Oxaliplatin (Page 6 of 10)

14 CLINICAL STUDIES

14.1 Adjuvant Treatment with oxaliplatin injection in Combination with Fluorouracil and Leucovorin

The efficacy of oxaliplatin injection in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in an international, multicenter, randomized (1:1) trial (The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC], NCT00275210) in patients with stage II (Dukes’ B2) or III (Dukes’ C) colon cancer who had undergone complete resection of the primary tumor. Patients were randomized to receive oxaliplatin injection with fluorouracil/leucovorin or fluorouracil/leucovorin alone for a total of 6 months (i.e., 12 cycles). Table 14 shows the dosing regimens for the two arms.

Eligible patients were between 18 and 75 years of age, had histologically proven stage II (T3 -T4 N0 M0; Dukes’ B2) or III (any T N1-2 M0; Dukes’ C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., greater than or equal to 15 cm from the anal margin) and had undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease and carcino-embyrogenic antigen (CEA) less than 10 ng/mL. Additional eligibility criteria were no prior chemotherapy, immunotherapy or radiotherapy; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 (Karnofsky Performance Status greater than or equal to 60%); no pre-existing neuropathy; and absolute neutrophil count (ANC) greater than or equal to 1.5×109 /L, platelets greater than or equal to 100 x 109 /L, serum creatinine less than or equal to 1.25 x upper limit normal (ULN), total bilirubin less than 2 x ULN, and aspartate transaminase (AST)/alanine transaminase (ALT) less than 2 x ULN. The major efficacy outcome was 3-year disease-free survival (DFS).

Table 14: Dosing Regimens in Adjuvant Treatment Study
Treatment Arm Dose Regimen
Oxaliplatin Injection + FU/LV (FOLFOX4) (N =1123)Day 1: Oxaliplatin Injection: 85 mg/m2 (2-hour infusion) + LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)every 2 weeks 12 cycles
FU/LV (N=1123)Day 1: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion) Day 2: LV: 200 mg/m2 (2-hour infusion), followed by FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusionevery 2 weeks 12 cycles

There were 2246 patients enrolled, of whom 1347 (60%) had Stage III disease. Tables 15 and 16 show the baseline characteristics and exposure to oxaliplatin injection.

Table 15: Baseline Characteristics in Adjuvant Treatment Study
Oxaliplatin Injection + Infusional FU/LV N=1123 Infusional FU/LV N=1123
Sex: Male (%)56.152.4
Female (%)43.947.6
Median age (years)61.060.0
<65 years of age (%)64.466.2
≥65 years of age (%)35.633.8
KPS (%)
10029.730.5
9052.253.9
804.43.3
7013.211.9
≤600.60.4
Primary site (%)
Colon including cecum54.654.4
Sigmoid31.933.8
Recto sigmoid12.910.9
Other including rectum0.60.9
Bowel obstruction (%)
Yes17.919.3
Perforation (%)
Yes6.96.9
Stage at Randomization (%)
II (T=3,4 N=0, M=0)40.139.9
III (T=any, N=1,2, M=0)59.659.3
IV (T=any, N=any, M=1)0.40.8
Staging – T (%)
T10.50.7
T24.54.8
T376.075.9
T419.018.5
Staging – N (%)
N040.239.9
N139.439.4
N220.420.7
Staging – M (%)
M10.40.8
Table 16: Exposure to Oxaliplatin Injection in Adjuvant Treatment Study
Oxaliplatin Injection + Infusional FU/LV N=1108 Infusional FU/LV N=1111
Median Relative Dose Intensity (%)
FU84.497.7
Oxaliplatin Injection80.5N/A
Median Number of Cycles1212
Median Number of Cycles with oxaliplatin injection11N/A

The median duration of follow-up was approximately 77 months. In the overall and the stage III colon cancer populations, DFS was statistically significantly improved in the oxaliplatin injection-containing arm compared to fluorouracil/leucovorin alone; however, a statistically significant improvement in DFS was not observed in Stage II patients. No significant differences in overall survival (OS) were detected in the overall population or those with Stage III disease. Table 17 and Figures 1 and 2 summarize the 5-year DFS rates in the overall randomized population and in patients with stage II and III disease based on an intention-to-treat (ITT) analysis.

Table 17: Summary of DFS Analysis in Adjuvant Treatment Study – ITT Population
Parameter Oxaliplatin Injection + Infusional FU/LV Infusional FU/LV
Overall
Number of patients11231123
Number of events – relapse or death (%)304 (27.1)360 (32.1)
5-yr Disease-free survival % (95% CI)73.3 (70.7, 76.0)67.4 (64.6, 70.2)
Hazard ratio (95% CI)0.80 (0.68, 0.93)
Stratified Log rank testp=0.003
Stage III (Dukes’ C)
Number of patients672675
Number of events –relapse or death (%)226 (33.6)271 (40.1)
5-yr Disease-free survival % (95% CI)66.4 (62.7, 70.0)58.9 (55.2, 62.7)
Hazard ratio (95% CI)0.78 (0.65, 0.93)
Log rank testp=0.005
Stage II (Dukes’ B2)
Number of patients451448
Number of events – relapse or death (%)78 (17.3)89 (19.9)
5-yr Disease-free survival % (95% CI)83.7 (80.2, 87.1)79.9 (76.2, 83.7)
Hazard ratio (95% CI)0.84 (0.62, 1.14)
Log rank testp=0.258
A hazard ratio of less than 1 favors Oxaliplatin Injection + Infusional FU/LV Data cut off for disease-free survival June 1, 2006

Figure 1: Kaplan-Meier Curves of Disease-Free Survival (cutoff: 1 June 2006) in Adjuvant Treatment Trial – ITT Population

Figure 1
(click image for full-size original)

Figure 2: Kaplan-Meier Curves of Disease-Free Survival in Stage III Patients (cutoff: 1 June 2006) in Adjuvant Treatment Trial – ITT Population

Figure 2
(click image for full-size original)

Table 18 summarizes the OS results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

Table 18: Summary of OS Analysis in Adjuvant Treatment — ITT Population
Parameter Oxaliplatin Injection + Infusional FU/LV Infusional FU/LV
Overall
Number of patients11231123
Number of death events (%)245 (21.8)283 (25.2)
Hazard ratio (95% CI)0.84 (0.71, 1.00)
Stage III (Dukes’ C)
Number of patients672675
Number of death events (%)182 (27.1)220 (32.6)
Hazard ratio (95% CI)0.80 (0.65, 0.97)
Stage II (Dukes’ B2)
Number of patients451448
Number of death events (%)63 (14.0)63 (14.1)
Hazard ratio (95% CI)1.00 (0.70, 1.41)
A hazard ratio of less than 1 favors Oxaliplatin Injection + Infusional FU/LV Data cut off for overall survival January 16, 2007

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