ODAC Reaffirms Safety of Camptosar Bolus Injections

January 1, 2002

SILVER SPRING, Maryland-Due to concerns about the postmarketing safety of the bolus or Saltz regimen of Camptosar (irinotecan, Pharmacia) combined with fluorouracil (5-FU) and leucovorin (IFL) as a first-line treatment for metastatic colorectal cancer, the Food and Drug Administration asked its Oncologic Drugs Advisory Committee (ODAC) to review the issue.

SILVER SPRING, Maryland—Due to concerns about the postmarketing safety of the bolus or Saltz regimen of Camptosar (irinotecan, Pharmacia) combined with fluorouracil (5-FU) and leucovorin (IFL) as a first-line treatment for metastatic colorectal cancer, the Food and Drug Administration asked its Oncologic Drugs Advisory Committee (ODAC) to review the issue.

By a 15 to 0 vote, ODAC members reaffirmed the safety of the combination treatment and rejected the idea that FDA remove its use from the agency’s approved labeling for Camptosar.

ODAC members also unanimously rejected changing the starting dose for bolus IFL injections, but did support making some modification to the Camptosar label. After some discussion, the committee generally suggested that the FDA and Pharmacia work out the exact wording changes.

The FDA approved the IFL combination in April 2000 for first-line use in metastatic colorectal cancer and listed two regimens for delivering the drugs—the bolus injection and a slower infusion method known as the Douillard regimen.

The agency’s concern was stimulated by an analysis of a North Central Cancer Treatment Group (NCCTG) trial (N9741) that, using a new approach to assess mortality, showed an increase in deaths among patients who received IFL bolus injections. This study, which involved 841 colorectal cancer patients, used the IFL bolus regimen as the control against two other arms—oxaliplatin/5-FU/leucovorin and irinotecan/oxaliplatin.

Assessing Mortality

Instead of assessing mortality by the usual 30 days from last treatment, Study N9741 used 60 days from start of therapy. According to an FDA analysis of the study data, the results showed that deaths from all causes were 4.8% for the IFL bolus regimen vs 1.8% in each of the two experimental arms.

The finding was a misperception "based on an early and unfortunate comparison," said Langdon Miller, MD, Pharmacia Corp.’s vice president for research and development, oncology. "The comparison between the arms was not meaningful because the therapeutic benefit of the experimental arms had not been established."

Dr. Miller presented a detailed analysis that compared the findings from Study N9741 with those from the pivotal study of the bolus regimen, designated 0038. It compared the IFL bolus injection to an infusion of 5-FU and leucovorin.

Using the assessment of "deaths of any cause within 60 days from start of therapy," mortality in study N9741 for the IFL bolus regimen was 4.5%. In study 0038, it was 6.7% in the IFL bolus arm and 7.3% in the 5-FU/leucovorin arm.

FDA medical reviewer Isagani Chico, MD, presented the FDA’s analysis. It, too, showed a higher mortality at 60 days from the start of therapy in study 0038 for the IFL bolus injection than for study N9741, 6.4% vs 4.8%.

After the agency’s presentation, panel member George W. Sledge, Jr., MD, professor of medicine and pathology, Indiana University School of Medicine, asked Dr. Chico if the FDA agreed with Pharmacia’s analysis. "Yes, mostly," Dr. Chico replied.

ODAC members refused to endorse lowering the starting doses of the IFL bolus regimen from the current 125 mg/m2 for Camptosar and 500 mg/m² for 5-FU to 100 mg/m² and 500 mg/m², respectively. They did agree, however, that some further label modifications were advisable.

Specifically, the committee unanimously recommended a change in the wording regarding retreatment of patients who develop diarrhea. The current labeling says "patients must be diarrhea-free for 24 hours prior to retreatment." Because some patients have a level of diarrhea prior to beginning treatment with Camptosar, the panel suggested adding to that wording the phrase "or return to baseline stool function."