Front-Line Regimens That Integrate Irinotecan and Oxaliplatin Produce Median Survival Approaching 3 Years

PORTLAND, Oregon—Median survival for patients with advanced colorectal cancer treated with front-line regimens that include irinotecan (CPT-11,Camptosar) or oxaliplatin (Eloxatin) is approaching 3 years. "That is an absolutely remarkable figure to me," said Charles D. Blanke, MD, in a review of new approaches to colorectal cancer treatment. Dr. Blanke is director of the gastrointestinal malignancies program at the Oregon Health Sciences University Cancer Institute in Portland.

In regimens commonly used in the United States, irinotecan is usually given weekly for 4 weeks, while in Europe, it is given every 3 weeks, but there is little effect on toxicity, according to Dr. Blanke. "Basically, no matter how you give irinotecan, the dose-limiting toxicities are the same: neutropenia and grade 3/4 diarrhea," he said.

Statistically Significant

Median survival with irinotecan monotherapy is 8 to 12 months, but Dr. Blanke said that irinotecan combination regimens are now producing much longer median survival in both front-line and second-line therapy.

"Studies comparing irinotecan to best supportive care as second-line treatment showed that irinotecan improved median survival by almost 3 months, from 6.5 to 9.2 months. There was a dramatic difference in the survival curves, and this was highly statistically significant," Dr. Blanke said.

A European trial randomizing patients to second-line treatment with irinotecan or infusional fluorouracil (5-FU) improved survival from 8.5 months to nearly 11 months, "a truly remarkable figure," Dr. Blanke said.

Full Doses in Combination

Researchers have been concerned about possible toxicity in combination regimens, but Dr. Blanke said that phase I trials of irinotecan with infusional 5-FU as second-line treatment have shown that it is possible to give full doses of irinotecan (125 mg/m²) and of 5-FU (500 mg/m²) without undue adverse effects. Sequence was also unimportant. "Remarkably, in these heavily pretreated patients 17% responded to treatment in one study," Dr. Blanke said.

A phase III trial, which compared irinotecan/fluorouracil/leucovorin to fluorouracil/leucovorin, was done at Memorial Sloan-Kettering Cancer Center in New York. Dr. Blanke said that progression-free survival was 7 months vs 4.3 months (P = .004), and median survival was 12.6 months vs 4.8 months (P = .004). "Investigators were surprised to find that adding the third drug did not change the toxicity profile very much,’’ Dr. Blanke said. "Triple therapy lowered the risk of death by 23%. We are now seeing a median survival of 15 months with irinotecan/fluorouracil/leucovorin, and of course this has become the standard of care."

The move to continuous infusion of 5-FU rather than bolus administration was based on concern over the drug’s short half-life. "Fluoropyrimidines are cell-cycle specific, and the half-life of bolus 5-FU is about 11 minutes. A continuous-infusion schedule produces less toxicity with five times greater dose intensity. There was less neutropenia. Infusional 5-FU was at least as efficacious and perhaps more so than bolus administration," Dr. Blanke said.

Oxaliplatin Combinations

Combinations of 5-FU with oxaliplatin have also been tested. Dr. Blanke said that comparing FOLFOX4 (fluorouracil, leucovorin, oxaliplatin) to bolus IFL (irinotecan, fluorouracil, leucovorin), time to progression was longer, median survival was longer, 1-year overall survival was longer, and overall response was higher with the oxaliplatin-containing combination.

Investigators have also asked whether FOLFOX6 (fluorouracil, leucovorin, oxaliplatin) is more effective given before or after FOLFIRI (fluorouracil, leucovorin, irinotecan). They found that regardless of schedule, diarrhea was about 10% to 15% (vs 23% with older regimens). Response was 56% with FOLFIRI first vs 54% with FOLFOX6 first.

"More than half of patients are now having objective responses to modern chemotherapy," Dr. Blanke said. "Eighty percent of patients did not progress during their time on study, and median overall survival for front-line patients with colorectal cancer is approaching 3 years."

One of the most important unresolved issues with irinotecan is how to mitigate toxicity. Most patients do not stay on schedule at full doses, and researchers are exploring changing to a 2-week on, 1-week off schedule, repeated twice.

Modifying eligibility criteria for patients treated with irinotecan is also being considered. "Patients need to be healthier than we formerly thought. They should probably have performance status (PS) of 1. The PS 2 patients do not do as well and tend to get very sick," Dr. Blanke said.

More Frequent Monitoring Also Important

"Putting people on irinotecan on day 1 and seeing them 7 weeks later just does not work, even though we all do it. We need to be seeing these people weekly and modifying their doses weekly," Dr. Blanke said.

Clinicians should also consider abdominal cramping as serious an adverse event as diarrhea. Dr. Blanke said that either cramping or diarrhea should trigger modification or disruption of the treatment schedule "even for a lowly grade 2 event."

"We also have to determine whether we should consider using irinotecan in high-risk resected patients immediately after surgery. Many of us tend to give 5-FU/leucovorin to the average patient. When we see a young person with four nodes, out comes the irinotecan or oxaliplatin. Certainly the combination may be more effective than just 5-FU/leucovorin, but I think the toxicity is particularly important in potentially cured patients. You haven’t done them a favor if you bump them off."