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Oxaliplatin Combinations as First-Line Therapy in Advanced Colorectal Cancer
Research inBrief Oxaliplatin Combinations as First-Line Therapy in Advanced Colorectal Cancer Rationale • Until recently, the standard of care in clinical practice for the treatment of advanced or metastatic colorectal cancer consisted of 5-fluorouracil (5-FU) and leucovorin (LV) with response rates (RRs) ranging from 11%-23%.1 The addition of irinotecan to either bolus 5FU/LV (Saltz regimen2) or infusional 5FU/LV resulted in higher RRs and survival of patients with metastatic colorectal cancer compared with 5-FU/LV alone.3 Toxicity, particularly diarrhea with or without concomitant neutropenia, became a concern with irinotecan combined with bolus 5-FU/LV and resulted in recent recommendations for appropriate patient selection and close monitoring.4 • Oxaliplatin is a third-generation platinum compound that is noted for its in vitro and in vivo antitumoral activity, more tolerable adverse-event profile compared to other platinum agents, and synergistic antitumor effects when combined with 5-FU or irinotecan.5 Oxaliplatin has recently been approved by the US Food and Drug Administration (FDA) for metastatic colorectal cancer patients who had recurred or progressed within 6 months of therapy with bolus 5FU/LV and irinotecan. • A phase III study in 420 previously untreated advanced colorectal cancer patients compared infusional 5-FU/LV alone with oxaliplatin in combination with infusional 5-FU/LV (FOLFOX 4 regimen).6 This study showed that patients treated with FOLFOX 4 had significantly better RRs (51% vs. 22%; P = 0.0001) and longer progression-free survival (9.0 months vs. 6.2 months; P =
0.0003). The addition of oxaliplatin to 5FU/LV increased overall survival (16.2 months vs. 14.7 months), but this difference did not reach statistical significance (P = 0.12). A second oxaliplatin-based combination investigating a different chronomodulated schedule of 5-FU/LV versus chronomodulated 5-FU/LV in combination with oxaliplatin has also shown promising clinical activity.7 In addition, there have been several phase I/II studies investigating the combination of irinotecan and oxaliplatin. These studies have shown an RR of 41% in advanced colorectal cancer patients who had previously been treated with 5-FU–based regimens.8 • Goldberg and colleagues from the Mayo Clinic and the North Central Cancer Treatment Group, in collaboration with 4 other cancer cooperative groups in the United States, have conducted a randomized phase III study (N9741) to compare the efficacy and safety of the irinotecan/5-FU/LV versus the experimental oxaliplatin/5-FU/LV and oxaliplatin/irinotecan combination regimens as first-line therapy in patients
78 • Clinical Colorectal Cancer August 2002
• The 1-year follow-up results of the initially randomized patients were presented at the 38th Annual Meeting of the American Society of Clinical Oncology held in May 2002 in Orlando, Florida.9
A Phase III Study (N9741) Comparing Irinotecan/5-FU/LV to Oxaliplatin-Containing Regimens in Advanced Colorectal Cancer Study Design This study included adult patients with histologically confirmed unresectable metastatic colorectal cancer, measurable disease, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. Patients were required to have a life expectancy ≥ 12 weeks and adequate bone marrow, hepatic, and renal functions. No prior chemotherapy for metastatic disease was allowed. Patients were stratified according to
Figure 1: N9741 Treatment Schema
Stratified by: - Performance status - Age - Prior therapy
R A N D O M I Z E (n = 795)
Medical Writer: Kavita Maung, PhD Reviewed by: Edward Chu, MD, and Mace Rothenberg, MD
with advanced colorectal cancer.
Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
Control Arm Arm I (Saltz Regimen) (n = 264) Irinotecan 125 mg/m2 I.V. 5-FU 500 mg/m2 I.V. plus LV 20 mg/m2 I.V. Weekly for 4 out of 6 weeks Arm II (FOLFOX 4 Regimen) (n = 267) Oxaliplatin 85 mg/m2 I.V. day 1 5-FU 400 mg/m2 bolus + 600 mg/m2 I.V. as a 22-hour infusion on days 1 and 2 LV 200 mg/m2 I.V. days 1 and 2 Every 2 weeks Arm III (n = 264) Oxaliplatin 85 mg/m2 I.V. day 1 Irinotecan 200 mg/m2 I.V. day 1 Every 3 weeks
Table 1: Response and Survival Arm I Irinotecan/5-FU/LV (n = 264)
Arm II Oxaliplatin/5-FU/LV (n = 267)
Arm III Irinotecan/Oxaliplatin (n = 264)
6.9
8.8
6.7
–
0.0009
> 0.50
Median Survival (Months)
14.1
18.6
16.5
1-Year Survival
58%
71%
65%
value*†
–
0.002
Immature
Irinotecan/5-FU/LV (n = 245)
Oxaliplatin/5-FU/LV (n = 246)
Irinotecan/Oxaliplatin (n = 250)
29%
38%
28%
–
0.03
0.89
Endpoint Median Time to Disease Progression (Months) P value*
P
Response Rate P value*
*Two-sided P value compared to Saltz regimen †P value is for overall survival Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
PS, age, and prior adjuvant or immunotherapy. Patients were randomized to 1 of 3 treatment arms (Figure 1). Patients in arm I received irinotecan 125 mg/m2 intravenously (I.V.) followed by LV 20 mg/m2 plus 5-FU 500 mg/m2 I.V. weekly for 4 weeks followed by 2 weeks of rest. Treatment cycles were repeated every 6 weeks. Early deaths on arm I led to dose reductions of irinotecan from 125 mg/m2 to 100 mg/m2 and of 5-FU from 500 mg/m2 to 400 mg/m2. In arm II, patients received oxaliplatin 85 mg/m2 I.V. on day 1 and LV 200 mg/m2 and 5-FU 400 mg/m2 bolus and 600 mg/m2 as a 22hour infusion on days 1 and 2, repeated every 2 weeks. In arm III, patients received oxaliplatin 85 mg/m2 I.V. plus irinotecan 200 mg/m2 I.V. on day 1 with cycles repeating every 3 weeks. Treatment was continued until unacceptable toxicity or disease progression.
Results The first 795 patients enrolled in this study prior to a change in the dosing of the irinotecan/5-FU/LV arm were analyzed for this presentation. The treatment arms were well balanced, and approximately 16% of patients had received prior adjuvant chemotherapy. The oxaliplatin/5-FU/LV arm resulted in a significantly higher RR, longer time to disease progression, and improved median survival when compared to the control arm of irinotecan/5-FU/LV. An RR of
38% was achieved in patients on the oxaliplatin/5-FU/LV arm compared with 29% in patients on the irinotecan/5-FU/ LV arm (P = 0.03; Table 1). At a median follow-up of 12 months, the median time to disease progression was the longest in patients on the oxaliplatin/5-FU/LV arm at 8.8 months compared with 6.9 months in patients on the irinotecan/5-FU/LV arm (P = 0.0009). The overall survival was also higher in patients treated on the oxaliplatin/5-FU/LV arm compared to patients on the irinotecan/5-FU/LV regimen (P = 0.002). The RR, time to disease progression, and overall survival for the irinotecan/oxaliplatin arm was similar to the irinotecan/5-FU/LV arm although the
data is not felt to be sufficiently mature at this time for final statistical analysis. Seven hundred fifty-seven patients were evaluable for toxicity (Table 2). Grade 3/4 neutropenia was seen in 39% and 47% of patients in irinotecan/5FU/LV and oxaliplatin/5-FU/LV arms, respectively, but febrile neutropenia was more common with irinotecan/5-FU/LV (14%) compared with oxaliplatin/5FU/LV (4%; P = 0.001). Grade 3/4 diarrhea was significantly higher in patients on irinotecan/5-FU/LV at 33% compared with only 13% of patients on the oxaliplatin/5-FU/LV arm (P = 0.001). The incidence of nausea (P = 0.002) and vomiting (P = 0.001) was also reduced in patients treated with oxaliplatin/5-FU/LV when compared with patients treated with irinotecan/5-FU/LV.
Conclusion The results of this study demonstrated that oxaliplatin, when combined with 5FU/LV, results in promising activity as first-line therapy for patients with advanced colorectal cancer. Patients treated with the oxaliplatin/5-FU/LV combination showed significant improvement in time to disease progression, overall survival, and RR compared to patients on standard irinotecan/5-FU/LV regimen. In addition, oxaliplatin/5-FU/LV was associated with a more favorable toxicity profile when compared to the irinotecan/5-FU/LV treatment arm. These
Table 2: N9741 Grade 3/4 Toxicities P Value Arm III (Arm I vs. Irinotecan/Oxaliplatin Arm II) (n = 250)
Arm I Irinotecan/5-FU/LV (n = 251)
Arm II Oxaliplatin/5-FU/LV (n = 256)
Neutropenia
39%
47%
0.08
35%
Febrile neutropenia
14%
4%
0.001
11%
Diarrhea
33%
13%
0.001
27%
Nausea
15%
6%
0.002
18%
Vomiting
12%
4%
0.001
22%
Dehydration
8%
4%
0.09
6%
Paresthesias
2%
18%
0.001
6%
Toxicity Hematologic
Nonhematologic
Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
Clinical Colorectal Cancer August 2002
• 79
results may be related, in part, to the fact that administration of 5-FU via continuous infusion as in the FOLFOX 4 regimen has been shown to achieve better efficacy and reduced toxicity than bolus administration of 5-FU as in the Saltz regimen.10 Moreover, 52% of patients on the oxaliplatin/5-FU/LV arm received irinotecan at time of progression, while only 17% of patients on the irinotecan/5-FU/LV arm received oxaliplatin at progression. While this fact should not affect the overall RR and time to disease progression observed with oxaliplatin/5-FU/LV, such a crossover design may have potentially contributed to the differences in median survival in favor of oxaliplatin/5-FU/LV. At present, patient accrual continues only to the oxaliplatin/5FU/LV arm. The US Food and Drug Administration (FDA) has granted approval for oxaliplatin as second-line therapy for advanced colorectal cancer. However, approval of oxaliplatin by the FDA as firstline therapy, based on the positive results of the N9741 clinical trial, remains in question for a number of reasons.11 First, the N9741 phase III study was initiated 2 years ago to compare the clinical efficacy of 6 different treatment regimens, 2 arms of which were terminated due to unacceptable toxicity. Accrual to the 5-FU/LV Mayo Clinic arm was
80 • Clinical Colorectal Cancer August 2002
stopped when the Saltz regimen became the standard of care in the spring of 2000. 2 The primary endpoint of this randomized study was to compare response rate and progression-free survival. Of note, this trial was not designed to investigate the effects of the respective treatment arms on patient survival. Second, N9741 compares combination regimens and not single agents, and for this reason, the efficacy of oxaliplatin as a single agent cannot be determined. Finally, administration of 5-FU via continuous infusion (FOLFOX 4 regimen) has shown better efficacy and reduced toxicity than bolus administration of 5-FU (Saltz regimen). Thus, the potential role of infusional versus bolus 5-FU schedules must be taken into account.
04.
05.
06.
07.
08.
References 01. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992; 10:896-903. 02. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343:905-914. 03. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a
09.
10.
11.
multicentre randomised trial. Lancet 2000; 355:1041-1047. Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801-3807. Laadem A, Cvitkovic E. [Oxaliplatin: a first DACH-platinum in oncology]. Bull Cancer 2001; 88 Spec No:S9-S13. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:29382947. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18:136-147. Wasserman E, Kalla S, Misset J, et al. Oxaliplatin (L-OHP) and irinotecan (CPT-11) phase I/II studies: results in 5-FU refractory (FR) colorectal cancer (CRC) patients (pts). Proc Am Soc Clin Oncol 1999; 18:238a (Abstract #913). Cited by: Goldberg R, Morton R, Sargent D, et al. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI intergroup study. Proc Am Soc Clin Oncol 2002; 21:128a (Abstract #511). Goldberg RM, Morton RF, Sargent DJ, et al. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI intergroup study. Proc Am Soc Clin Oncol 2002; 21:128a (Abstract #511). O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331:502-507. The Cancer Letter 2002; 28:1-8.
0.0003). The addition of oxaliplatin to 5FU/LV increased overall survival (16.2 months vs. 14.7 months), but this difference did not reach statistical significance (P = 0.12). A second oxaliplatin-based combination investigating a different chronomodulated schedule of 5-FU/LV versus chronomodulated 5-FU/LV in combination with oxaliplatin has also shown promising clinical activity.7 In addition, there have been several phase I/II studies investigating the combination of irinotecan and oxaliplatin. These studies have shown an RR of 41% in advanced colorectal cancer patients who had previously been treated with 5-FU–based regimens.8 • Goldberg and colleagues from the Mayo Clinic and the North Central Cancer Treatment Group, in collaboration with 4 other cancer cooperative groups in the United States, have conducted a randomized phase III study (N9741) to compare the efficacy and safety of the irinotecan/5-FU/LV versus the experimental oxaliplatin/5-FU/LV and oxaliplatin/irinotecan combination regimens as first-line therapy in patients
78 • Clinical Colorectal Cancer August 2002
• The 1-year follow-up results of the initially randomized patients were presented at the 38th Annual Meeting of the American Society of Clinical Oncology held in May 2002 in Orlando, Florida.9
A Phase III Study (N9741) Comparing Irinotecan/5-FU/LV to Oxaliplatin-Containing Regimens in Advanced Colorectal Cancer Study Design This study included adult patients with histologically confirmed unresectable metastatic colorectal cancer, measurable disease, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. Patients were required to have a life expectancy ≥ 12 weeks and adequate bone marrow, hepatic, and renal functions. No prior chemotherapy for metastatic disease was allowed. Patients were stratified according to
Figure 1: N9741 Treatment Schema
Stratified by: - Performance status - Age - Prior therapy
R A N D O M I Z E (n = 795)
Medical Writer: Kavita Maung, PhD Reviewed by: Edward Chu, MD, and Mace Rothenberg, MD
with advanced colorectal cancer.
Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
Control Arm Arm I (Saltz Regimen) (n = 264) Irinotecan 125 mg/m2 I.V. 5-FU 500 mg/m2 I.V. plus LV 20 mg/m2 I.V. Weekly for 4 out of 6 weeks Arm II (FOLFOX 4 Regimen) (n = 267) Oxaliplatin 85 mg/m2 I.V. day 1 5-FU 400 mg/m2 bolus + 600 mg/m2 I.V. as a 22-hour infusion on days 1 and 2 LV 200 mg/m2 I.V. days 1 and 2 Every 2 weeks Arm III (n = 264) Oxaliplatin 85 mg/m2 I.V. day 1 Irinotecan 200 mg/m2 I.V. day 1 Every 3 weeks
Table 1: Response and Survival Arm I Irinotecan/5-FU/LV (n = 264)
Arm II Oxaliplatin/5-FU/LV (n = 267)
Arm III Irinotecan/Oxaliplatin (n = 264)
6.9
8.8
6.7
–
0.0009
> 0.50
Median Survival (Months)
14.1
18.6
16.5
1-Year Survival
58%
71%
65%
value*†
–
0.002
Immature
Irinotecan/5-FU/LV (n = 245)
Oxaliplatin/5-FU/LV (n = 246)
Irinotecan/Oxaliplatin (n = 250)
29%
38%
28%
–
0.03
0.89
Endpoint Median Time to Disease Progression (Months) P value*
P
Response Rate P value*
*Two-sided P value compared to Saltz regimen †P value is for overall survival Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
PS, age, and prior adjuvant or immunotherapy. Patients were randomized to 1 of 3 treatment arms (Figure 1). Patients in arm I received irinotecan 125 mg/m2 intravenously (I.V.) followed by LV 20 mg/m2 plus 5-FU 500 mg/m2 I.V. weekly for 4 weeks followed by 2 weeks of rest. Treatment cycles were repeated every 6 weeks. Early deaths on arm I led to dose reductions of irinotecan from 125 mg/m2 to 100 mg/m2 and of 5-FU from 500 mg/m2 to 400 mg/m2. In arm II, patients received oxaliplatin 85 mg/m2 I.V. on day 1 and LV 200 mg/m2 and 5-FU 400 mg/m2 bolus and 600 mg/m2 as a 22hour infusion on days 1 and 2, repeated every 2 weeks. In arm III, patients received oxaliplatin 85 mg/m2 I.V. plus irinotecan 200 mg/m2 I.V. on day 1 with cycles repeating every 3 weeks. Treatment was continued until unacceptable toxicity or disease progression.
Results The first 795 patients enrolled in this study prior to a change in the dosing of the irinotecan/5-FU/LV arm were analyzed for this presentation. The treatment arms were well balanced, and approximately 16% of patients had received prior adjuvant chemotherapy. The oxaliplatin/5-FU/LV arm resulted in a significantly higher RR, longer time to disease progression, and improved median survival when compared to the control arm of irinotecan/5-FU/LV. An RR of
38% was achieved in patients on the oxaliplatin/5-FU/LV arm compared with 29% in patients on the irinotecan/5-FU/ LV arm (P = 0.03; Table 1). At a median follow-up of 12 months, the median time to disease progression was the longest in patients on the oxaliplatin/5-FU/LV arm at 8.8 months compared with 6.9 months in patients on the irinotecan/5-FU/LV arm (P = 0.0009). The overall survival was also higher in patients treated on the oxaliplatin/5-FU/LV arm compared to patients on the irinotecan/5-FU/LV regimen (P = 0.002). The RR, time to disease progression, and overall survival for the irinotecan/oxaliplatin arm was similar to the irinotecan/5-FU/LV arm although the
data is not felt to be sufficiently mature at this time for final statistical analysis. Seven hundred fifty-seven patients were evaluable for toxicity (Table 2). Grade 3/4 neutropenia was seen in 39% and 47% of patients in irinotecan/5FU/LV and oxaliplatin/5-FU/LV arms, respectively, but febrile neutropenia was more common with irinotecan/5-FU/LV (14%) compared with oxaliplatin/5FU/LV (4%; P = 0.001). Grade 3/4 diarrhea was significantly higher in patients on irinotecan/5-FU/LV at 33% compared with only 13% of patients on the oxaliplatin/5-FU/LV arm (P = 0.001). The incidence of nausea (P = 0.002) and vomiting (P = 0.001) was also reduced in patients treated with oxaliplatin/5-FU/LV when compared with patients treated with irinotecan/5-FU/LV.
Conclusion The results of this study demonstrated that oxaliplatin, when combined with 5FU/LV, results in promising activity as first-line therapy for patients with advanced colorectal cancer. Patients treated with the oxaliplatin/5-FU/LV combination showed significant improvement in time to disease progression, overall survival, and RR compared to patients on standard irinotecan/5-FU/LV regimen. In addition, oxaliplatin/5-FU/LV was associated with a more favorable toxicity profile when compared to the irinotecan/5-FU/LV treatment arm. These
Table 2: N9741 Grade 3/4 Toxicities P Value Arm III (Arm I vs. Irinotecan/Oxaliplatin Arm II) (n = 250)
Arm I Irinotecan/5-FU/LV (n = 251)
Arm II Oxaliplatin/5-FU/LV (n = 256)
Neutropenia
39%
47%
0.08
35%
Febrile neutropenia
14%
4%
0.001
11%
Diarrhea
33%
13%
0.001
27%
Nausea
15%
6%
0.002
18%
Vomiting
12%
4%
0.001
22%
Dehydration
8%
4%
0.09
6%
Paresthesias
2%
18%
0.001
6%
Toxicity Hematologic
Nonhematologic
Abbreviations: 5-FU = 5-fluorouracil; LV = leucovorin
Clinical Colorectal Cancer August 2002
• 79
results may be related, in part, to the fact that administration of 5-FU via continuous infusion as in the FOLFOX 4 regimen has been shown to achieve better efficacy and reduced toxicity than bolus administration of 5-FU as in the Saltz regimen.10 Moreover, 52% of patients on the oxaliplatin/5-FU/LV arm received irinotecan at time of progression, while only 17% of patients on the irinotecan/5-FU/LV arm received oxaliplatin at progression. While this fact should not affect the overall RR and time to disease progression observed with oxaliplatin/5-FU/LV, such a crossover design may have potentially contributed to the differences in median survival in favor of oxaliplatin/5-FU/LV. At present, patient accrual continues only to the oxaliplatin/5FU/LV arm. The US Food and Drug Administration (FDA) has granted approval for oxaliplatin as second-line therapy for advanced colorectal cancer. However, approval of oxaliplatin by the FDA as firstline therapy, based on the positive results of the N9741 clinical trial, remains in question for a number of reasons.11 First, the N9741 phase III study was initiated 2 years ago to compare the clinical efficacy of 6 different treatment regimens, 2 arms of which were terminated due to unacceptable toxicity. Accrual to the 5-FU/LV Mayo Clinic arm was
80 • Clinical Colorectal Cancer August 2002
stopped when the Saltz regimen became the standard of care in the spring of 2000. 2 The primary endpoint of this randomized study was to compare response rate and progression-free survival. Of note, this trial was not designed to investigate the effects of the respective treatment arms on patient survival. Second, N9741 compares combination regimens and not single agents, and for this reason, the efficacy of oxaliplatin as a single agent cannot be determined. Finally, administration of 5-FU via continuous infusion (FOLFOX 4 regimen) has shown better efficacy and reduced toxicity than bolus administration of 5-FU (Saltz regimen). Thus, the potential role of infusional versus bolus 5-FU schedules must be taken into account.
04.
05.
06.
07.
08.
References 01. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992; 10:896-903. 02. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343:905-914. 03. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a
09.
10.
11.
multicentre randomised trial. Lancet 2000; 355:1041-1047. Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801-3807. Laadem A, Cvitkovic E. [Oxaliplatin: a first DACH-platinum in oncology]. Bull Cancer 2001; 88 Spec No:S9-S13. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:29382947. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18:136-147. Wasserman E, Kalla S, Misset J, et al. Oxaliplatin (L-OHP) and irinotecan (CPT-11) phase I/II studies: results in 5-FU refractory (FR) colorectal cancer (CRC) patients (pts). Proc Am Soc Clin Oncol 1999; 18:238a (Abstract #913). Cited by: Goldberg R, Morton R, Sargent D, et al. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI intergroup study. Proc Am Soc Clin Oncol 2002; 21:128a (Abstract #511). Goldberg RM, Morton RF, Sargent DJ, et al. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI intergroup study. Proc Am Soc Clin Oncol 2002; 21:128a (Abstract #511). O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331:502-507. The Cancer Letter 2002; 28:1-8.