TOKYO, Japan—“I remain convinced that irinotecan is one of
the most active agents for the treatment of lung cancer, both
non–small-cell and small-cell,” stated David H. Johnson,
MD, professor of medicine and director of medical oncology at
Vanderbilt University Medical Center, Nashville. Dr. Johnson was
leadoff speaker at a seminar titled ‘‘Current Status of
Irinotecan in Lung Cancer’’ held in conjunction with the
9th World Conference on Lung Cancer. The meeting was supported by an
educational grant from Pharmacia Oncology, Yakult Honsha Co., Ltd.,
Daiichi Pharmaceutical Co., Ltd., and Aventis Pharma S.A.
Dr. Johnson recalled being impressed with irinotecan (Camptosar)
about a decade ago while visiting the National Cancer Institute in
Tokyo, where irinotecan was undergoing initial studies. This drug
‘‘was extremely active,” Dr. Johnson said, “in
fact more so than any that I had witnessed in my previous experience
in the United States.’’
More recently, he was impressed by the complete remissions achieved
by 2 out of 20 patients with stage IV non–small-cell lung cancer
enrolled in a trial of irinotecan and cisplatin (Platinol) at
Vanderbilt. “Actually those were the first two and until
recently the only two complete remissions I’d ever seen in my
experience with stage IV disease,” he noted.
Developed in Japan, irinotecan is “a semisynthesized derivative
of camptothecin, which was originally isolated from the Chinese plant Camptotheca
acuminata,” explained Masahiro Fukuoka, MD, professor of
the 4th Department of Internal Medicine, Kinki University School of
Medicine, Osaka. Originally synthesized in 1983, irinotecan was first
approved in Japan in 1994 for small-cell lung cancer and hematologic
malignancies, he reported. This was followed by approvals in France
in 1995 and in the United States in 1996, he said. Clinical trials,
he noted, have shown irinotecan is active not only in lung cancer and
hematologic malignancies but also in colorectal, gastric, ovarian,
and cervical cancers.
“Irinotecan is transformed to the active metabolite SN-38 by
carboxylesterase, primarily in the liver,” Dr. Fukuoka said. A
potent inhibitor of topoisomerase I, irinotecan affects some DNA
replication processes, he noted. “Fecal excretion is the
dominant route of elimination,” he explained, passing more than
60% of the dose. Urinary excretion, he added, accounts for about 30%.
Emerging Standard
Noriyuki Masuda, MD, PhD, chief, 2nd Department of Internal Medicine,
Osaka Prefectural Habikino Hospital, Osaka, reported that his group
has been studying irinotecan, also known as CPT-11, alone or in
combination with other cytotoxic agents for more than 10 years in
non–small-cell lung cancer. In particular, he noted, “the
combination of CPT-11 and cisplatin has been studied as the emerging
standard for the treatment of lung cancer in Japan.”
Two phase III trials, reported Dr. Masuda, have compared the
irinotecan/cisplatin combination with vindesine/cisplatin regimens.
In one, no differences in response rates or median survival were seen
when a regimen of cisplatin 80 mg/m² on day 1 and vindesine 3
mg/m² on days 1, 8, and 15 was compared with treatment with the
same dose of cisplatin plus irinotecan 60 mg/m² on days 1, 8,
and 15. The median survival in both arms of the study was about 45
weeks.
The other study, however, showed significant survival differences in
stage IV disease, reported Dr. Masuda, with a median survival of 50
weeks for cisplatin/irinotecan vs 36.4 weeks for cisplatin/vindesine.
The dosage schedules for these drugs were the same as in the other
phase III trial. This trial also included a third arm in which
irinotecan was administered alone at a dose of 100 mg/m² on days
1, 8, and 15. Overall 1-year survival rates were 47% for
cisplatin/irinotecan, 38% for cisplatin/vindesine, and 42% for
irinotecan alone.
“Further studies are needed,” said Dr. Masuda, “to
demonstrate whether CPT-11 plus cisplatin is superior in survival to
other new drug combination regimens for advanced non–small-cell
lung cancer and to evaluate the role of CPT-11 in combination therapy
with other promising new agents for advanced non–small-cell lung cancer.”
Weekly Approach
Corey J. Langer, MD, codirector of thoracic oncology, Fox Chase
Cancer Center, Philadelphia, reported that Fox Chase and Vanderbilt
University have joined forces for a trial in which both irinotecan
and cisplatin are given weekly to patients with advanced
non–small-cell lung cancer. The weekly dose of irinotecan is 65
mg/m² and that of cisplatin is 30 mg/m². Both drugs are
given for 4 weeks and cycles are repeated every 6 weeks.
Among the first 49 patients, the majority of whom had stage IV
disease, the overall response rate is 36%, median time to progression
is 6.9 months, and 1-year survival rate is 46%. “The weekly
approach appears to be more active and clearly looks better
tolerated,” Dr. Langer said. Relative dose intensity was
“well maintained for both agents,” he observed, with that
for irinotecan being 89%. As a result, he indicated, “phase III
studies are currently in development comparing this weekly approach
to other more standard regimens.”
In an ongoing trial at Fox Chase, radical thoracic radiation at a
dose of 63 Gy is being combined with a weekly irinotecan/cisplatin
regimen, Dr. Langer reported. The starting dose of irinotecan is 30
mg/m² and the protocol calls for escalation by 10 mg/m² up
to a maximum of 70 mg/m². The cisplatin dose is fixed at 25
mg/m².
So far, 10 patients have been enrolled and the median number of
treatments is 6. The response rate is 77%, Dr. Langer revealed, and
at a 10-month median follow-up, 8 of the 10 patients are free of
disease progression. “Absolutely no grade- 3 esophagitis”
has occurred, he said.
JCOG Clinical Trials
For the past decade, the Japan Cooperative Oncology Group (JCOG) has
studied irinotecan in various chemotherapy regimens as well as in
combination with radiotherapy for activity against small-cell lung
cancer, recounted Tomohide Tamura, MD, head of internal medicine,
National Cancer Center Hospital, Tokyo. “Irinotecan may be one
of the most active agents against small-cell lung cancer,” Dr.
Tamura noted.
A recent JCOG phase III study comparing an irinotecan/cisplatin
regimen with the standard etoposide (VePesid)/cis-platin treatment of
small-cell lung cancer showed clear differences in extensive disease,
Dr. Tamura indicated. Stopped after an interim analysis revealed the
superiority of the irinotecan/cisplatin regimen, the trial achieved
median survivals of 13.5 months in the irinotecan/cisplatin arm and
9.3 months in the etoposide/cisplatin.
“Based on the results of this trial,” said Dr. Tamura,
“irinotecan plus cisplatin is considered to be a standard
treatment against extensive-stage small-cell lung cancer.” Under
the protocol, irinotecan 60 mg/m² was given on days 1, 8, and 15
and cisplatin 60 mg/m² on day 1 in four 28-day cycles. The
study’s other arm also repeated cycles four times, but the cycle
length was 3 weeks, with etoposide 100 mg/m² administered on
days 1 and 3 and cisplatin 80 mg/m² on day 1.
Currently, JCOG is investigating three-drug combinations of
irinotecan, etoposide, and cisplatin in extensive small-cell lung
cancer, Dr. Tamura revealed. In limited-stage disease, he added, a
study is exploring the value of concurrent etoposide and cisplatin
plus twice- daily radiotherapy followed by three courses of irinotecan/cisplatin.
More US Studies
In the United States, planning is under way for a study similar to
the JCOG trial that showed an advantage for irinotecan/cisplatin in
small-cell lung cancer, said Alan B. Sandler, associate professor of
medicine, Vanderbilt University, Nashville. “The plan in the
United States is for a confirmatory trial looking at the combination
of cisplatin and irinotecan, using a day 1 and day 8 weekly regimen
every 21 days with the comparison arm being cisplatin and
etoposide,” he explained.
The 21-day cycle is being considered, he added, because with the
28-day schedule used in Japan, “approximately 40% to 50% of
patients do not receive day-15 CPT-11 due to either hematologic or
diarrheal complications.” The Southwest Oncology Group, he
noted, is considering a phase III trial using the same dosing
schedules as those used in the JCOG study.
Second-Line Therapy
The efficacy of irinotecan in second-line therapy for small-cell lung
cancer, reported Dr. Sandler, was explored in a US trial led by his
Vanderbilt colleague, Russell DeVore, MD. Of the 44 evaluable
patients, 27 were considered refractory or resistant to therapy
because they “either failed prior therapy or relapsed within 90
days of cessation of therapy,” Dr. Sandler noted.
The other 17 patients were categorized as “sensitive”
because their relapses occurred more than 90 days after initial
chemotherapy ended. Used as a single agent in this trial, irinotecan
was given at a dose of 125 mg/m² each week in the first months
of 6-week cycles.
“Only one patient in the refractory population responded to
therapy, as opposed to 29% of patients in the sensitive group,”
reported Dr. Sandler. The overall median survival was 4.8 months, 5.9
months for the sensitive group, and 3.7 months for the refractory
cohort. Irinotecan, he observed, “appears to be well tolerated
in patients with sensitive relapsed small-cell lung cancer.” In
studies of a variety of agents as second-line therapy, he noted,
response rates have ranged from approximately 10%-30%.
Further study of irinotecan is warranted in previously untreated
patients with extensive disease, Dr. Sandler concluded.
