A new era of combination therapy has begun

1. A new era of combination therapy has begun Eric Van Cutsem University Hospital GasthuisbergLeuven, Belgium

2. With the publication of 4-year disease-free survival (DFS) from the MOSAIC trial [1], combination chemotherapy with oxaliplatin could be considered as an additional treatment option in the adjuvant setting. Numerous adjuvant combination regimens are being evaluated including: CALGB89803: irinotecan plus bolus 5-FU/LV PETACC-3: irinotecan plus 5-FU/LV (FOLFIRI) NSABP C-07: bolus 5-FU/LV plus oxaliplatin MOSAIC: oxaliplatin plus 5-FU/LV (FOLFOX) XELOXA: Xeloda plus oxaliplatin (XELOX) AVANT: XELOX + Avastin/FOLFOX + Avastin QUASAR 2: Xeloda plus irinotecan (XELIRI) + Avastin The only studies to report primary endpoint data thus far are the CALGB89803 and MOSAIC studies, the former showing no advantage for IFL versus 5-FU/LV [2] and the latter showing an improvement in DFS for the combination regimen, FOLFOX [1]. No combination regimen has yet shown a significant improvement in overall survival with relatively short follow-up. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).With the publication of 4-year disease-free survival (DFS) from the MOSAIC trial [1], combination chemotherapy with oxaliplatin could be considered as an additional treatment option in the adjuvant setting. Numerous adjuvant combination regimens are being evaluated including: CALGB89803: irinotecan plus bolus 5-FU/LV PETACC-3: irinotecan plus 5-FU/LV (FOLFIRI) NSABP C-07: bolus 5-FU/LV plus oxaliplatin MOSAIC: oxaliplatin plus 5-FU/LV (FOLFOX) XELOXA: Xeloda plus oxaliplatin (XELOX) AVANT: XELOX + Avastin/FOLFOX + Avastin QUASAR 2: Xeloda plus irinotecan (XELIRI) + Avastin The only studies to report primary endpoint data thus far are the CALGB89803 and MOSAIC studies, the former showing no advantage for IFL versus 5-FU/LV [2] and the latter showing an improvement in DFS for the combination regimen, FOLFOX [1]. No combination regimen has yet shown a significant improvement in overall survival with relatively short follow-up. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).

3. CALGB 89803: IFL as adjuvant treatment for stage III colon cancer This phase III randomized study evaluated whether IFL was superior to weekly bolus 5-FU/LV (Roswell Park regimen) after curative resection for stage III colon cancer. Eligible patients had TxN1-2M0 disease and no prior chemotherapy. Patients received IFL: irinotecan 125mg/m2 (90-minute infusion) followed by leucovorin 20mg/m2 i.v. bolus and then 5-FU 500mg/m2 i.v. bolus, administered for 4 weeks, followed by a 2-week break, for 5 cycles (30 weeks total) Roswell Park regimen: leucovorin 500mg/m2 i.v. over 2 hours plus 5-FU 500mg/m2, 1 hour after the start of leucovorin, administered for 6 weeks, followed by a 2-week break, for 4 cycles (32 weeks total). A total of 1264 patients were randomized between April, 1999 and April, 2001. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).This phase III randomized study evaluated whether IFL was superior to weekly bolus 5-FU/LV (Roswell Park regimen) after curative resection for stage III colon cancer. Eligible patients had TxN1-2M0 disease and no prior chemotherapy. Patients received IFL: irinotecan 125mg/m2 (90-minute infusion) followed by leucovorin 20mg/m2 i.v. bolus and then 5-FU 500mg/m2 i.v. bolus, administered for 4 weeks, followed by a 2-week break, for 5 cycles (30 weeks total) Roswell Park regimen: leucovorin 500mg/m2 i.v. over 2 hours plus 5-FU 500mg/m2, 1 hour after the start of leucovorin, administered for 6 weeks, followed by a 2-week break, for 4 cycles (32 weeks total). A total of 1264 patients were randomized between April, 1999 and April, 2001. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).

4. CALGB 89803: DFS not improved with IFL in stage III colon cancer Median follow up is 2.6 years, and 67% of total expected deaths and 85% of total expected failures have occurred. IFL shows no improvement over 5-FU/LV in terms of either overall survival (p=0.88) or DFS (p=0.84); futility boundaries for both of these endpoints have been exceeded so far 18 deaths have occurred on the IFL arm during treatment versus 6 deaths on the 5-FU/LV arm (p=0.008). In stage III colon cancer, IFL, as compared to 5-FU/LV, is associated with a greater degree of neutropenia, neutropenic fever, and death on treatment, with no associated clinical benefit. Weekly bolus IFL should therefore not be used in the management of stage III colon cancer. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).Median follow up is 2.6 years, and 67% of total expected deaths and 85% of total expected failures have occurred. IFL shows no improvement over 5-FU/LV in terms of either overall survival (p=0.88) or DFS (p=0.84); futility boundaries for both of these endpoints have been exceeded so far 18 deaths have occurred on the IFL arm during treatment versus 6 deaths on the 5-FU/LV arm (p=0.008). In stage III colon cancer, IFL, as compared to 5-FU/LV, is associated with a greater degree of neutropenia, neutropenic fever, and death on treatment, with no associated clinical benefit. Weekly bolus IFL should therefore not be used in the management of stage III colon cancer. Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500).

5. PETACC-3: adjuvant 5-FU/LV + irinotecan vs infused 5-FU/LV in stage II/III colon cancer 1� objective DFS at 3 years for stage III patients 2� endpoints OS RFS safety correlation of outcome with molecular markers 2� analysis DFS and RFS in stage II and III Efficacy data will be presented at ASCO 2005 PETACC-3 is a randomized, open-label, multicenter study. Patients are randomized to one of two treatment arms arm I: patients may receive irinotecan (30�90-minute infusion), leucovorin i.v. over 2 hours and 5-FU i.v. over 22 hours on days 1 and 2 every 2 weeks for 6 months. as an alternative schedule, patients receive irinotecan (30�90-minute infusion), leucovorin i.v. over 2 hours and 5-FU i.v. over 24 hours weekly for 6 months. arm II: patients receive leucovorin and 5-FU as in arm I. The primary objective is to compare the disease-free survival at 3 years of patients with resected stage III colon cancer treated with adjuvant LV5FU2 with or without irinotecan Secondary endpoints include comparing the relapse-free survival at 3 years overall survival at 5 years the safety profiles of these treatment regimens the quality-adjusted survival and correlating the expression of putative prognostic markers (e.g. thymidylate synthase, telomerase, topoisomerase, MSI, LOH) with disease-free and overall survival secondary efficacy analyses include RFS and DFS in the pooled stage II/III population. Efficacy results will be presented at ASCO 2005.PETACC-3 is a randomized, open-label, multicenter study. Patients are randomized to one of two treatment arms arm I: patients may receive irinotecan (30�90-minute infusion), leucovorin i.v. over 2 hours and 5-FU i.v. over 22 hours on days 1 and 2 every 2 weeks for 6 months. as an alternative schedule, patients receive irinotecan (30�90-minute infusion), leucovorin i.v. over 2 hours and 5-FU i.v. over 24 hours weekly for 6 months. arm II: patients receive leucovorin and 5-FU as in arm I. The primary objective is to compare the disease-free survival at 3 years of patients with resected stage III colon cancer treated with adjuvant LV5FU2 with or without irinotecan Secondary endpoints include comparing the relapse-free survival at 3 years overall survival at 5 years the safety profiles of these treatment regimens the quality-adjusted survival and correlating the expression of putative prognostic markers (e.g. thymidylate synthase, telomerase, topoisomerase, MSI, LOH) with disease-free and overall survival secondary efficacy analyses include RFS and DFS in the pooled stage II/III population. Efficacy results will be presented at ASCO 2005.

6. MOSAIC trial design The MOSAIC trial was designed to demonstrate an increase in DFS in stage II and III colon cancer with FOLFOX4 versus LV5FU2. A total of 2246 patients with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive LV5FU2 or FOLFOX4 every 2 weeks for 12 cycles. The primary endpoint was disease-free survival, secondary endpoints included safety and overall survival. Andr� T et al. N Engl J Med 2004;350:2343�51.The MOSAIC trial was designed to demonstrate an increase in DFS in stage II and III colon cancer with FOLFOX4 versus LV5FU2. A total of 2246 patients with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive LV5FU2 or FOLFOX4 every 2 weeks for 12 cycles. The primary endpoint was disease-free survival, secondary endpoints included safety and overall survival. Andr� T et al. N Engl J Med 2004;350:2343�51.

7. MOSAIC trial: superior DFS with FOLFOX versus LV5FU2 in stage III colon cancer Adjuvant FOLFOX provided a statistically significant improvement in disease-free survival in the intent-to-treat population (p=0.002; hazard ratio = 0.77, 95% CI:0.65�0.91) [1] the hazard ratio of 0.77 translates into a 23% reduction in the risk of recurrence in patients receiving FOLFOX versus those receiving LV5FU2. In patients with stage III colon cancer, FOLFOX provided a 23% reduction in the risk of relapse (hazard ratio = 0.76, 95%CI:0.62�0.92) [1] at 3 years, 72.2% of patients in the FOLFOX arm were disease-free compared with 65.3% in the LV5FU2 arm the p value for the difference between the treatment arms has not been reported for the stage III subgroup, although with 0.92 as the upper limit of the hazard ratio, it would be very surprising if the difference is not statistically significant. In patients with stage II colon cancer, FOLFOX provided an 20% reduction in the risk of relapse (hazard ratio = 0.80, 95%CI:0.56�1.15). The p value for the difference between the treatment arms has not been reported for the stage II subgroup. 1. Andr� T et al. N Engl J Med 2004;350:2343�51.Adjuvant FOLFOX provided a statistically significant improvement in disease-free survival in the intent-to-treat population (p=0.002; hazard ratio = 0.77, 95% CI:0.65�0.91) [1] the hazard ratio of 0.77 translates into a 23% reduction in the risk of recurrence in patients receiving FOLFOX versus those receiving LV5FU2. In patients with stage III colon cancer, FOLFOX provided a 23% reduction in the risk of relapse (hazard ratio = 0.76, 95%CI:0.62�0.92) [1] at 3 years, 72.2% of patients in the FOLFOX arm were disease-free compared with 65.3% in the LV5FU2 arm the p value for the difference between the treatment arms has not been reported for the stage III subgroup, although with 0.92 as the upper limit of the hazard ratio, it would be very surprising if the difference is not statistically significant. In patients with stage II colon cancer, FOLFOX provided an 20% reduction in the risk of relapse (hazard ratio = 0.80, 95%CI:0.56�1.15). The p value for the difference between the treatment arms has not been reported for the stage II subgroup. 1. Andr� T et al. N Engl J Med 2004;350:2343�51.

8. Four-year follow-up: FOLFOX versus LV5FU2 With a median follow-up of 4 years (48.6 months), a 24% reduction in the relative risk of relapse was observed with the FOLFOX4 combination in the overall population (p=0.0008). For stage III patients, the probability of remaining disease-free at 4 years is 61.0% in the LV5FU2 arm and 69.7% in the FOLFOX4 arm, translating into a relative risk reduction of 25% in this subset of patients. For stage II patients, 4-year DFS was 81.3% in the LV5FU2 arm versus 85.1% in the FOLFOX4 arm (relative risk reduction of 20%). In the overall population, 84.0% and 82.4% patients are still alive in the FOLFOX4 and LV5FU2 arms, respectively. Follow-up is ongoing for a minimum of 5 years for each patient for final survival analysis. So far, FOLFOX has shown no benefit in overall survival versus LV5FU2. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Eloxatin US Prescribing Information 11/04.With a median follow-up of 4 years (48.6 months), a 24% reduction in the relative risk of relapse was observed with the FOLFOX4 combination in the overall population (p=0.0008). For stage III patients, the probability of remaining disease-free at 4 years is 61.0% in the LV5FU2 arm and 69.7% in the FOLFOX4 arm, translating into a relative risk reduction of 25% in this subset of patients. For stage II patients, 4-year DFS was 81.3% in the LV5FU2 arm versus 85.1% in the FOLFOX4 arm (relative risk reduction of 20%). In the overall population, 84.0% and 82.4% patients are still alive in the FOLFOX4 and LV5FU2 arms, respectively. Follow-up is ongoing for a minimum of 5 years for each patient for final survival analysis. So far, FOLFOX has shown no benefit in overall survival versus LV5FU2. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Eloxatin US Prescribing Information 11/04.

9. FOLFOX versus LV5FU2: grade 3/4 adverse events The profile of grade 3/4 side effects reflects the increase in the overall incidence of toxicities (all grades) observed by FOLFOX compared with LV5FU2 [1]. FOLFOX was associated with a higher incidence of grade 3/4: neutropenia (41 vs 5% with LV5FU2) sensory neuropathy (12 vs 0% with LV5FU2) diarrhea (11 vs 7% with LV5FU2) vomiting (6 vs 1% with LV5FU2) allergy (3.0 vs 0.2% with LV5FU2) febrile neutropenia (0.7 vs 0.1% with LV5FU2) thrombocytopenia (1.7 vs 0.4% with LV5FU2). After median follow-up of 4 years, 3.4% of patients presented either with persisting localized paresthesias of moderate intensity (2.7%) or with paresthesias that may interfere with functional activities (0.7%) [2]. 1. Andr� T et al. N Engl J Med 2004;350:2343�51. 2. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167).The profile of grade 3/4 side effects reflects the increase in the overall incidence of toxicities (all grades) observed by FOLFOX compared with LV5FU2 [1]. FOLFOX was associated with a higher incidence of grade 3/4: neutropenia (41 vs 5% with LV5FU2) sensory neuropathy (12 vs 0% with LV5FU2) diarrhea (11 vs 7% with LV5FU2) vomiting (6 vs 1% with LV5FU2) allergy (3.0 vs 0.2% with LV5FU2) febrile neutropenia (0.7 vs 0.1% with LV5FU2) thrombocytopenia (1.7 vs 0.4% with LV5FU2). After median follow-up of 4 years, 3.4% of patients presented either with persisting localized paresthesias of moderate intensity (2.7%) or with paresthesias that may interfere with functional activities (0.7%) [2]. 1. Andr� T et al. N Engl J Med 2004;350:2343�51. 2. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167).

10. Xeloda combinations: a new era in adjuvant treatment

11. X-ACT study: Xeloda is at least as effective as 5-FU/LV (DFS) in stage III colon cancer In the X-ACT trial, 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 trend towards superior DFS with Xeloda was confirmed in the per-protocol analysis with a hazard ratio of 0.89 (95% CI: 0.76�1.04). Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509).In the X-ACT trial, 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 trend towards superior DFS with Xeloda was confirmed in the per-protocol analysis with a hazard ratio of 0.89 (95% CI: 0.76�1.04). Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509).

12. First-line XELOX in MCRC: an effective and well-tolerated alternative to FOLFOX Will this benefit translate into the adjuvant setting? In metastatic CRC, Xeloda has demonstrated a higher response rate vs 5-FU/LV, similar TTP and OS with a favorable safety profile [1]. The response rates, median time to progression and median overall survival seen with first-line XELOX in the large phase II trial in the metastatic setting were comparable with those seen with infused 5-FU/LV plus oxaliplatin (FOLFOX4) regimens [2�4] in other trials. The safety profile of XELOX [1] also compares favorably with that of FOLFOX [3,4]. Notably, XELOX is associated with a much lower incidence of grade 3/4 neutropenia (7% with XELOX vs 42% with FOLFOX4), presumably due to the absence of a �bolus 5-FU� element in XELOX. Note the low incidence of grade 3 hand-foot syndrome with XELOX (3%, with grade 1/2 in 33%), which may be due to the 20% lower dose of Xeloda used in XELOX compared with the monotherapy studies. This phase II protocol was not clear in terms of prophylaxis advice patients receiving XELOX should receive 5-HT3 antagonists and steroids prior to oxaliplatin infusion secondly, preventative oral anti-emetics should also be administered for late nausea/vomiting induced by oxaliplatin and any nausea/vomiting induced by Xeloda. Patient education is extremely important. Patients should be taught to recognize side effects and to interrupt Xeloda immediately upon the development of grade 2 toxicities and call their doctor/nurse for further advice [5]. �� 1.Van Cutsem E et al. Br J Cancer, 2004;90:1190-97. 2. Cassidy J et al. J Clin Oncol 2004;22:2084�91. 3. de Gramont A et al. J Clin Oncol 2000;18:2938�47. 4. Goldberg RM et al. J Clin Oncol 2004;22:23-30. 5. Marse H et al. Eur J Oncol Nurs. 2004;8 Suppl 1:S16-30.In metastatic CRC, Xeloda has demonstrated a higher response rate vs 5-FU/LV, similar TTP and OS with a favorable safety profile [1]. The response rates, median time to progression and median overall survival seen with first-line XELOX in the large phase II trial in the metastatic setting were comparable with those seen with infused 5-FU/LV plus oxaliplatin (FOLFOX4) regimens [2�4] in other trials. The safety profile of XELOX [1] also compares favorably with that of FOLFOX [3,4]. Notably, XELOX is associated with a much lower incidence of grade 3/4 neutropenia (7% with XELOX vs 42% with FOLFOX4), presumably due to the absence of a �bolus 5-FU� element in XELOX. Note the low incidence of grade 3 hand-foot syndrome with XELOX (3%, with grade 1/2 in 33%), which may be due to the 20% lower dose of Xeloda used in XELOX compared with the monotherapy studies. This phase II protocol was not clear in terms of prophylaxis advice patients receiving XELOX should receive 5-HT3 antagonists and steroids prior to oxaliplatin infusion secondly, preventative oral anti-emetics should also be administered for late nausea/vomiting induced by oxaliplatin and any nausea/vomiting induced by Xeloda. Patient education is extremely important. Patients should be taught to recognize side effects and to interrupt Xeloda immediately upon the development of grade 2 toxicities and call their doctor/nurse for further advice [5]. �� 1.Van Cutsem E et al. Br J Cancer, 2004;90:1190-97. 2. Cassidy J et al. J Clin Oncol 2004;22:2084�91. 3. de Gramont A et al. J Clin Oncol 2000;18:2938�47. 4. Goldberg RM et al. J Clin Oncol 2004;22:23-30. 5. Marse H et al. Eur J Oncol Nurs. 2004;8 Suppl 1:S16-30.

13. XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) vs 5-FU / LV 1� objective DFS: XELOX >5-FU / LV 2� endpoints survival tolerability convenience pharmacoeconomics Safety data to be reported: ASCO 2005 Roche XELOXA trial A total of 1886 patients with surgically resected chemotherapy-na�ve stage III colon cancer have been randomized 1:1. Patients are receiving 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 is preselected by each center prior to study start. The primary endpoint is to show that DFS is superior with XELOX versus bolus 5-FU/LV. Secondary objectives include overall survival, tolerability, convenience and pharmacoeconomic outcomes; also, pharmacogenetic and tumor marker studies are being performed. The first safety data will be reported at the upcoming ASCO 2005 congress. Roche XELOXA trial A total of 1886 patients with surgically resected chemotherapy-na�ve stage III colon cancer have been randomized 1:1. Patients are receiving 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 is preselected by each center prior to study start. The primary endpoint is to show that DFS is superior with XELOX versus bolus 5-FU/LV. Secondary objectives include overall survival, tolerability, convenience and pharmacoeconomic outcomes; also, pharmacogenetic and tumor marker studies are being performed. The first safety data will be reported at the upcoming ASCO 2005 congress.

14. QUASAR2: adjuvant XELIRI � Avastin versus Xeloda 1� objective DFS 2� endpoints survival tolerability The UK QUASAR 2 study A total of 3510 patients with surgically resected stage II/III colon cancer will be recruited, starting 2005. Patients will receive eight cycles of standard Xeloda monotherapy, eight cycles of standard XELIRI or eight cycles of standard XELIRI plus 16 cycles of Avastin(7.5mg/m2). The primary objective is DFS, with pair-wise comparisons. Secondary objectives include 5-year overall survival, safety, health economics and pharmacogenetic/tumor marker analyses.The UK QUASAR 2 study A total of 3510 patients with surgically resected stage II/III colon cancer will be recruited, starting 2005. Patients will receive eight cycles of standard Xeloda monotherapy, eight cycles of standard XELIRI or eight cycles of standard XELIRI plus 16 cycles of Avastin(7.5mg/m2). The primary objective is DFS, with pair-wise comparisons. Secondary objectives include 5-year overall survival, safety, health economics and pharmacogenetic/tumor marker analyses.

15. AVANT: adjuvant FOLFOX � Avastin versus XELOX + Avastin 1� objective: DFS 2� endpoints: overall survival; safety Roche AVANT trial Recruitment: 3450 patients (planned) with chemotherapy-na�ve high-risk stage II or stage III colon cancer. The trial is recruiting patients who have undergone a complete tumor resection within 4 to 8 weeks prior to randomization. In the first phase, patients will receive FOLFOX4 (12 x 2-week cycles), XELOX plus Avastin (7.5mg/kg) in eight 3-weekly cycles or FOLFOX4 plus Avastin (5.0mg/kg) in 12 2-weekly cycles. In the second phase patients in arm A will receive no further treatment (observation only). Patients in arms B and C will receive Avastin monotherapy (7.5mg/kg, 30 min i.v. infusion, day 1, every 3 weeks) for a further 6 months. The primary endpoint is DFS; secondary endpoints include overall survival and tolerability.Roche AVANT trial Recruitment: 3450 patients (planned) with chemotherapy-na�ve high-risk stage II or stage III colon cancer. The trial is recruiting patients who have undergone a complete tumor resection within 4 to 8 weeks prior to randomization. In the first phase, patients will receive FOLFOX4 (12 x 2-week cycles), XELOX plus Avastin (7.5mg/kg) in eight 3-weekly cycles or FOLFOX4 plus Avastin (5.0mg/kg) in 12 2-weekly cycles. In the second phase patients in arm A will receive no further treatment (observation only). Patients in arms B and C will receive Avastin monotherapy (7.5mg/kg, 30 min i.v. infusion, day 1, every 3 weeks) for a further 6 months. The primary endpoint is DFS; secondary endpoints include overall survival and tolerability.

16. Landmark trials: recent evidence Xeloda has shown a strong trend towards improved DFS and a trend towards improved overall survival compared with bolus 5-FU/LV in the adjuvant setting [1]. FOLFOX has also shown an improvement in DFS compared with the infusional regimen LV5FU2, but as yet has not shown superior overall survival [2]. In contrast, IFL has shown no improvement in either DFS or overall survival and is not recommended for the adjuvant treatment of colon cancer [3]. 1. Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509). 2. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 3. Saltz LB et al. Proc Am Soc Clin Oncol 2004;23:246 (Abst 3500). Xeloda has shown a strong trend towards improved DFS and a trend towards improved overall survival compared with bolus 5-FU/LV in the adjuvant setting [1]. FOLFOX has also shown an improvement in DFS compared with the infusional regimen LV5FU2, but as yet has not shown superior overall survival [2]. In contrast, IFL has shown no improvement in either DFS or overall survival and is not recommended for the adjuvant treatment of colon cancer [3]. 1. Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509). 2. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 3. Saltz LB et al. Proc Am Soc Clin Oncol 2004;23:246 (Abst 3500).

17. Landmark trials: upcoming evidence

18. Xeloda has potential to replace 5-FU/LV in adjuvant treatment Xeloda proven to be at least equivalent to 5-FU/LV for stage III colon cancer XELOX provides potential to optimize oxaliplatin-based combination similar high efficacy and favorable safety profile compared to FOLFOX in MCRC, with improved convenience Ongoing trials will elucidate benefits of Xeloda with irinotecan and biological agents Xeloda should be preferred to i.v. 5-FU/LV Xeloda has the potential to replace 5-FU/LV in combinations As we have seen during this meeting, the landscape of adjuvant treatment for colon cancer is changing. The FOLFOX combination has been shown to significantly improve DFS in patients with surgically resected stage II/III colon cancer [1]. Xeloda is at least as equivalent to bolus 5-FU/LV, the previous standard, in terms of DFS [2]. In the metastatic setting, Xeloda has been shown to be an effective and well-tolerated alternative to 5-FU/LV in combination regimens such as XELOX and XELIRI [3,4]. In addition, XELOX provides the potential to optimize oxaliplatin-based combinations in the adjuvant setting. As a highly active oral agent, Xeloda provides more convenient adjuvant treatment and simplified combination regimens. The large ongoing clinical trial program in the adjuvant setting further explore the benefits of Xeloda-based versus 5-FU-based combinations. A large body of clinical evidence shows that Xeloda should be preferred to 5-FU/LV in the adjuvant setting, replacing 5-FU/LV as monotherapy and possibly also replacing it in combination regimens. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509). 3. Cassidy J et al. J Clin Oncol 2004;22:2084�91. 4. Patt YZ et al. Proc ESMO Annals Oncol 2004;15:iii88 (Abst 238P).As we have seen during this meeting, the landscape of adjuvant treatment for colon cancer is changing. The FOLFOX combination has been shown to significantly improve DFS in patients with surgically resected stage II/III colon cancer [1]. Xeloda is at least as equivalent to bolus 5-FU/LV, the previous standard, in terms of DFS [2]. In the metastatic setting, Xeloda has been shown to be an effective and well-tolerated alternative to 5-FU/LV in combination regimens such as XELOX and XELIRI [3,4]. In addition, XELOX provides the potential to optimize oxaliplatin-based combinations in the adjuvant setting. As a highly active oral agent, Xeloda provides more convenient adjuvant treatment and simplified combination regimens. The large ongoing clinical trial program in the adjuvant setting further explore the benefits of Xeloda-based versus 5-FU-based combinations. A large body of clinical evidence shows that Xeloda should be preferred to 5-FU/LV in the adjuvant setting, replacing 5-FU/LV as monotherapy and possibly also replacing it in combination regimens. 1. de Gramont A et al. Proc ASCO GI Cancers Symposium 2005 (Abst 167). 2. Cassidy J et al. Proc Am Soc Clin Oncol 2004;23:14 (Abstract 3509). 3. Cassidy J et al. J Clin Oncol 2004;22:2084�91. 4. Patt YZ et al. Proc ESMO Annals Oncol 2004;15:iii88 (Abst 238P).

19. European authorities approve Xeloda as adjuvant treatment for colon cancer The European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) 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 offical 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. 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 offical 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.