Longer Survival With FOLFOX4 in Metastatic Colorectal Cancer Patients

ROCHESTER, Minnesota—An interim analysis of the North American Intergroup Study N9741 suggests that oxaliplatin (Eloxatin, investigational in the United States) plus infusional fluorouracil (5-FU)/leucovorin (FOLFOX) may be the new standard of care for patients with metastatic colorectal cancer.

"Treatment with FOLFOX resulted in significantly increased time to progression, overall survival, and response rate when compared to irinotecan (CPT-11, Camptosar)/bolus 5-FU/leucovorin (IFL)," Richard M. Goldberg, MD, professor of oncology, Mayo Medical School, said at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 511). "The toxicity profile favors FOLFOX over IFL," he added.

The primary goal of the study was to compare times to tumor progression. The trial, which at one time had six different arms, underwent several modifications: In March 1999 to include oxaliplatin; in March 2000, when IFL became the standard of care; and in April 2001 to address IFL toxicity, which led to a dose reduction in the IFL arm. However, the findings reported at ASCO include results only from the 765 patients enrolled in the three final arms prior to lowering the IFL dose. The three regimens were as follows:

• IFL (Saltz regimen): irinotecan 125 mg/m² plus leucovorin 20 mg/m² and bolus 5-FU 500 mg/m² on days 1, 8, 15, and 22 every 6 weeks

• FOLFOX4 (de Gramont regimen): oxaliplatin 85 mg/m² on day 1, followed by leucovorin 200 mg/m² and a loading dose of 5-FU at 400 mg/m². The loading dose is followed by a 22-hour infusion of 5-FU at 600 mg/m². The 5-FU and leucovorin are repeated on days 1 and 2 every 2 weeks.

• IROX (Wasserman regimen): oxaliplatin 85 mg/m² plus irinotecan 200 mg/m² on day 1 every 3 weeks.

A planned interim intent-to-treat analysis was conducted in April 2002, because 81% of the planned events had occurred, and upon review, the North Central Cancer Treatment Group data monitoring committee recommended the study’s release. "The stopping boundaries for the comparison of IFL and FOLFOX were crossed," Dr. Goldberg said.

The median age of the 795 patients was 61 years; 94% to 95% had an ECOG performance score of 0 to 1, and 15% to 16% had received prior adjuvant therapy. At the time of this analysis, the median follow-up for living patients was 12 months, and approximately 70% of patients had shown disease progression.

The median time to progression was 6.9 months for IFL, 8.8 months for FOLFOX4, and 6.7 months for irinotecan plus oxaliplatin (see table below). "The time to progression curves for IFL and FOLFOX diverged early, and this separation was maintained until 2 years from study entry," Dr. Goldberg said.

Median overall survival with IFL was 14.1 months, with FOLFOX 18.6 months, and with IROX 16.5 months, Dr. Goldberg said. "One year after they had been enrolled on the study, 58%, 71%, and 65% of patients were alive, respectively." The response rates were IFL 29%, FOLFOX 38%, and IROX 28%.

Toxicity

Severe nausea, vomiting, diarrhea, and febrile neutropenia were significantly more common with IFL, Dr. Goldberg said. Paresthesias were significantly more common with FOLFOX. Neutropenia was more common with FOLFOX and dehydration with IFL, but these differences were not statistically significant.

Time to discontinuing protocol-specific chemotherapy (for any reason) was similar in the IFL and FOLFOX arms, but the reasons patients stopped treatment differed. Therapy ended for 70% of IFL patients due to disease progression or death, compared with 45% receiving FOLFOX. "This is because more FOLFOX patients discontinued their treatment due to toxicity, primarily because of late-occurring neuropathies in responding patients," Dr. Goldberg said.

He noted that, since oxaliplatin is not FDA approved, "more patients received irinotecan as second-line therapy after FOLFOX than could receive oxaliplatin after IFL."

Between 59% and 67% of patients went on to second-line treatment, he said. Among patients randomized to IFL, only 17% received oxaliplatin second line. In contrast, after FOLFOX, 52% of patients were given irinotecan. After IROX, 45% of patients received 5-FU.

Dr. Goldberg believes there may be some advantages to infusional 5-FU, "certainly in terms of toxicity, possibly borderline in terms of activity," but that results of the current study "cannot be used to assess the impact of infusion vs bolus 5-FU in the drug combinations tested."

Further, he said, "to my knowledge there has never been a study published in which patients were randomized to bolus 5-FU vs infusion 5-FU that showed a statistically significant survival advantage in patients with metastatic colorectal cancer."

Dr. Goldberg emphasized that all three regimens have merit as first-line treatment for advanced colorectal cancer. "Based on our data and that from other studies, there are currently three agents—5-FU and its prodrugs, irinotecan, and oxaliplatin—that are active in the treatment of metastatic colorectal cancer," Dr. Goldberg said. "We feel that the FOLFOX regimen has notable activity and an advantageous toxicity profile in comparison to IFL. I think future studies will have to define exactly the optimal sequence and combination of these drugs."

The discussant for the ASCO paper, Leonard Saltz, MD, associate professor of oncology, Memorial Sloan-Kettering Cancer Center, said that the most important take-home message from N9741 "is that oxaliplatin plays an important role in the treatment of metastatic colorectal cancer. Oxali-platin should be made available in the United States, and we can also conclude that FOLFOX is an appropriate first-line regimen."

Three Questions

Dr. Saltz said that three questions about the study remain unanswered: The relative contribution of bolus vs 5-FU infusion to the study results, the relative contribution of oxaliplatin vs irinotecan, and the impact of second-line therapy on survival.

Dr. Saltz also discussed the role of capecitabine (Xeloda) in oxaliplatin or irinotecan first-line combinations. "We have some interesting phase I and II data but no randomized comparisons yet," he said. One of the proposed Intergroup trials for metastatic colorectal cancer, he said, would compare FOLFOX4 as a standard control arm to the investigational arm of oxaliplatin and capecitabine (XELOX), plus or minus the COX-2 inhibitor celecoxib (Celebrex).

Dr. Saltz concluded that "all three drugs are necessary for optimal outcome," and that "the data available to date do not provide compelling evidence to support any one regimen as a clear standard of care."

He stressed that the availability of multiple effective agents offers the opportunity to customize treatment to individual patients, based on patient preferences regarding toxicity. "We need to ask them how they feel about infusion catheters and ambulatory infusion pumps," he said. Dr. Goldberg noted that N9741 included a quality-of-life component that will be
analyzed in the near future.