NCCN Updates Colon Ca Guidelines

HOLLYWOOD, Florida—The National Comprehensive Cancer Network (NCCN) has added an oxaliplatin (Eloxatin)-containing regimen for the treatment of advanced colorectal cancer to its updated 2003 guidelines for colorectal cancer treatment, as well as new recommendations for the use of radiation therapy (see box).

Speaking at the NCCN’s 8th Annual Meeting, Leonard Saltz, MD, said that irinotecan (Camptosar)/ fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin/5-FU/LV regimens, in metastatic colo-rectal cancer (both NCCN recommended options), appear to be comparable but have differing toxicity profiles. For both regimens, infusional 5-FU schedules appear to offer modest safety advantages over bolus schedules.

Dr. Saltz, associate attending physician, Memorial Sloan-Kettering Cancer Center, identified oxaliplatin and irino-tecan as "the two major new players that really need to be thought about carefully in colorectal cancer in US treatment."

In Dr. Saltz’s 2000 phase III randomized study of irinotecan and bolus 5-FU/LV, compared with the Mayo Clinic regimen of 5-FU/LV, the irinotecan combination showed a near doubling of response rate (51% vs 28%) and a significant improvement in progression-free survival (7.3 months vs 4.0 months), with increases in diarrhea but decreases in grade 4 neutropenia. In addition, overall survival increased by a significant 2.2 months (14.8 months vs 12.6 months, P = .04).

About the same time, in a European trial, the de Gramont (FOLFOX4) oxaliplatin/infusional 5-FU/LV regimen vs 5-FU/LV alone in metastatic colorectal cancer produced a 51% response rate (vs 22%) with improved progression-free survival (9.0 months vs 6.2 months). Overall survival was improved a nonsignificant 1.5 months (16.2 vs 14.7).

There were increases in diarrhea, neutropenia, and grade 3 neuropathy with the oxaliplatin combination. Dr. Saltz called neuropathy "a new issue we have to get comfortable dealing with."

Importance of N9741

The most important trial for understanding the new options, Dr. Saltz said, is the North Central Cancer Treatment Group(NCCTG)/Intergroup N9741 trial (Goldberg et al: Proc ASCO, May 18-21, 2002, abstract 511). This trial compared three arms of approximately 280 patients per arm: irinotecan/bolus 5-FU/LV (IFL or Saltz), oxaliplatin/infusional 5-FU/LV (FOLFOX4), and irinotecan/oxaliplatin (Wasserman).

There were inherent flaws with the trial design: The irinotecan arm had bolus 5-FU/LV and the oxaliplatin arm infusional 5-FU/LV, and oxaliplatin, which was then investigational, was not available for second-line therapy for the IFL group.

Initial reports from N9741 suggested that mortality in the IFL arm was higher than previously reported. These reports, however, turned out to be erroneous. "The error resulted from a comparison of the reported investigator-judged treatment-related death rate on the earlier trial with a new metric, the 60-day mortality, on the N9741 trial," Dr. Saltz said.

Since the 60-day mortality metric had never been used before, it had not been calculated for the previous studies, he said. When the 60-day mortality was calculated for the original trial comparing IFL with the Mayo Clinic schedule of 5-FU/LV, the 60-day mortality was 6.8% for IFL and 7.3% for the Mayo Clinic 5-FU/LV control arm. Subsequent reviews of previous 5-FU/LV studies involving more than 3,000 patients over the past decade confirmed that the baseline level of 60-day mortality consistently ran in the range of 5% to 7%, he said.

"So the 60-day, all-cause mortality for IFL in N9741 was, in fact, not higher than had been reported in previous studies of IFL," Dr. Saltz said. He stressed, that 60-day mortality was, however, lower (1.6%) with the experimental FOLFOX4 regimen.

Dr. Saltz pointed to another significant finding, that ECOG 2—performance status (PS) 2—patients did comparatively poorly (vs PS 0 or 1 patients) over a wide range of adverse events, with all of the survival advantage in the better PS patients. "The take-home message: Patients who are ECOG PS 2 don’t tolerate the combination regimens well enough to benefit from them," he said.

Turning to the efficacy results, Dr. Saltz reported a highly significant 4.5-month median overall survival advantage for the FOLFOX4 regimen (see Table). "This is probably the largest improvement we have ever seen in a trial of colorectal cancer," Dr. Saltz said. Response rates with both combination regimens, he commented, were lower than those seen in prior trials.

"The first thing this tells us is that oxaliplatin plays an important role in the treatment of metastatic colorectal cancer," he said. The other conclusion is that FOLFOX4 is an appropriate first-line regimen. To the question as to whether it is the standard first-line regimen, Dr. Saltz answered, "Probably not, but it is one of the options."

To address the question, "Is oxali-platin superior to irinotecan in the same context with the same infusional 5-FU schedule," Dr. Saltz referred to the FOLFOX6 vs FOLFIRI trial (Tournigand et al: Proc ASCO, May 12-15, 2001, abstract 494) with 226 patients randomized to receive FOLFIRI (irinotecan 180 mg/m² IV plus simplified LV/5-FU every 2 weeks) or FOLFOX6 (oxaliplatin 100 mg/m² IV plus simplified LV/5-FU every 2 weeks), with planned crossover after progression. Simplified LV/5-FU consists of LV 400 mg/m² and 5-FU 400 mg/m² bolus on day 1 followed by 5-FU 2.4 to 3 g/m² 46-hour continuous infusion on day 1, every 2 weeks.

While the study is underpowered, Dr. Saltz said, the overall survival curves were nearly identical (P = .9). "This is a compelling argument that we really do have options here, and we can look for other reasons to decide which one to use." Partial plus complete response rates at 56% for FOLFIRI and 54% for FOLFOX; times to progression of 8.5 months and 8.1 months, respectively; and overall survival of 20.4 months and 21.5 months, respectively, support that conclusion.

Corroboration from upcoming trials, Dr. Saltz noted, is necessary. Also, the relative contributions of bolus vs infu-sional 5-FU, the relative value of oxali-platin vs irinotecan, and the effects of second-line therapy on survival need further investigation.

Dr. Saltz noted that phase III trials in patients refractory to irinotecan/5-FU/LV, have shown oxaliplatin not to be active as a single agent, but active with an agent that has already failed (with 5-FU/LV). "The take-home message: Please don’t use oxaliplatin as a single agent. Use it in combination," Dr. Saltz said.

With FOLFOX and FOLFIRI appearing comparable in efficacy and with neither agent qualifying as "standard of care," Dr. Saltz noted that toxicity considerations may influence choice. Patients may have different preferences regarding toxicity, and physicians may have different comfort or experience levels with these agents and regimens, he said.

The order of drug administration "is not likely to be of critical importance and is likely to vary between patients. But in order to optimize results, all active agents need to be available and seriously considered in all patients," he said.

Finally, Dr. Saltz underscored the need for clinical trials of new drug combinations and strategies. "Despite substantial advances, chemotherapy for colorectal cancer remains inadequate," he said.