14.2 Combination Therapy with Oxaliplatin and 5-fluorouracil/leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer
A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus 5-fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, oxaliplatin in combination with infusional 5-fluorouracil/leucovorin and a combination of oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0,1, or 2. Patients had to have granulocyte count ≥ 1.5 x 109 /L, platelets ≥ 100 x 109 /L, hemoglobin ≥ 9.0 gm/dL, creatinine ≤ 1.5 x ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 x ULN, and alkaline phosphatase ≤ 5 x ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (<65 vs. ≥65 years). Although no post study treatment was specified in the protocol, 65 to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the oxaliplatin plus 5-fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.
The following table presents the dosing regimens of the three arms of the study.
Table 20 – Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
|Oxaliplatin + 5-FU/LV (FOLFOX4)(N=267)||Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) + LV 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)Day 2: LV 200 mg/m2 (2-hour infusion), followed by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)||every 2 weeks|
|Irinotecan + 5-FU/LV (IFL)(N=264)||Day 1: irinotecan 125 mg/m2 as a 90–min infusion + LV 20 mg/m2 as a 15-min infusion or intravenous push, followed by 5-FU 500 mg/m2 intravenous bolus weekly x 4||every 6 weeks|
|Oxaliplatin + Irinotecan (IROX)(N=264)||Day 1: Oxaliplatin: 85 mg/m2 intravenous(2-hour infusion) + irinotecan 200 mg/m2 intravenous over 30 minutes||every 3 weeks|
The following table presents the demographics of the patient population entered into this study.Table 21 – Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
|Oxaliplatin +5-FU/LV(N=267)||Irinotecan + 5-FU/LV(N=264)||Oxaliplatin + irinotecan(N=264)|
|Sex: Male (%)||58.8||65.2||61.0|
|Median age (years)||61.0||61.0||61.0|
|<65 years of age (%)||61||62||63|
|≥65 years of age (%)||39||38||37|
|Involved organs (%)|
|Liver + other||41.2||38.6||40.9|
|Other (including lymph nodes)||11.6||11.0||12.9|
|Prior radiation (%)||3.0||1.5||3.0|
|Prior surgery (%)||74.5||79.2||81.8|
|Prior adjuvant (%)||15.7||14.8||15.2|
The length of a treatment cycle was 2 weeks for the oxaliplatin and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the oxaliplatin plus irinotecan regimen. Patients treated with the oxaliplatin and 5-fluorouracil/leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/leucovorin. The following table summarizes the efficacy results.Table 22 – Summary of Efficacy
|Oxaliplatin +5-FU/LV(N=267)||irinotecan +5-FU/LV(N=264)||Oxaliplatin +irinotecan(N=264)|
|Number of deaths N (%)||155 (58.1)||192 (72.7)||175 (66.3)|
|Median survival (months)||19.4||14.6||17.6|
|Hazard Ratio and (95% confidence interval)||0.65 (0.53 to 0.80)†|
|TTP (ITT, investigator assessment)|
|Percentage of progressors||82.8||81.8||89.4|
|Median TTP (months)||8.7||6.9||6.5|
|Hazard Ratio and (95% confidence interval)‡||0.74 (0.61 to 0.89)†|
|Response Rate (investigator assessment)§|
|Patients with measurable disease||210||212||215|
|Complete response N (%)||13 (6.2)||5 (2.4)||7 (3.3)|
|Partial response N (%)||82 (39.0)||64 (30.2)||67 (31.2)|
|Complete and partial response N (%)||95 (45.2)||69 (32.5)||74 (34.4)|
|95% confidence interval||(38.5 to 52.0)||(26.2 to 38.9)||(28.1 to 40.8)|
†Compared to irinotecan plus 5-fluorouracil/leucovorin (IFL) arm
§ Based on all patients with measurable disease at baseline
‡A hazard ratio of less than 1.00 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin
The numbers in the response rate and TTP analysis are based on unblinded investigator assessment. Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin and 5-fluorouracil/leucovorin combination and oxaliplatin plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.
Figure 4 – Kaplan-Meier Overall Survival by treatment arm A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in oxaliplatin plus 5-fluorouracil/leucovorin versus irinotecan plus 5-fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.
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