Cole S et al. Proc ASCO 2005 (Abst 3591)

14. Trend to superior DFS with Xeloda (ITT)
Estimated probability
3-year DFS
Xeloda (n=1 004) 64.2%
5-FU/LV (n=983) 60.6%
1.0
0.8
0.6
0.4
HR=0.87 (95% CI: 0.75–1.00)
Compared to HR upper limit 1.20, p<0.0001
Absolute difference
at 3 years: 3.6%
In the phase III X-ACT trial of adjuvant Xeloda versus bolus 5-FU/LV (Mayo Clinic regimen), Xeloda showed a strong trend towards superior DFS compared with 5-FU/LV in the intent-to-treat analysis (p=0.0528)
at 3 years, 3.6% more patients receiving Xeloda were disease free compared with patients receiving 5-FU/LV
the superior DFS with Xeloda was confirmed in the per-protocol analysis with a hazard ratio of 0.89 (95% CI: 0.76–1.04).
The hazard ratio comparing DFS with Xeloda with that of 5-FU/LV was 0.87 (95% CI: 0.75–1.00). The upper limit of the confidence interval of 1.00 was significantly below both the 1.25 and 1.20 predefined margins for at least equivalence (p< in both cases), providing confidence that Xeloda is at least as effective as 5-FU/LV.
Cassidy J et al. J Clin Oncol 2004;22:247s (Abstract 3509).
Test for superiority p=0.0528
Years
Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

15. Estimated probability of a grade 3 / 4 adverse event
Fewer and later onset of key grade 3 / 4 adverse events with Xeloda versus 5-FU/LV
Estimated probability of a grade 3 / 4 adverse event
1.0
0.8
0.6
0.4
0.2
0.0
5-FU/LV
Xeloda
p<0.001
As adjuvant treatment for Dukes’ C colon cancer, Xeloda has a favorable safety profile compared with the current standard, 5-FU/LV (Mayo Clinic regimen) [1].
Overall, fewer treatment-related adverse events occurred in the Xeloda arm than with 5-FU/LV (4274 vs 4820, respectively).
The improved safety profile of adjuvant Xeloda versus 5-FU/LV is demonstrated by
significantly lower incidences of diarrhea, nausea/vomiting, stomatitis (including grade 3 or 4), alopecia, neutropenia (including grade 3 or 4), and febrile neutropenia/sepsis
significantly less early severe toxicity.
Overall, fewer treatment-related grade 3/4 adverse events occurred in the Xeloda arm (542 vs 568 with 5-FU/LV) [1].
Kaplan-Meier analyses confirmed that the incidence of predefined key grade 3/4 fluoropyrimidine toxicities is significantly (p<0.001) reduced throughout treatment with Xeloda compared with 5-FU/LV [2]. Key grade 3/4 toxicities included in this analysis were diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome and neutropenia. This analysis was predefined in the statistical analysis plan, and agreed with EU and US regulatory authorities to be the primary safety analysis of the trial.
The difference between 5-FU/LV and Xeloda is driven by large differences in neutropenia and stomatitis, but also smaller differences in nausea, vomiting, alopecia and diarrhea.
The most common treatment-related adverse event with adjuvant Xeloda is hand-foot syndrome
experience in the metastatic setting shows that hand-foot syndrome is effectively managed by adequate patient education, treatment interruption and, if necessary, dose reduction and rarely leads to treatment discontinuation or hospitalization [3].
1. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
2. Cassidy J et al. J Clin Oncol 2004;22:247s (Abstract 3509).
3. Cassidy J et al. Ann Oncol 2002;13:566–75.
Months
Grade 3 / 4 diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia
Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

16. Oral Xeloda offers freedom without a 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
Xeloda offers patients the freedom of an oral agent without a loss of effective management; compliance with the dosing schedule of Xeloda has been proven in several clinical trials. It provides effective and convenient treatment, but active patient management is crucial.
With oral Xeloda, patients can lead a more normal lifestyle than those receiving i.v. treatment, in addition, patients prefer oral chemotherapy.
Fewer hospital visits with Xeloda does not indicate that there will be a loss of effective side-effect management, but, patient education is a priority for the safe administration of Xeloda. To a greater degree than with i.v. chemotherapy, the patient must take an active role in the management of toxicity
it is necessary to establish clear communication lines between the patient and the clinic to ensure that patients will gain the maximum benefit from Xeloda chemotherapy.
From the patient’s perspective, less time spent receiving treatment in hospital means more face-to-face time with their families.

17. Flexibility with Xeloda: 28 opportunities for modifying dose per cycle
5-FU/LV
425 / 20mg/m2 (i.v. bolus)
Day 1 8 15 21 28
Repeat cycle at day 28
Xeloda 1 250mg/m2 twice daily (oral)
Days 1–14
Rest am
The dosing schedule for Xeloda consists of tablets taken twice daily over 14 days. So Xeloda dosing provides 28 opportunities per cycle for dose modification. If side effects develop, treatment can be interrupted until side effects have subsided and/or the number of tablets can be reduced for subsequent doses.
Clinical toxicity Dose adjustment for next cycle
(NCIC grade) During a course of therapy (% of starting dose)
Grade 1 Maintain dose level Maintain dose level
Grade 2
1st appearance Interrupt until resolved to grade 0/1 100%
2nd appearance Interrupt until resolved to grade 0/1 75%
3rd appearance Interrupt until resolved to grade 0/1 50%
4th appearance Discontinue treatment permanently
Grade 3
1st appearance Interrupt until resolved to grade 0/1 75%
2nd appearance Interrupt until resolved to grade 0/1 50%
3rd appearance Discontinue treatment permanently
Grade 4
1st appearance Discontinue treatment permanently, or
If physician deems it to be in the patient’s best
interest to continue, interrupt until resolved to
grade 0/1 50%
Repeat cycle at day 21 pm
Dose modification = interrupt, delay or reduce
= Administration of oral tablet at home; point at which dose modification can occur
= Visit to hospital/clinic for i.v. administration

18. Mean visits per patient
Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV
Mean visits per patient
3 0
2 0
1 0
Xeloda (n=995)
5-FU/LV (n=974)
Safety and medical resource utilization (MRU) data were collected prospectively during the X-ACT trial [1]:
throughout treatment
28 days after the last intake of study drug.
Data were collected on:
study drug administration
hospitalizations
visits to providers
medications for adverse events.
Descriptive statistics were used to summarize MRU results.
The prospective MRU sub-study of X-ACT showed that Xeloda provides benefits over 5-FU/LV in terms of reduced use of medical resources [1]
for every 100 patients treated, treatment with Xeloda required 2000 fewer ambulatory visits per treatment period compared with 5-FU/LV
only 9 ambulatory visits are required with Xeloda versus 30 with 5-FU/LV.
1. McKendrick JJ et al. Proc Am Soc Clin Oncol 2004;23:265 (Abst 3578; poster update)
AE treatment Drug administration Total
McKendrick JJ et al. J Clin Oncol Proc ASCO 2004;23:265 (Abst 3578; poster update)

19. Replacing infused 5-FU/LV with Xeloda: less time per patient
When compared with two infusional regimens (de Gramont and AIO), Xeloda has an administration time of only 30 minutes (for upfront patient education), 5–10 times less than the 5-FU/LV-based regimens (150–305 minutes).
Administration of the AIO regimen involves a 2-hour infusion of leucovorin plus a prolonged infusion of 5-FU, meaning that the patient must spend at least 2.5 hours receiving treatment.
Similarly, the de Gramont regimen involves a 2-hour infusion of leucovorin followed by a 5-FU bolus injection and then a prolonged infusion of 5-FU, meaning that again the patient must spend at least 2.5 hours in hospital receiving treatment.
In contrast, with the Xeloda combination the patient need only spend time in hospital receiving upfront education, because Xeloda is administered orally at home.
This indicates a substantial saving both in patient time and hospital resource for Xeloda. In addition, Xeloda requires less time for the patient to travel to and from hospital to receive treatment than i.v. 5-FU-based regimens, this means a further time saving for the patient as well as a saving in the cost of travel.
Total ‘chair’ time –305 30*
*Upfront patient education

20. Net costs per patient versus 5-FU/LV (£)
Xeloda is a uniquely ‘dominant’ treatment in cancer chemotherapy: UK perspective
Net costs per patient versus 5-FU/LV (£)
4 000
2 000
–2 000
–4 000
The major drivers for the cost analysis are the cost of the chemotherapy drugs and the cost of administration of treatment.
The number of treatment administration visits was increased almost four-fold with the i.v. 5-FU/LV regimen [1], the mean number of treatment administration visits per patient in 6 months was 7.38 in the Xeloda group and in the 5-FU/LV treatment group.
The additional £3004 required for infusion therapy is more than double the additional acquisition cost of Xeloda. Therefore, although the mean cost of chemotherapy drugs per patient was higher in the Xeloda arm, the mean cost of visits for chemotherapy administration were increased with 5-FU/LV compared with Xeloda [1].
Adjuvant Xeloda demonstrated an improved safety profile compared with i.v. 5-FU/LV [2,3] leading to approximately 10% fewer adverse event-related hospital admissions and 12% fewer days in hospital in the Xeloda treatment arm compared with the i.v. 5-FU/LV arm
the mean cost of hospitalizations was therefore lower with Xeloda than with 5-FU/LV.
The improved safety profile was also reflected in the need for fewer costly medications for the management of treatment-related adverse events with Xeloda (£86) versus 5-FU/LV (£345)
in particular, Xeloda reduced the need for the more expensive drugs, such as fluconazole for stomatitis, 5-HT3 antagonists for nausea/vomiting and cytokines for neutropenia.
From the societal perspective, Xeloda treatment was associated with cost savings of £1182 and £142 in respect of cost of time for travel, and travel costs.
The net effect of these cost differentials for 6-month adjuvant treatment for CRC is a £1864 (€2721) cost saving for each patient treated with Xeloda rather than 5-FU/LV.
The results of this pharmacoeconomic analysis show that Xeloda is a ‘dominant strategy’ in the adjuvant treatment of colon cancer [1].
‘Dominant strategy’ in pharmacoeconomic terms indicates that Xeloda offers greater benefits and lower costs versus 5-FU/LV. Xeloda has demonstrated consistent efficacy and safety benefits versus 5-FU/LV [2,3] and is cost saving compared with 5-FU/LV [1], providing economically significant quality-adjusted life-month gains.
1. Douillard J-Y et al. Ann Oncol 2004;15(Suppl. 3):iii73 (Abstract 274PD).
2. Cassidy J et al. J Clin Oncol 2004;22:247s (Abstract 3509).
3. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
Total Drugs Administration Hospital Medications Consultations
(€2 721) use
Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl. 3):iii73 (Abst 274PD)

21. 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 should be the first-choice fluoropyrimidine for the adjuvant treatment of colon cancer [1].
Xeloda has at least equivalent efficacy to bolus 5-FU/LV with a strong trend towards significantly improved DFS. Xeloda also showed a trend toward superior overall survival and significantly improved RFS.
The improved safety profile of Xeloda in the adjuvant setting mirrors that observed in the metastatic setting. However, Xeloda is associated with a higher incidence of hand-foot syndrome than 5-FU/LV.
Xeloda also offers the additional benefits of improved convenience and cost savings.
1. Cassidy J et al. J Clin Oncol 2004;22:247s (Abstract 3509).

22. Xeloda is an ideal combination partner in the adjuvant setting
In direct comparison, adjuvant XELOX is associated with less stomatitis, neutropenia and febrile neutropenia than bolus 5-FU/LV, but more neurosensory toxicity and hand-foot syndrome [1].
In the MOSAIC trial, FOLFOX4 was associated with an increased incidence of diarrhea, vomiting, and neurosensory toxicity plus considerably more neutropenia than LV5FU2, other side effects were similar in the two arms [2].
Safety data from the NSABP C-07 trial is limited, however, the incidence of diarrhea, vomiting and neutropenia was similar between FLOX and bolus 5-FU/LV, while the incidence of nausea and neurosensory toxicity was higher with the FLOX regimen [3].
Cross-trial comparison indicates that XELOX has a similar safety profile to FOLFOX with the exception of neutropenia, which is higher with the FOLFOX regimen and a favorable toxicity profile compared with FLOX given the higher rate of diarrhea with this regimen. As expected, all three combination regimens are associated with higher incidences of neurosensory toxicity than 5-FU/LV alone reflecting the use of oxaliplatin.
1. Schmoll H-J et al. J Clin Oncol Proc ASCO 2005 (Abstract 3523).
2. André T et al. N Engl J Med 2004;350:2343–51.
3. Wolmark N et al. J Clin Oncol Proc ASCO 2005 (Abstract LBA3500).
1Schmoll H-J et al. Proc ASCO 2005 (Abst 3523)
2André T et al. N Engl J Med 2004;350:2343–51
3Smith R et al. Proc Am Soc Clin Oncol 2003;22 (Abst 1181; poster update)

23. 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 treatment of colon cancer
Xeloda is at least as effective as 5-FU/LV for stage III colon cancer with a strong trend towards superior DFS, superior RFS and a trend towards superior overall survival. Xeloda also has
fewer grade 3/4 toxicities than 5-FU/LV
dosing flexibility, which improves side effect management
the convenience of oral administration, which allows patients to lead a more normal lifestyle
cost effectiveness.
In addition, Xeloda simplifies complex combination treatment.
Xeloda should be considered as the fluoropyrimidine of choice in the adjuvant treatment of colon cancer.

24. David Kerr University of Oxford Oxford, UK
Debate summary
David Kerr
University of Oxford Oxford, UK

25. 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
Adjuvant 5-FU/LV treatment has demonstrable benefits for patients but there is still a considerable discrepancy between the consensus recommendations for treatment and the reality of clinical practice [1].
40–50% of elderly patients (over 69 years of age) with stage III colorectal cancer do not receive adjuvant chemotherapy [2]. Evidence from a meta-analysis of seven trials suggests that these patients would receive considerable benefit from adjuvant therapy [3] and a more tolerable and convenient regimen might allow them the opportunity to do so.
There remains a need for more effective and convenient regimens to ensure that patients are getting the best possible treatment.
1. Grothey A et al. Med Klin 2002;97:270–7.
2. Hensley-Alford S et al. Proc Am Soc Clin Oncol 2003;22:748 (Abstract 3008).
3. Sargent DJ et al. New Engl J Med 2001;345:1091–7.
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)

26. 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
With a favorable benefit-to-risk ratio adjuvant Xeloda is at least as effective as 5-FU/LV, with a strong trend toward superior DFS and fewer grade 3/4 toxicities. Xeloda has
proven role in stage III
should also be considered for stage II patients
efficacy and safety benefits maintained in older patients
allows patients to lead a more normal lifestyle
cost savings with improved outcomes.
Xeloda should be considered the fluoropyrimidine of choice in the adjuvant treatment of colon cancer, whether in combination with oxaliplatin or used alone, as it provides a better balance in terms of risks and benefits.

27. Authorities have approved Xeloda as adjuvant treatment for colon cancer
EMEA approved Xeloda (31 March 2005)
. . . Xeloda is indicated for the adjuvant treatment of patients following surgery for stage III (Dukes’ stage C) colon cancer
On the 31st March, 2005, Xeloda received approval for the adjuvant treatment of colon cancer from the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP). The official indication for the Xeloda use label is as follows:
Xeloda is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer.
As of 15th June, 2005, Xeloda is also approved by the FDA.
FDA approved 15 June 2005

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