With the exception of surgically resectable liver or lung metastases, the majority of patients with metastatic colorectal cancer are treated primarily with systemic chemotherapy. It is now common for many of these patients to not only receive one, but two or more chemotherapy regimens during the course of their illness.
In a recently reported randomized trial, 45% of patients receiving first-line fluorouracil(Drug information on fluorouracil) (5-FU) and leucovorin received second-line irinotecan(Drug information on irinotecan) (CPT- 11, Camptosar). Most of the current available data for second-line therapy of colorectal cancer comes from phase II trials. These trials have all the limitations of other phase II trials. In addition, there is significant heterogeneity in the colorectal cancer population considered for "second-line" therapy. This group may include patients who first presented with metastatic disease, patients who have progressed rapidly after adjuvant therapy, patients who have had more than one resection for disease, and patients who may have had liver-directed therapy. In addition, as more knowledge develops on the molecular basis of disease, properties of the cancers themselves have been identified that may predict chemotherapy effects.
The data regarding the use of oxaliplatin(Drug information on oxaliplatin) as second-line (or later-line) chemotherapy will be highlighted herein. The article will demonstrate that phase II data in this setting are mature and that the time has come for randomized trials to establish the true role of oxaliplatin in second-line chemotherapy.
An important variable in future results of second-line therapy may be the shifting paradigm for first-line therapy. (Use of oxaliplatin (Eloxatin) as first-line therapy is discussed elsewhere.) Recently, two clinical trials compared fluorouracil (5-FU) and leucovorin with 5-FU, leucovorin, and irinotecan combination therapy. Both trials showed that the addition of irinotecan increased the response rate, time to progression, and overall survival compared to 5-FU and leucovorin alone, at the expense of potential added toxicity.[1-3] Thus, at least in the United States, many patients are now receiving a combination regimen as first-line therapy.
However, investigators initially assessed irinotecan as second-line therapy for metastatic colorectal cancer. In that respect, data from those trials remain the best framework in which to evaluate second-line oxaliplatin. Single-agent irinotecan as second-line therapy has yielded response rates of 10% to 22% and median survivals of 8 to 10 months. In two randomized trials, irinotecan also established a survival benefit over both best supportive care and second-line infusional 5-FU.[5,6] The trials had different eligibility criteria and, therefore, patient populations.[7-12]
The activity of single-agent oxaliplatin as second-line therapy was established in three trials reported in two articles.[7,13] In the trials by Machover et al, patients received intravenous infusions of oxaliplatin over 2 hours. Doses were repeated every 3 weeks. The study by Levi et al used a chronomodulated infusion, with the peak dose administered at 4 PM, over 5 days, also repeated every 3 weeks.
Response rates were 10% to 11%, with stable disease seen in 24% to 42% of patients. Median time to progression was 4.5 to 6 months and median survival was 8 to 9 months. These results are comparable to the results achieved with irinotecan as second-line therapy.[4-6]
The Folfox Regimens
De Gramont and colleagues have pioneered several regimens combining 5-FU and leucovorin with oxaliplatin.[7-11] The majority of these regimens are administered every 2 weeks, and contain infusions of leucovorin and 5-FU. Most also contain one or two bolus doses of 5-FU. For example, folfox4 (oxaliplatin, leucovorin, and fluorouracil) administers oxaliplatin at 85 mg/m2 over 2 hours on day 1. Patients then receive leucovorin at 200 mg/m2 over 2 hours on days 1 and 2 followed each day by bolus 5-FU at 400 mg/m2 on days 1 and 2 and 22 hours of infusional 5-FU 600 mg/m2 on days 1 and 2. These cycles are repeated once every 2 weeks, for up to 12 doses of oxaliplatin (Table 1).[7-12]
When combined, the response rate plus stable disease rate is generally greater than 50% for the folfox regimens. Of particular note, most of the patients in these trials had progressed while on the same 5-FU and leucovorin regimen that they later received on trial with the addition of oxaliplatin, suggesting that the addition of oxaliplatin resulted in the antitumor effect. Although these data are from phase II trials, response rates for the folfox regimens were higher than for single-agent oxaliplatin, suggesting a possible additive effect when combining 5-FU and oxaliplatin.
Differences in the incidence of toxicity were seen among the folfox regimens with grade 3/4 neutropenia occurring in 20% to 39% of patients receving folfox2, 3, 4, or 6, and grade 2/3 neuropathy in 16% to 29% of those receiving folfox2, 3, 4, or 6.
Chronomodulated 5-FU has also been combined with oxaliplatin in several phase II trials listed in Table 2.[14-18] Although two trials involved both previously untreated and previously treated patients, the data are separated when possible for patients with refractory disease. As with the folfox trials, response rates were high, ranging from 15% to 58%. In addition, a progression-free survival ranging from 5 to 10 months and an overall survival as high as 17 months was observed.
Recently, Giacchetti et al reported results that combined patients from some of the trials listed in Table 3 with other patients being considered for resection of hepatic metastases. In total, 196 patients had been treated with chronomodulated 5-FU and oxaliplatin. Of these, 60% had received only one previous chemotherapy regimen and 40% had received greater than or equal to two regimens. Median progression-free survival was 9 months and overall survival was 17 months. However, hepatic metastases were resected in 18% of patients.
With chronomodulation, grade 3/4 neutropenia occurred in less than 5% of patients, while grade 2 or higher neuropathy occurred in up to 32% of pretreated patients and grade 3/4 mucositis in up to 28% of patients.[14,15]
Other 5-FU Regimens
Several schedules and doses for 5-FU, leucovorin, and oxaliplatin have been investigated; many of these are listed in Table 3.[20-24] Although some of the bolus schedules for 5-FU appeared to yield lower response rates, overall survival was similar to that achieved with the folfox and chronomodulated schedules shown in Table 1 and Table 2. Table 3 is not a comprehensive list of all the trials performed, and more treatment schedules are likely to be tried. In fact, the Extended Access French Program (EAFP) allowed the use of over 25 different regimens of oxaliplatin in combination with 5-FU. This data set incorporated 490 patients from 147 centers, only 18 of whom received single-agent oxaliplatin.
Antitumor effects were reviewed for 370 patients, and 14.6% responded to therapy with a 9.7-month overall median survival. Response rates were higher for the biweekly oxaliplatin regimens (36.1%) than for the triweekly regimens (13.3%) but survivals were similar at 11.1 and 10.0 months, respectively. The current "compassionate-use trial" in the United States will accumulate progression and survival data that may help guide a decision on whether it is worthwhile to explore different regimens in a randomized fashion.
A single randomized phase II/III trial has been reported that compared oxaliplatin plus 5-FU vs one of two other second-line regimens, 5-FU or irinotecan. The trial was divided into two treatment arms with 49 patients assigned to the oxaliplatin plus 5-FU arm vs 36 patients in the control arm. The response rate was 37% for the oxalipatin plus 5-FU arm vs 11% for the control arm, and progression-free survival was 5.1 months vs 2.2 months for the oxaliplatin plus 5-FU and control arm, respectively.
The final data from this trial may help to clarify the role of oxaliplatin plus 5-FU in second-line therapy of colorectal cancer. However, interpretation may be limited by the inclusion of two different single-arm regimens in the "control" arm.
Overall, it appears that 5-FU plus oxaliplatin is active in the second-line therapy of colorectal cancer. A number of regimens have been tested as listed in Tables 1 to 3. While response rates for combination therapy often seem higher than response rates for single-agent oxaliplatin, survival does not appear to differ significantly.