Investigators Wrestle With Reasons for Toxic Deaths in North American Colorectal Cancer Trials

Investigators Wrestle With Reasons for Toxic Deaths in North American Colorectal Cancer Trials

COLORADO SPRINGS—Researchers from two large North American Intergroup
colorectal cancer trials found an unexpectedly high rate of toxic deaths in
trials containing irinotecan (Camptosar). No such problems had been apparently
observed by oncologists using the combination of irinotecan, 5-fluorouracil
(5-FU), and leucovorin (LV) (IFL) in routine clinical practice, and no such
problems had been identified in the pivotal registration and European studies.

After the higher than expected rates of early death were reported in April,
accrual to both North American studies was halted until the toxicity data could
be analyzed. Researchers from the North American and European trials, as well
as medical staff from Pharmacia Oncology, which manufactures irinotecan,
discussed the unanticipated toxicity problems on July 26, 2001, at the
University of Texas M. D. Anderson Cancer Center Investigators’ Workshop in
Colorado Springs.

Possible Explanations

These experts advised clinicians to be vigilant in treating diarrhea in
patients on IFL and to view the combination of diarrhea and neutropenia as a
red flag for increased risk of serious complications.

The North American Intergroup trials used bolus 5-FU in combination with
irinotecan and LV. Infusional fluorouracil, which is associated with a
generally lower incidence of neutropenia and diarrhea, is more commonly used in

Leonard Saltz, MD, and colleagues demonstrated last year that a schedule of
irinotecan, plus bolus 5-FU, and leucovorin was superior to the widely used
regimen of 5-FU/LV in terms of objective tumor response, progression-free
survival, and overall survival for patients with metastatic colorectal cancer.
This led to Food and Drug Administration (FDA) approval of IFL for initial
treatment of colorectal cancer, and IFL soon became widely accepted as the
standard of care.

The IFL combination moved into North American Intergroup trials in
comparison to oxaliplatin/5-FU/leucovorin and oxaliplatin/irinotecan in
metastatic disease (study N9741) and in comparison to 5-FU/leucovorin as
adjuvant treatment for patients with resected stage III disease (study C89803).
Irinotecan is also being studied in Europe on an infusional schedule of
irinotecan with 5-FU plus folinic acid vs 5-FU/folinic acid alone as adjuvant
treatment for resected stage III colon cancer.

Current Status of North American Trials

C89803 adjuvant trial

Dr. Saltz, who is associate attending physician in the Gastrointestinal
Oncology Service, Memorial Sloan-Kettering Cancer Center, New York City,
discussed toxicity data from both North American studies. The adjuvant therapy
trial, C89803 originally randomized patients with resected stage III colon
cancer to five cycles of irinotecan (125 mg/m²/wk × 4 wks, q 6 wks), 5-FU (500
mg/m²/wk × 4 wks, q 6 wks), and leucovorin (20 mg/m²/wk × 4 wks, q 6 wks) or
to four cycles of the Roswell Park regimen of 5-FU (500 mg/m²/wk × 6 wks, q 8
wks) and leucovorin (500 mg/m²/wk × 6 wks, q 8 wks). The accrual goal was
1,260 patients, and the study had enrolled 1,264 patients when accrual was
halted in April 2001.

North Central Cancer Treatment Group (NCCTG) advanced CRC trial (N9741)

By the time C89803 was closed to accrual, the N9741 trial of irinotecan,
5-FU, and leucovorin as first-line treatment for advanced colorectal cancer had
become quite complex. The original design of the NCCTG/Intergroup N9741 study
is shown below.

The original goals of N9741 were to compare time to tumor progression of
each of the five experimental arms to the Mayo Clinic 5-FU/leucovorin control
arm and to evaluate the survival rate, response rate, quality of life, and
toxicity of each arm. This design was further changed in March of 2000 after
the FDA approved IFL as first-line therapy for advanced colorectal cancer.

"Irinotecan plus bolus 5-FU and leucovorin became the ‘standard
treatment arm’ against which regimens were compared in N9741," Dr. Saltz
said. "At that point the Mayo Clinic 5-FU/leucovorin regimen was dropped
from the trial."

In March 2000, real-time toxicity monitoring identified unacceptable life
threatening (grade 4) and lethal (grade 5) toxicity rates in two of the study
arms (oxaliplatin/Mayo 5-FU and irinotecan/Mayo 5-FU). At that point the study
was redesigned to compare IFL to oxaliplatin/infusional 5-FU and to oxaliplatin/irinotecan.
In April 2001 real-time toxicity monitoring again identified unacceptably high
toxic deaths in the control arm (irinotecan/bolus 5-FU/leucovorin), and accrual
was suspended.

Erroneous Comparison

Dr. Saltz said that initial efforts to understand the toxicity data were
complicated by an erroneous comparison between the early death rate in these
two studies and data from his previous study of 5-FU/leucovorin with and
without irinotecan (study 0038).

"In both N9741 and C89803 trials, there was a strong trend toward
higher early death rates in the irinotecan/5-FU/leucovorin arms than in the
comparator arms," Dr. Saltz said. The real-time toxicity monitoring
identified 60-day mortality from start of treatment as 4.8% and 2.2% for IFL on
N9741 and C89803, respectively. However, deaths reported in study 0038 were
investigator adjudicated toxic deaths, not all deaths within 60 days of
starting treatment. When deaths within 60 days were examined in the 0038 study,
the 60-day all-cause mortality was 6.7%, which was comparable to the 7.3%
60-day all-cause mortality in the Mayo 5-FU/LV control arm in that study. This
highlights the importance of doing randomized controlled studies and the risk
of drawing conclusions from nonrandomized data."

Dr. Saltz said that the death rates within 60 days of the first dose in the
0038 study showed no difference among the three treatment arms: irinotecan
alone, irinotecan plus 5-FU and leucovorin, and 5-FU/leucovorin. Incidences of
nonlethal toxicities for the IFL regimen in 0038, N9741, and C89803 appear to
be similar.


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