1. Phase III studies of Xeloda® in colorectal cancer (CRC)
Two phase III trials with identical protocols (one in the Americas, one in Europe, Israel and Australasia)
Patients were randomised to first-line
Xeloda: 1,250mg/m2 twice daily for 14 days followed by a 7-day rest period
Mayo Clinic regimen: leucovorin (LV) 20mg/m FU 425mg/m2 days 1–5 every 28 days, i.v. bolus
1. Phase III studies of Xeloda® in colorectal cancer (CRC)
Two randomised, multicentre, open-label, phase III trials were undertaken to compare oral Xeloda with i.v. bolus 5-FU/leucovorin (Mayo Clinic regimen) as first-line treatment for metastatic colorectal cancer (CRC).
One trial was conducted in the Americas1 and the other was performed in centres throughout Europe, Australia, New Zealand, Israel and Taiwan.2 The trials were identical in terms of study design, patient selection criteria, conduct and monitoring.
The primary objective of the studies was to demonstrate that patients receiving oral Xeloda as first-line treatment for metastatic CRC achieve a response rate at least equivalent to that achieved with Mayo Clinic regimen. Secondary objectives included comparison of efficacy in terms of time to disease progression, overall survival, duration of response and time to first response, and comparison of the safety profile, quality of life (QoL) and medical resource utilisation in the two treatment groups. Patients were randomised to treatment with either Xeloda (1,250mg/m2 twice daily for 14 days followed by a 7-day rest period; n=603) or Mayo Clinic regimen (20mg/m2 leucovorin (LV) followed by 425mg/m2 5-FU, administered as an i.v. bolus on days 1–5 every 28 days; n=604).
It was predefined to pool the data to obtain information on a large (>1,200) patient population. Therefore, a prospectively designed, integrated analysis of results from the two studies was performed using data from 603 patients treated with Xeloda and 604 patients treated with Mayo Clinic regimen.3 The results of the integrated analysis are presented in the following slides.
1. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282–92.
2. Van Cutsem E, Twelves C, Cassidy J et al. Oral Xeloda® (capecitabine) compared with intravenous 5-fluorouracil plus leucovorin (Mayo Clinic regimen) in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol (submitted).
3. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).

2. Baseline characteristics
The baseline characteristics of patients in the two treatment groups were well balanced.1 The median age was 64 years in the Xeloda group and 63 years in the 5-FU/LV group. The predominant metastatic site was the liver in approximately three-quarters of patients in both treatment arms and the lungs in 12% and 14% of each group, respectively. Approximately one-quarter of patients in both treatment groups had received prior adjuvant treatment.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol 2000;11(Suppl. 4):60 (Abstract 263).
KPS = Karnofsky Performance Score
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

3. Overall tumour response rate
Tumour assessment was performed before the start of treatment and at weeks 6, 12, 18, 24, 30, 39 and 48 by the investigators based on World Health Organization (WHO) criteria. The primary endpoint, response rate, was significantly superior in patients treated with Xeloda (25.7%) compared with Mayo Clinic regimen (16.7%, p<0.0002).1 This supports the results of the individual studies, which both demonstrated a superior response rate with Xeloda.2,3 Tumours were also assessed by an Independent Review Committee (IRC) consisting of a panel of radiologists blinded to study treatment, investigator’s assessment and the clinical condition of patients. The IRC used only digitised imaging to assess tumours. The superior efficacy of Xeloda was confirmed by the IRC-assessed response rates (22.4% with Xeloda vs 13.2% with Mayo Clinic regimen, p<0.0001).
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
2. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282–92.
3. Van Cutsem E, Twelves C, Cassidy J et al. Oral Xeloda® (capecitabine) compared with intravenous 5-fluorouracil plus leucovorin (Mayo Clinic regimen) in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol (submitted).
PR = partial response; CR = complete response
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

4. Response rates by subpopulation
Xeloda (n=603)
5-FU/LV (n=604) 40 35 30 25 20 15 10 5 * *
Response rate (%) * *
4. Response rates by subpopulation
When response rates were analysed by subpopulation, Xeloda was found to achieve consistently significantly superior response rates compared with Mayo Clinic regimen.1 A particularly impressive difference was seen in patients who had received prior adjuvant treatment, where the response rate with Xeloda was 21.1% compared with only 9.0% with Mayo Clinic regimen.
The response rate in patients with metastases predominantly in the liver was 25.6% with Xeloda and 16.6% with Mayo Clinic regimen. Corresponding values for patients with lung metastases were 33.3% and 10.3%. Xeloda also resulted in higher response rates in the subgroups of patients with a single metastatic site (37.8% vs 23.5%) or with multiple metastatic sites (21.8% vs 14.8%).
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263). * *
Prior No prior Liver† Lung† Single Multiple
adjuvant adjuvant metastatic metastatic site sites
*p<0.05
†Predominant site of metastases
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

5. Time to first response Xeloda (n=603) 5-FU/LV (n=604) Patients (%)
The time of first response in patients who responded to Xeloda therapy is displayed in 6-week intervals to provide an indication of time to first response. Responses occurred at least as early in the treatment course with Xeloda as with Mayo Clinic regimen, and in each time period tumour responses occurred more frequently with Xeloda.1
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
0–63 64– –147 >147
Study day
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

6. Time to disease progression*
1.0
0.8
0.6
0.4
0.2
Xeloda (n=603)
5-FU/LV (n=604)
Median (CI) Xeloda: 4.6 (4.3–5.3) 5-FU/LV: 4.7 (4.3–5.4)
Hazard ratio = (0.885–1.123)
Log-rank p=0.9535
Estimated probability
6. Time to disease progression
Time to disease progression, defined as time from randomisation to progressive disease or death in patients with no evidence of disease progression, was equivalent with Xeloda and Mayo Clinic regimen (median 4.6 months vs 4.7 months, respectively).1 These data confirmed the results of the individual trials. They were also supported by the analysis of time to treatment failure, which included in addition all patients who withdrew from treatment because of adverse events or treatment refusal. The median time to treatment failure was 4.2 months with Xeloda and 3.6 months with Mayo Clinic regimen.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
4.6
4.7
Time (months)
*or death
Hoff PM. Ann Oncol 2000;11 (Suppl. 4):60 (Abst 263)

7. Median (CI) Xeloda: 12.9 (12.0–14.0) 5-FU/LV: 12.8 (11.8–14.0)
Overall survival
1.0
0.8
0.6
0.4
0.2
Xeloda (n=603)
5-FU/LV (n=604)
Median (CI) Xeloda: 12.9 (12.0–14.0) 5-FU/LV: 12.8 (11.8–14.0)
Hazard ratio = (0.85–1.08)
Log-rank p=0.48
Estimated probability
7. Overall survival
Overall survival was equivalent with Xeloda and Mayo Clinic regimen (log-rank p=0.48, hazard ratio = 0.96),1 meaning that the risk of death is reduced by 4%. These data confirm the results of the individual trials.2,3 Median survival was 12.9 months with Xeloda and 12.8 months with Mayo Clinic regimen. A multivariate Cox regression analysis confirmed, as expected, that poor KPS, presence of liver metastases, high alkaline phosphatase concentration at baseline and multiple metastatic sites at baseline were prognostic factors for poor survival.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
2. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282–92.
3. Van Cutsem E, Twelves C, Cassidy J et al. Oral Xeloda® (capecitabine) compared with intravenous 5-fluorouracil plus leucovorin (Mayo Clinic regimen) in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol (submitted).
12.8
12.9
Time (months)
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

8. Summary of efficacy
Oral Xeloda achieves at least equivalent efficacy compared with 5-FU/LV
Superior (p<0.0002) response rates
Equivalent time to disease progression
Equivalent overall survival
8. Summary of efficacy
The integrated analysis of data from more than 1,200 patients with metastatic CRC indicate that first-line treatment with Xeloda results in significantly superior response rates compared with Mayo Clinic regimen (26% vs 17%, p<0.0002).1 In addition, response rates in subgroups of patients consistently supported these results. The response rate of 21.1% with Xeloda in patients who had received prior adjuvant treatment compared particularly favourably with the 9.0% response rate in patients treated with Mayo Clinic regimen. Furthermore, the time to disease progression and overall survival were equivalent in the two treatment groups.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

9. Most common treatment-related clinical adverse events
Xeloda (n=596)
5-FU/LV (n=593) * *
Patients (%)
9. Most common treatment-related clinical adverse events
Results of the safety analysis indicated that Xeloda has an improved safety profile compared with Mayo Clinic regimen.1 Of the seven clinical adverse effects most commonly associated with fluoropyrimidine therapy, four (stomatitis, diarrhoea, nausea and alopecia) were significantly less common with Xeloda than with Mayo Clinic regimen (p<0.001). Only hand-foot syndrome was more common in patients receiving Xeloda and this cutaneous effect could be easily managed with treatment interruption and, if necessary, dose reduction. Vomiting and fatigue occurred at similar rates in both groups. The majority of treatment-related adverse events were mild to moderate in intensity.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263). * * *
Diarrhoea Stomatitis Hand-foot Nausea Vomiting Alopecia Fatigue
syndrome
*p<0.001
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

10. Grade 3/4 treatment-related adverse events
Xeloda (n=596)
5-FU/LV (n=593)
Patients (%)
10. Grade 3/4 treatment-related adverse events
There were more grade 3 and 4 adverse events in the Mayo Clinic regimen group than in the Xeloda group (396 vs 369 events), and more patients treated with Mayo Clinic regimen experienced grade 4 adverse events (5.1% vs 3.0% with Xeloda).1 The most common treatment-related grade 3 or 4 adverse event with Mayo Clinic regimen was stomatitis (grade 3: 14.2%; grade 4: 0.5% compared with 2.0% and 0.2%, respectively, with Xeloda). Hand-foot syndrome was the most common grade 3 adverse event with Xeloda (grade 3: 17.1%; grade 4: not applicable), but this could be managed by individual dose titration. Less than two-thirds (61%) of all hand-foot syndrome patients required treatment for grade 3 hand-foot syndrome, with therapy almost always consisting of emollients. In contrast, 89% of patients in the Mayo Clinic regimen group who developed grade 3/4 stomatitis required treatment for this adverse effect. Neutropenic fever and sepsis were significantly less common in patients treated with Xeloda than in the Mayo Clinic regimen group.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263). * * *
Diarrhoea Stomatitis Hand-foot Nausea Vomiting Neutropenic
syndrome† fever + sepsis
*p<0.0001
†Grade 4 not applicable
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

11. Most common grade 3/4 laboratory abnormalities
Myelosuppression was very rare with Xeloda. Grade 3 or 4 neutropenia as a laboratory abnormality was significantly more common with Mayo Clinic regimen than with Xeloda (21.1% vs 2.2%), resulting in a significantly higher incidence of neutropenic fever and sepsis and more associated hospitalisations.1
Hyperbilirubinaemia (using the strict grading criteria of the old National Cancer Institute of Canada Common Toxicity Criteria [NCIC CTC] scale) occurred more frequently in the Xeloda group. However, it tended to be an isolated laboratory abnormality affecting primarily the indirect bilirubin. This effect has been observed with other oral fluoropyrimidines and it has been suggested that hyperbilirubinaemia is a class effect. In addition, in the Xeloda trials hyperbilirubinaemia was rarely associated with the development of hepatobiliary or other abnormalities. Baseline elevations of liver function parameters, including any grade of total bilirubin, transaminase or alkaline phosphatase elevations, did not correlate with hyperbilirubinaemia during treatment with Xeloda. Hepatobiliary abnormalities resulted in treatment discontinuation in only two patients receiving Xeloda (0.3%) and four patients receiving the Mayo Clinic regimen (0.7%).
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
NCIC common toxicity criteria; ULN = upper limit of normal
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

12. Hospitalisations for treatment-related adverse events
Xeloda (n=596)
5-FU/LV (n=593) *
No. of hospitalisations
12. Hospitalisations for key adverse events
Treatment-related hospitalisations for adverse events were significantly less common with Xeloda than with Mayo Clinic regimen (76 vs 113 hospitalisations, respectively p<0.005). Similarly, significantly fewer patients receiving Xeloda were hospitalised (11.6% vs 18.0% with Mayo Clinic regimen, p<0.005).1 Hospitalisation was significantly more common with Mayo Clinic regimen for stomatitis (3.5% vs 0.2%) and neutropenic fever/sepsis (2.9% vs 0.2%). By contrast, hospitalisation for hand-foot syndrome, the most common adverse event with Xeloda treatment, occurred in only two patients receiving Xeloda (for less than 24 hours in one patient and less than 8 hours in the other), demonstrating that this localised, cutaneous side effect did not present a major clinical problem.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263). * *
Overall
Diarrhoea
Vomiting
Stomatitis
Hand-foot syndrome
Infections
Neutropenic fever + sepsis
*p<0.005
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

13. Incidence and timing of dose modification
Fewer patients in the Xeloda group required dose modification for adverse events than in the Mayo Clinic regimen group (33.9% vs 42.2%, p=0.0037).1 In addition, dose modifications for toxicities occurred later in the Xeloda group than in the Mayo Clinic regimen group. The median time to first-level dose reduction (reduction to 75% of the baseline Xeloda dose or 70–80% of baseline 5-FU dose) was 2.5 months in the Xeloda group compared with 1.2 months with 5-FU/LV. Later dose modification potentially avoids side effects in patients who do not respond. The median time to second-level dose reduction (reduction to 50% of the baseline Xeloda dose or 49–64% of baseline 5-FU/LV dose) was 3.6 months in the Xeloda group and 3.2 months in the 5-FU/LV group. The baseline demographic characteristics of the patients requiring Xeloda dose modification were similar to those of patients not requiring dose modification for adverse events.
1. Cassidy J, Twelves C. Effective dose-modification (DM) scheme for the management of toxicities with capecitabine therapy: data from metastatic colorectal cancer (mCRC) phase III trials. Capecitabine CRC Study Group. Ann Oncol 2000;11(Suppl. 4):62 (Abstract 271).
*P= †Reduction to 75% of baseline Xeloda dose or 70–80% of baseline 5-FU dose ‡Reduction to 50% of baseline Xeloda dose or 49–64% of baseline 5-FU dose
Cassidy J. Ann Oncol 2000;11(Suppl. 4):62 (Abst 271)

14. Xeloda® dose modification: impact on efficacy
The risk of disease progression or death was not increased in patients requiring Xeloda dose modification
for patients with any dose reduction, hazard ratio = 0.97
for patients with dose reductions to 50% of baseline dose, hazard ratio = 1.06
The Xeloda dose modification scheme was effective in preventing the recurrence of toxicities
14. Xeloda® dose modification: impact on efficacy
The efficacy of Xeloda was maintained in patients requiring dose modification.1 The risk of disease progression or death was not increased in patients requiring Xeloda dose reduction from the standard starting dose for adverse events compared with those not requiring dose modification. There was no increase in hazard ratio (HR) for patients treated with Xeloda who required a dose reduction (to either 75% or 50% of the baseline dose) for adverse events (HR=0.97, not significant), and only a minor increase in HR for Xeloda patients requiring dose reductions for adverse events to 50% of baseline dose (HR=1.06, not significant). Similar analysis in the Mayo Clinic regimen group demonstrated a moderate (12%), but not statistically significant, increase in the risk of disease progression or death for patients receiving the Mayo Clinic regimen who required any dose reduction (HR=1.12). There was a 30% increase (not significant) in the risk of disease progression or death in patients receiving the Mayo Clinic regimen who required dose reduction to 49%–64% of baseline 5-FU dose (HR=1.30).
1. Cassidy J, Twelves C. Effective dose-modification (DM) scheme for the management of toxicities with capecitabine therapy: data from metastatic colorectal cancer (mCRC) phase III trials. Capecitabine CRC Study Group. Ann Oncol 2000;11(Suppl. 4):62 (Abstract 271).
Cassidy J. Ann Oncol 2000;11(Suppl. 4):62 (Abst 271)

15. Xeloda® dose modification: impact on adverse events
100 80 60 40 20
Grade 2
Grade 3
Grade 4
No. of patients
15. Xeloda® dose modification: impact on adverse events
The Xeloda dose modification scheme was effective in managing the three key adverse events characteristic of infused fluoropyrimidines (diarrhoea, hand-foot syndrome and stomatitis).1 Following dose reduction for hand-foot syndrome (138 patients), only 25 patients and 20 patients experienced a grade 2 or grade 3 recurrence, respectively. Following dose reduction for diarrhoea (89 patients), only 14 patients and seven patients experienced further grade 2 or grade 3 diarrhoea, respectively, with no patients experiencing further grade 4 diarrhoea. None of the patients receiving Xeloda experienced grade 4 stomatitis. Following dose modification for grade 2/3 stomatitis (30 patients), there was no further grade 3 stomatitis and six patients experienced a grade 2 recurrence.
1. Cassidy J, Twelves C. Effective dose-modification (DM) scheme for the management of toxicities with capecitabine therapy: data from metastatic colorectal cancer (mCRC) phase III trials. Capecitabine CRC Study Group. Ann Oncol 2000;11(Suppl. 4):62 (Abstract 271).
Before After Before After Before After
Hand-foot syndrome* Diarrhoea Stomatitis
*Grade 4 not applicable
Cassidy J. Ann Oncol 2000;11(Suppl. 4):62 (Abst 271)

16. Patient education
Patient education is essential for the management of Xeloda toxicities
Patients should be educated to
recognise the symptoms and severity of side effects
interrupt treatment upon the development of moderate or more severe toxicities
contact their oncology team (physician, nurse or pharmacist) for further advice
16. Patient education
Patient education is essential for anyone receiving cytotoxic chemotherapy in an outpatient setting. Patients receiving Xeloda should be educated to recognise side effects and their severity. It is important that patients interrupt treatment upon the development of a moderate or more severe toxicity and, if necessary, contact their oncology team (physician, nurse or pharmacist) for further advice. Patients should be reassured that efficacy will not be compromised if treatment is interrupted or modified. Patient follow-up procedures, such as a telephone call after the first week of treatment, can help to ensure optimal management of adverse events, particularly in patients receiving Xeloda for the first time.

17. Summary of safety
Compared with 5-FU/LV, oral Xeloda provides clinically
meaningful improvements
Significantly lower incidence of diarrhoea, stomatitis, nausea and alopecia
Significantly less grade 3/4 stomatitis and neutropenia leading to less neutropenic fever/sepsis
More hand-foot syndrome, but rarely led to hospitalisation or withdrawal
Fewer and later dose reductions
Significantly lower treatment-related hospitalisation rate
17. Summary of safety
Xeloda has an improved safety profile when compared with Mayo Clinic regimen, and results in significantly less diarrhoea, stomatitis, nausea and alopecia.1 Grade 3 or 4 adverse events were less frequent with Xeloda treatment and there was significantly less grade 3/4 neutropenia, leading to significantly less neutropenic fever and sepsis and associated hospitalisations. In addition, grade 3/4 stomatitis was significantly less common and resulted in significantly fewer hospitalisations in patients treated with Xeloda compared with Mayo Clinic regimen. Hand-foot syndrome was more common with Xeloda than with Mayo Clinic regimen but could be managed by treatment interruption and, if necessary, dose reduction. Moreover, hand-foot syndrome, which is typically observed with protracted infusion 5-FU, led to brief hospitalisation in only two patients, compared with 21 patients hospitalised for stomatitis in the Mayo Clinic regimen group. Fewer patients in the Xeloda group required dose modification for adverse events, which also occurred later than in the Mayo Clinic regimen group. In addition, the overall hospitalisation rate was significantly lower in the Xeloda group (11.6% vs 18.0%, p<0.005), reflecting the favourable safety profile of Xeloda.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

18. Xeloda® monotherapy in CRC: conclusions
Xeloda is a convenient oral agent for first-line treatment of metastatic CRC
High efficacy (superior response rate, equivalent overall survival and time to disease progression) compared with i.v. 5-FU/LV (Mayo Clinic regimen)
Better tolerated than i.v. 5-FU/LV
18. Xeloda® monotherapy in CRC: conclusions
The integrated analysis of data from both phase III trials confirms the results of the individual trials, demonstrating that Xeloda is a convenient, oral agent that is highly effective as first-line treatment for metastatic CRC. Compared with Mayo Clinic regimen, Xeloda treatment results in a superior response rate and equivalent overall survival and time to disease progression in the first-line treatment of metastatic CRC.1 The safety benefits of Xeloda compared with Mayo Clinic regimen are demonstrated by:
Significantly lower incidence of diarrhoea, stomatitis, nausea and alopecia
Significantly lower incidence of grade 3/4 stomatitis and grade 3/4 neutropenia leading to neutropenic fever/sepsis
Fewer and later dose reductions
Significantly lower treatment-related hospitalisation rate.
Xeloda therefore provides a viable and convenient new treatment option for the first-line treatment of metastatic CRC. In addition, the confirmed efficacy and superior safety profile suggest that Xeloda may be an attractive agent for use as adjuvant therapy or for incorporation into combination regimens, which is discussed later.
1. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
This opens perspectives for adjuvant treatment and for combination treatment in advanced CRC

19. Xeloda® as adjuvant treatment for colon cancer: X-ACT study
Open-label, randomised, multicentre, phase III trial
Recruitment of 1,956 Dukes’ C colon cancer patients is on target for completion in 2001
Xeloda 1,250mg/m2 twice daily, days 1–14 every 21 days x 8 versus 4-weekly Mayo Clinic regimen x 6
Disease-free survival as 1° endpoint
2° endpoints: overall survival, safety, quality of life, health economics, measurement of biochemical markers in selected centres
19. Xeloda® as adjuvant treatment for colon cancer: X-ACT study
A phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), is evaluating Xeloda as adjuvant treatment for Dukes’ C colon cancer. This large, global trial is being conducted in 27 countries with the recruitment of 1,956 patients undergoing surgery for colon cancer and is on target for completion in Patients are randomised to receive either eight cycles of intermittent Xeloda 1,250mg/m2 twice daily for 14 days followed by a 7-day rest period or six cycles of 4-weekly Mayo Clinic regimen.
The primary objective of the trial is to demonstrate at least equivalent disease-free survival with Xeloda compared with Mayo Clinic regimen. In addition, overall survival, safety, QoL and health economics will be assessed. The activity of the biochemical markers thymidine phosphorylase, dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase will be measured in tumour tissue samples collected during surgery at selected centres and these will be evaluated in relation to treatment outcome.

20. Phase III trials in CRC: study regimen versus Mayo Clinic regimen‡§
Numerous attempts have been made to improve the efficacy of therapy for metastatic CRC through refinement of 5-FU-based regimens and development of new agents, such as raltitrexed (a thymidylate synthase inhibitor), UFT (the 5-FU prodrug tegafur plus uracil, a DPD substrate), which is administered with LV, and Xeloda. Several of the new regimens have been evaluated in phase III trials, almost all of which were conducted in similar patient populations using the Mayo Clinic regimen (bolus 5-FU/LV) as a comparator.
This slide summarises phase III trials comparing the most active 5-FU-based regimens and the new agents with bolus 5-FU/LV.1–7 As with Xeloda, none of the regimens demonstrated a significant impact on overall survival, but there were marked differences in terms of time to disease progression and response rates. Some regimens, such as UFT/LV and raltitrexed, result in significantly inferior time to disease progression, while other approaches, such as Xeloda and the de Gramont and AIO regimens, are associated with significant improvements in response rates and/or time to disease progression. These characteristics, as well as factors such as convenience and safety profiles, should be taken into consideration when choosing the most appropriate therapy for patients with CRC.
References
1. De Gramont A, Bosset J-F, Milan C et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French Intergroup study. J Clin Oncol 1997;15:80815.
2. Schmoll HJ, Köhne CH, Lorenz M et al. Weekly 24h infusion of high-dose (HD) 5-fluorouracil (5-FU24h) with or without folinic acid (FA) vs. bolus 5-FU/FA (NCCTG/Mayo) in advanced colorectal cancer (CRC): a randomized phase III study of the EORTC GITCCG and the AIO. Proc Am Soc Clin Oncol 2000;19:241a (Abstract 935).
3. Petrelli N, Douglass HO, Herrera L et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 1989;7:1419–26.
4. Cunningham D, Zalcberg JR, Rath U et al. Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol 1996;7:961–5.
5. Cocconi G, Cunningham D, Van Cutsem E et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol ;16:2943–52.
6. Pazdur R, Douillard J-Y, Skillings JR et al. Multicenter phase III study of 5-fluorouracil (5-FU) or UFT™ in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol ;18:263a (Abstract 1009).
7. Hoff PM. Capecitabine as first-line treatment for colorectal cancer (CRC): integrated results of 1207 patients (pts) from 2 randomized, phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol ;11(Suppl. 4):60 (Abstract 263).
Study regimen/Mayo Clinic regimen; *p£0.01
†Response rate reported for measurable patients only (79% of ITT population)
‡Comparator arm: i.v. bolus 5-FU 500mg/m2, days 1–5 every 28 days, without LV §Comparator arm: LV 200mg/m2 plus 5-FU 400mg/m2, days 1–5 every 28 days