New Analyses Establish the Addition of Irinotecan to Fluorouracil/Leucovorin as the New Standard of Care for First-Line Rx of Metastatic Colorectal Cancer

NEW ORLEANS—New data demonstrate that the recently approved combination of irinotecan (Camptosar), 5-fluorouracil (5-FU), and leucovorin (LV) in-creases overall survival when used as first-line therapy in patients with metastatic colorectal cancer, without a significant increase in side effects.

Scientists presented three new analyses of two studies that were the basis of the Food and Drug Administration’s approval this spring of the topoisomerase inhibitor irinotecan with 5-FU/LV for first-line therapy of metastatic colorectal cancer, a highly resistant malignancy and the second leading cause of cancer deaths in North America.

Leonard Saltz, MD, one of the presenters and associate attending physician, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, called the drug trio “the new reference standard.”

Langdon Miller, MD, vice president of clinical oncology, Pharmacia Co., Peapack, NJ, reported that on average, patients receiving irinotecan and 5-FU have a significantly improved tumor control and longer survival than the patients receiving 5-FU/LV, the therapy that has been standard for metastatic colorectal cancer for several decades.

Mature Data Reanalyzed

Dr. Saltz and his colleagues conducted a meta-analysis of the two studies, one based in North America and the other in Europe, reanalyzing the data on each participant as if they were part of one large study.

“With the meta-analysis, we found that the P values became more statistically significant,” Dr. Saltz told ONI. “The smaller the P value, the more confidence we have in the validity of the results.”

Response rates, time to progression, and survival were superior to those revealed when the original studies were reported individually. Originally, the European data showed a survival advantage, while the American study did not, Dr. Saltz said.

Now that the data have matured, both studies reveal a survival advantage for the patients receiving irinotecan/5-FU/LV. Combined survival for the irinotecan/5-FU/LV patients was 15.9 months, compared to 13.3 months for the 5-FU/LV group.

In the meta-analysis of data from 842 patients in the two studies, the combined response rate was 37% for irinotecan/5-FU/LV vs 21% for 5-FU/LV.

Combined time to tumor progression was 6.9 months in the irinotecan/5-FU/LV group, compared with 4.3 months for those receiving 5-FU/LV.

Side effects were “tolerable and treatable,” and there were no more treatment-associated deaths than with the previous treatment, Dr. Saltz reported.

“It’s clear that this is a better way to treat patients than what we were doing before,” he said.

Subgroups Analyzed

Robert D. Knight, MD, director of clinical research and oncology at Pharmacia, presented a reanalysis by subgroup of the North American study. The researchers investigated a variety of factors, including age (up to age 65 and older than 65), gender, performance status, organ sites affected by metastatic disease, the presence of liver metastases (liver metastasis is associated with poor prognosis in any cancer), and serum LDH level (higher lactate dehydrogenase levels are associated with poor prognosis).

“No matter which subgroup we looked at, the patients always did better on the irinotecan/5-FU/LV arm than they did on the 5-FU/LV arm. So everyone had the chance to benefit from the addition of irinotecan to their treatment,” Dr. Knight said.

Even the elderly and those who had poor performance status did well on irinotecan/5-FU/LV, Dr. Knight said, despite the belief in clinical oncology that older, frail people might be less likely to tolerate a combination therapy or a new drug administered after earlier treatments.

Those patients who showed the greatest improvement in survival had normal LDH and normal performance status, regardless of all the other factors. For this group, median overall survival on irinotecan/5-FU/LV was 26 months vs 16 months with 5-FU/LV.

Age, gender, and other factors did not influence outcome based on the type of therapy used. Other factors did, but to a lesser degree than LDH and performance status, Dr. Knight said. These were serum bilirubin, only one site of organ metastasis, and normal vs elevated white blood cell count.

Response rates (greater than 50% shrinkage) analyzed by baseline tumor area and organ site were also better in all patient subgroups receiving irinotecan/5-FU/LV than in those given 5-FU/LV, Dr. Knight reported.

Median time to progression also improved with irinotecan/5-FU/LV. The greatest improvement occurred in those with normal serum LDH; these patients had a median time to progression of just over 9 months, compared with a little more than 4 months for those receiving traditional treatment.

Dr. Knight said the next step in development of the therapy is to study it as an adjuvant to surgery. At least two large trials comparing irinotecan/5-FU/LV with 5-FU/LV in this setting are under way now, one in the US and Canada and another in Europe.

A new treatment that adds a new drug to an older one may improve survival, but it may also cause adverse effects that lower quality of life, Dr. Miller said.

“The question is: Are these toxicities offset by other quality-of-life improvements related to improved disease control?” Dr. Miller asked. “In the end, what is the trade-off?”

Dr. Miller reported quality-of-life data from the North American study. “We have shown that by adding irinotecan to 5-FU/LV, we lengthened life without impairing the patients’ quality of life,” Dr. Miller said. “This was achieved with a modest increase in diarrhea, but neutropenia and mucositis were decreased.”

Patients in the irinotecan arm had a higher rate of diarrhea than the 5-FU arm, but its average duration was only a couple of days, he said, and patients reported that “it wasn’t a major issue.”

New Standard of Care

The discussant for the ASCO session, Daniel G. Haller, MD, professor of medicine, University of Pennsylvania Cancer Center, said that the data presented by Dr. Saltz contains an “unambiguous message.”

In the United States, Dr. Haller said, “the combination of 5-FU, leucovorin, and irinotecan represents a new standard of practice and the new control arm for clinical trials. And the combination has been approved by the FDA, with either bolus or infusional fluorouracil.”

Dr. Haller suggested that it might be time for US oncologists to “hold the Mayo,” in light of the toxicity and efficacy of the Mayo regimen and the superiority of the irinotecan combination.

He told ONI that the new therapy “showed superiority in the most important endpoint, overall survival, without a marked increase in toxicity of treatment. It met the FDA review criteria for new drug approval, giving it one of the strongest imprimaturs.”

Dr. Haller’s comments echoed those of Dr. Saltz, who concluded that his group’s meta-analysis “further strengthens the conclusion that CPT-11 [irinotecan]/5-FU/LV represents a new reference standard in the first-line treatment of patients with metastatic colorectal cancer.”

Dr. Haller commented that although the prolongation of life in the overall meta-analysis was “not long (2 to 3 months), it was clinically and statistically significant.”

Dr. Saltz commented that patients want to know the best a physician can do and said of the new therapy, “Even if it’s slightly better, it’s better. As a doctor, I want to give the best treatment available.”

Dr. Haller said he looks forward to studies to assess the relative benefits of combinations in different patient populations, based on patient demographics and tumor biology.