ORLANDO-A phase III clinical trial of first-line therapy in advanced colorectal cancer showed improved progression-free survival (PFS) for weekly infusional FUFOX-fluorouracil/folinic acid (5-FU/FA)/oxaliplatin (Eloxatin)-compared with the Mayo bolus 5-FU/FA (leucovorin in the United States) regimen, Axel Grothey, MD, University of Halle, Halle, Germany, said at the American Society of Clinical Oncology 38th Annual Meeting (abstract 512).
ORLANDOA phase III clinical trial of first-line therapy in advanced colorectal cancer showed improved progression-free survival (PFS) for weekly infusional FUFOXfluorouracil/folinic acid (5-FU/FA)/oxaliplatin (Eloxatin)compared with the Mayo bolus 5-FU/FA (leucovorin in the United States) regimen, Axel Grothey, MD, University of Halle, Halle, Germany, said at the American Society of Clinical Oncology 38th Annual Meeting (abstract 512).
The fact that salvage therapies appeared to contribute to the long median survival seen in both arms supports making all active drugsoxaliplatin, irinote-can (CPT-11, Camptosar), and 5-FU/FA)available to all patients, Dr. Grothey said.
Dr. Grothey noted that at the time the FUFOX study was designed, the Mayo bolus 5-FU/FA regimen was the standard treatment for advanced colorectal cancer. Combination protocols with 5-FU/FA plus either irinotecan or oxaliplatin were showing high clinical activity, and infusional 5-FU/FA as a first-line therapy was demonstrating increased response rates and slightly prolonged progression-free survival, but with no effect on overall survival.
Because randomized trials comparing infusional 5-FU/FA plus oxaliplatin with the standard Mayo clinic protocol had not been conducted, Dr. Grothey and his colleagues embarked on the current trial.
The trial included 252 advanced colo-rectal cancer patients treated at 60 centers, randomized to FUFOX (n=123, oxaliplatin 50 mg/m2 2-hour infusion, 5-FU 2,000 mg/m2 24-hour infusion, FA 500 mg/m2, on days 1, 8, 15, and 22 every 5 weeks) or the standard Mayo regimen (n=129, 5-FU bolus 425 mg/m2, FA 20 mg/m2, on days 1 to 5 every 4 weeks).
Among FUFOX patients, 15.4% had received prior adjuvant chemotherapy, compared with 24.8% in the Mayo arm (P = .084). Ten patients withdrew prior to therapy and another four prior to completion of a full cycle, leaving 242 for the safety evaluation and 238 for the efficacy evaluation. The primary endpoint was progression-free survival.
Progression-free survival (intent-to-treat) was 7.8 months for FUFOX, compared with 5.3 months for the Mayo regimen (P = .0001). Early progressive disease in the Mayo group accounted for an early separation of curves favoring the FUFOX regimen. At median follow-up of 32.5 months, overall survival among patients evaluable for efficacy was 16.1 months for the Mayo group and 21.4 months for FUFOX (not significant).
Confirmed responses were significantly higher for the FUFOX arm (see Table), with combined complete and partial response rates more than double that of the Mayo arm.
Dr. Grothey noted that grade 3-4 hematologic toxicities were less frequent and less severe with FUFOX (neutropenia, 23.4% vs 6.7%, P = .006). Among nonhematologic toxicities, nausea was more common with FUFOX (11.0% vs 3.2%, P = .023), as was diarrhea (27.15 vs 16.9%, P = .063).
After 8 cycles (oxaliplatin cumulative dose 1,200 mg/m2), grade 3-4 sensory neuropathies, a known effect with accumulating oxali-platin doses, had occurred in 17% of patients receiving FUFOX (1.7% grade 4). Only 5.1% discontinued FUFOX due to sensory neuropathies.
For 60-day all-cause mortality, Dr. Grothey reported that there were no deaths due to early progression in the FUFOX arm, compared with 6 deaths (4.8%) for the Mayo regimen. There were four toxic deaths (3.2%) in the Mayo arm and one (0.9%) in the FUFOX arm. Overall, there was one death in the FUFOX arm and 11 in the Mayo arm (8.9% vs 0.9%, P = .0057).
Treatment discontinuations due to adverse events were more common in the FUFOX arm (25.4% vs 4.0%, P < .0001). However, death (8.9% vs 1.7%, P = .02) and progressive disease (71.0% vs 51.7%, P = .0024) were significantly more common reasons for discontinuation in the Mayo arm. Complete response with secondary surgery accounted for more discontinuations in the FUFOX arm (5.9% vs 1.6%, not significant).
Dr. Grothey pointed out that many patients received salvage therapies in the further course of disease, such that 54.2% of Mayo patients and 74.8% of FUFOX patients had received both oxaliplatin and irinotecan. "Efficient salvage therapies likely contributed to the long median survival in both treatment arms, supporting the strategy of making all active drugs available to all patients," Dr. Grothey said.
He also showed that in recent trials from 2000 to 2002, as the percentage of patients receiving three drugs has increased from 5% to 75% in the current study, median overall survival has increased from 14.8 months (Saltz) to 21.4 months (Grothey).
He concluded: "The study reconfirms that infusional 5-FU/FA is the optimal schedule of 5-FU administration in combination protocols." Dr. Grothey said further that the fact that there were no deaths due to early progressive disease in the FUFOX arm "suggests the usefulness of the FUFOX protocol for patients with high tumor volume or rapidly progressing disease."
Discussant Leonard B. Saltz, MD, Memorial Sloan-Kettering Cancer Center, agreed that salvage therapies may have played a role in longer survival, but pointed out that the study information does not allow that effect to be elucidated. "I would like to strongly reiterate that all three drugs are necessary for optimal outcome," he said.