NEW ORLEANS—A meta-analysis of two independent phase III randomized multicenter studies “further strengthens the conclusion that the combination of irinotecan(Drug information on irinotecan) (CPT-11, Camptosar)/fluorouracil (5-FU)/leucovorin represents a new reference standard in the first-line treatment of patients with metastatic colorectal cancer,” said Leonard Saltz, MD, associate attending physician, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center.
The combination significantly improved response rate, lengthened time to tumor progression, and prolonged survival, compared with 5-FU/leucovorin alone, Dr. Saltz said at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO).
In the first trial, conducted primarily in North America, as well as Australia and New Zealand, patients were randomized to receive the combination—bolus 5-FU 500 mg/m² plus leucovorin 20 mg/m² plus irinotecan 125 mg/m² weekly for 4 weeks followed by a 2-week rest—or the Mayo Clinic bolus 5-FU/leucovorin regimen.
Eligible patients had histologically proven colorectal cancer; unresectable measurable metastases; performance status of 0, 1, or 2; and no prior chemotherapy for metastatic disease.
In the second trial, conducted primarily in Europe, patients received infusional 5-FU weekly or biweekly. Centers selected which 5-FU schedule they would use, and patients were randomized to that schedule with or without irinotecan.
The entry criteria for this study were essentially the same as for the North American trial.
“Post-accrual follow-up is mature in both studies,” Dr. Saltz said, “20 months and 19 months, respectively.”
Confirmed response rates for the North American trial were 39% for the irinotecan combination vs 21% for 5-FU/leucovorin alone (P <.0001), and for the European trial, 35% vs 22%, respectively (P = .005), Dr. Saltz reported. In the meta-analysis, response rates were 37% for 5-FU/leucovorin/irinotecan, compared with 21% for 5-FU/leucovorin alone (P <.0001).
Time to tumor progression in the North American trial was 7 months for the combination vs 4.3 months for 5-FU/leucovorin alone (P = .004), and in the European trial, 6.7 months vs 4.4 months, respectively (P < .001). The meta-analysis showed a time to tumor progression of 6.9 months vs 4.3 months, respectively (P = .0001).
“I call your attention to the more significant P values and the narrowing of the confidence intervals,” Dr. Saltz said, “indicating the increased confidence that we gain from larger numbers.”
He added that in a Cox regression analysis performed to compensate for potentially important prognostic variables, the superiority of the irinotecan combination therapy remained at the same significance (P = .0001).
Overall survival in the North American trial was 14.8 months for the combination vs 12.6 months for 5-FU/leucovorin alone (P = .042), and in the European trial, 17.4 months vs 14.1 months, respectively (P = .032).
Results from the meta-analysis for overall survival—15.9 months vs 13.3 months, respectively—were now highly statistically significant (P = .003), again with narrowing of the confidence intervals. In the Cox regression model, the superiority of the irinotecan combination remained highly statistically significant (P = .0008).
A Question About Crossovers
In the question-and-answer session following his presentation, Dr. Saltz was asked how many control patients in the trials had crossed over to receive irinotecan and whether this could have affected the results.
He responded that in the North American trial, 55% of control patients received irinotecan as second-line therapy. “National databases show that approximately 70% of patients go on to get second-line therapy, and 80% of those are irinotecan based, which works out to about 56%,” he said, “so this trial accurately reflects the incidence of patients who are able to go on to second-line therapy with irinotecan.”
He reminded the audience that “not everyone who progresses through a first-line regimen is well enough for a second-line regimen.” Patients failing 5-FU who have poor performance status, bowel obstruction, or elevated bilirubin, for example, would not be candidates for second-line irinotecan. “It is possible that one of the reasons we’re seeing an advantage for first-line combination therapy is the increased number of patients who are exposed to both drugs,” he said.
When an audience member suggested that the combination therapy with irinotecan should not be the new standard because “second-line treatment in the control arm has never been tested prospectively,” Dr. Saltz strongly disagreed.
“For the reasons I just outlined, I think that we have prospectively tested that question,” he said. “I would point out that you simply can’t mandate second-line therapy in trials, because patients are frequently not well enough to receive it. I think this trial fairly accurately reflects sequential vs concurrent administration of irinotecan.”
New Standard of Practice
The discussant, Daniel G. Haller, MD, professor of medicine, University of Pennsylvania Cancer Center, said that “although the planned primary endpoints of these trials were progression-free survival and response rates, respectively, both trials reached the regulatory measure of success, a statistically significant 2- to 3-month improvement in median survivorship.”
In the United States, Dr. Haller said, “the combination of 5-FU/leucovorin and irinotecan represents a new standard of practice and a new control arm for clinical trials.” He added that the combination has been approved by the FDA with either bolus or infusional fluorouracil(Drug information on fluorouracil).
Referring to a subgroup analysis also presented at the ASCO meeting (abstract #991), Dr. Haller said, “It appears that the combination is the standard for all patients.” He added that the abstract “suggests that the survival benefits appear greatest in the good-risk patients, but that all patients entering these trials have benefited.”
Dr. Haller also pointed out (referring to abstract #2443 presented at the ASCO meeting) that the benefit was achieved “without a marked recorded increase in toxicity or a negative impact on quality of life.”
