Introduction
The American Cancer Society estimates that 130,200 cases of colorectal cancer are diagnosed in the United States each year. Of these, 32,000 are stage IV (ie, metastatic disease) at the time of original diagnosis. In addition, each year, another 39,000 patients previously diagnosed with stage I to stage III disease develop metastatic disease. As a result, approximately 71,000 people annually present with metastatic colorectal cancer. Approximately 10% of these patients will have isolated hepatic metastases that can be surgically resected, while the remainder will be candidates for systemic chemotherapy.
For nearly 40 years, the mainstay of chemotherapy for patients with metastatic colorectal cancer has been fluorouracil(Drug information on fluorouracil) (5-FU). Three meta-analyses assessed the efficacy of single-agent 5-FU vs biochemical modulation of 5-FU with leucovorin, sequential treatment with methotrexate(Drug information on methotrexate) followed by 5-FU, and bolus administration vs IV infusion of 5-FU.[1-3] Regimens that included either leucovorin or methotrexate or 5-FU administered as an infusion improved the response rate significantly (by 50% to 100%), but the improvement in overall survival was modest, from 0.5 to 2 months (Table 1). Notably, overall survival with 5-FU-based regimens consistently averaged 12 months or less.
A European trial demonstrated that the schedule of administration regimen of 5-FU influences both efficacy and safety. This trial randomized patients with metastatic colorectal cancer and no prior treatment for metastatic disease to treatment with the de Gramont regimen (combining leucovorin and an IV bolus dose and infusion of 5-FU plus leucovorin administered over 2 hours for 2 consecutive days every 2 weeks) or the Mayo Clinic regimen (consisting of leucovorin and a daily bolus injection of 5-FU for 5 consecutive days every 4 to 5 weeks).[4]
The response rate with the de Gramont regimen was more than twice that of the Mayo Clinic regimen (32.6% vs 14.5%; P = .0004), and progression-free survival was significantly higher (6.4 mo vs 5.1 mo; P = .001). There was a trend toward improved median survival with the de Gramont regimen that did not reach statistical significance (14.3 months vs 13.1 months; P = .067). However, the de Gramont regimen was associated with lower rates of grade 3/4 neutropenia, mucositis, and diarrhea, but higher rates of grade 1 and 2 epistaxis and conjunctivitis.
The emergence of two novel cytotoxic agents, irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) and oxaliplatin(Drug information on oxaliplatin) (Eloxatin), over the past 5 years caused a marked change in the direction of clinical trials in patients with metastatic colorectal cancer. Rather than focus on biochemical modulation of 5-FU, recent clinical trials have evaluated the impact of adding each of these agents to standard therapy. This review will concentrate on data from two randomized trials that evaluated 5-FU/leucovorin, with or without oxaliplatin, in this setting.
Overview of Oxaliplatin
Like other platinum compounds, oxaliplatin inhibits DNA replication and transcription through the formation of intra- and interstrand DNA adducts. However, unlike cisplatin(Drug information on cisplatin) (Platinol) or carboplatin(Drug information on carboplatin) (Paraplatin), oxaliplatin is a diaminocyclohexane (DACH) platinum (Figure 1). The DNA adducts of oxaliplatin are bulkier and more hydrophobic than those of cisplatin or carboplatin, and these properties contribute to its enhanced activity in inhibiting DNA synthesis and its lack of cross-resistance with cisplatin and carboplatin.[6-8]
Oxaliplatin platinates DNA much faster than does cisplatin—15 minutes for oxaliplatin vs an average of 48 hours for cisplatin. However, unlike cisplatin and carboplatin, oxaliplatin adducts are less susceptible to DNA excision repair enzymes, and have equivalent activity in DNA mismatch repair-proficient and -deficient cells in vitro.[9]
Activity Spans Several Cell Lines
In preclinical studies, oxaliplatin demonstrated activity against six of eight colorectal cancer cell lines in the National Cancer Institute automated screening panel, whereas cisplatin and carboplatin had no activity against these cell lines (Figure 2).[7] In in vitro studies, oxaliplatin was synergistic with 5-FU and leucovorin.[9-11] In one series, oxaliplatin and 5-FU demonstrated synergy in 78% of the situations tested, including four human colorectal cancer cell lines, three different drug administration sequences, and three different durations of exposure to 5-FU.
In phase I studies, oxaliplatin was administered over 2 to 6 hours on an every 3-week schedule. The dose-limiting toxicity in phase I studies was cumulative, reversible paresthesia, and occurred at a dose of 180 to 200 mg/m2.[12,13] Therefore, the dose of oxaliplatin chosen for phase II studies was 130 mg/m2 administered on an every 3-week schedule. In order to accommodate the every 2-week scheduling of the de Gramont regimen, a dose of 85 mg/m2 was selected in order to maintain a stable dose intensity of 42.5 mg/m2/wk.
Oxaliplatin as First-Line Therapy for Advanced Colorectal Cancer
The clinical activity of oxaliplatin monotherapy has recently been reviewed.[14] In two phase II trials conducted in patients with previously untreated colorectal cancer, 12% and 24% of those who received 130 mg/m2 of single-agent oxaliplatin achieved objective responses. The median durations of response were 6 and 7 months, the median times to tumor progression were 4 months in both studies, and the median survivals were 13 and 14.5 months.
Two phase II trials evaluated the combination of 5-FU/leucovorin and oxaliplatin as initial therapy for patients with metastatic colorectal cancer.[15,16] Both were performed using chronomodulated drug administration schedules, and both reported impressive objective response rates of 59% and 67%. The median progression-free survivals were 8.4 and 11 months, and median survivals were 15 and 18.5 months.
These results prompted the initiation of two randomized trials of 5-FU/leucovorin, with or without oxaliplatin, as first-line chemotherapy in patients with metastatic colorectal cancer. In one trial, the drugs were administered in a chronomodulated fashion, and in the other, they were given using a nonchronomodulated, biweekly schedule.
Phase III Pivotal Trial: de Gramont 5-FU/Leucovorin With or Without Oxaliplatin
This European multinational, multicenter phase III trial (also known as EFC 2962) evaluated the contribution of oxaliplatin as first-line treatment in patients with metastatic colorectal cancer.[17] Between August 1995 and July 1997, 420 patients were enrolled in the trial. Eligibility criteria included histologically confirmed adenocarcinoma of the colon or rectum, inoperable metastatic disease at enrollment, no prior immunotherapy or chemotherapy for metastatic disease (but adjuvant chemotherapy that had been completed at least 6 months prior to enrollment was allowed), at least one bidimensionally measurable lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan, a World Health Organization (WHO) performance status (PS) ≤ 2, and adequate serum chemistry values and bone marrow reserve.
Patients randomized to the control arm were treated with leucovorin 200 mg/m2 IV over 2 hours, followed by 5-FU 400 mg/m2 administered as an IV bolus followed by a 22-hour infusion at 600 mg/m2 on days 1 and 2 every 2 weeks. Patients randomized to the experimental arm received the same schedule of 5-FU plus leucovorin, with oxaliplatin 85 mg/m2 IV over 2 hours on day 1 only.
The primary end point of the trial was progression-free survival. Secondary end points included response rate as determined by an independent review panel based on a confirmatory scan obtained at 4 weeks, overall survival, quality of life (QOL), and safety of the regimens. The null hypothesis was that there was no difference in progression-free survival, and the alternative hypothesis was that there would be a 43% difference in median progression-free survival (from 7 to 10 months), which was considered a clinically significant improvement. The study was designed to have ³ 80% power to detect a significant difference at the 0.05 level.
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