NEW ORLEANSTreatments combining irinotecan (Camptosar) with
other drugs are active and well-tolerated in patients with advanced
and metastatic pancreatic and ovarian cancer, according to two
reports presented at the 36th annual meeting of the American Society
of Clinical Oncology.
Based on phase II results, patient accrual has begun at 75
institutions for a phase III trial of irinotecan and gemcitabine (Gem-zar)
as first-line therapy of advanced and metastatic pancreatic cancer,
said Caio Max S. Rocha Lima, MD, assistant professor of medicine,
Medical University of South Carolina, Charleston.
In Dr. Rocha Limas phase II study, irinotecan and gemcitabine
were administered on days 1 and 8 for 3 weeks to 45 patients with
locally advanced and metastatic pancreatic cancer, three of whom had
had prior radiation therapy.
Of these, nine (20%) showed a tumor response, and 13 (32.5%) had a
reduction of 50% in CA 19-9, a tumor marker that is elevated in a
majority of patients with pancreatic cancer. Median survival was 6
months, with a range of 9 to 12.2 months.
The researchers reported that toxicity was modest. Only
4.2% experienced significant vomiting, while 6.7% experienced serious
diarrhea. Grade 3-4 neutropenia was reported in 15.5% of patients. As
many as 6.7% experienced thrombocytopenia.
Dr. Rocha Lima agreed that the combination is spurring hopes for new
treatment approaches in pancreatic cancer, which tends to be
aggressive and is associated with very short survival.
Before gemcitabine, there was very little evidence that any
therapy could have an impact on the quality of life or survival of
patients with this disease, he told ONI. In a
randomized pivotal trial where gemcitabine was compared to 5-FU,
gemcitabine resulted in a ninefold improvement in clinical
This pivotal trial led to FDA approval of gemcitabine in the therapy
of pancreatic cancer. Trying to build on that is one of the
approaches one might take to improve outcome in the disease, he said.
Toru Sugiyama, MD, PhD, department of obstetrics and gynecology,
Kurume University, Kurume, Japan, combined irinotecan with cisplatin
(Platinol) as first-line therapy for advanced epithelial ovarian
cancer in 26 patients.
Irinotecan was administered intravenously on days 1, 8, and 15, with
cisplatin on day 1. Cycles were repeated every 28 days for at least
Median overall survival was 38 months, with a range of 4.1 to 60 or
more months, Dr. Sugiyama reported. The team was able to record an
objective response in 19 of 25 evaluable patients. Two of these
patients experienced complete response, defined as complete
disappearance of all known disease for 4 weeks. Seventeen experienced
a partial response, defined as a reduction of greater than 50% in the
sum of the length-width products of all indicator lesions.
Two patients experienced stable disease, two had progressive disease,
and in two, image-guided evaluation of response was judged to
be unfeasible at the time of independent extramural review, Dr.
Progressive disease was defined as an increase of greater than 25% in
the sum of the products of all indicator lesions, the reappearance of
any lesion that had disappeared, or appearance of any new lesion.
Stable disease was defined as any situation that did not qualify as
response or progression.
The major toxic effects were leukopenia, neutropenia, and
diarrhea, Dr. Sugiyama said. Grade 3-4 leukopenia, neutropenia.
and diarrhea occurred in 17 patients (68%), 20 patients (83%), and
five patients (20%), respectively.
The neutropenia was quickly ameliorated with the administration of
G-CSF (Neupogen) or by omitting irinotecan on day 8 or 15, Dr.
Sugiyama said, with no resulting delay in the next chemotherapy
cycle. Diarrhea and vomiting also improved with treatment.
Dr. Sugiyama said that irinotecan may have applications in clear-cell
carcinoma, which has a more aggressively malignant course than
adenocarcinoma of the ovary.
Pilot studies have suggested a combination of irinotecan and
cisplatin may be effective in these patients. Dr. Sugiyamas
team is planning to start a phase III study comparing irinotecan plus
cis-platin with paclitaxel (Taxol) plus carboplatin (Paraplatin) for
Mace Rothenberg, MD, associate professor of medicine, Vanderbilt
University Medical Center, Nashville, called the results from Japan
encouraging and reasonable enough to pursue phase III studies.
The response rate was within the range of what might be expected from
other drug combinations used in ovarian cancer treatment, such as
paclitaxel and cisplatin. However, he added, it isnt so
far outside the realm of what we have achieved with other regimens
that I would make it my standard of therapy. Its important to
be realistic, Dr. Rothenberg said.
The strategy of giving irinotecan over weeks, with cisplatin dosage
administered all at once on the first day of the cycle, was pioneered
in Japan, Dr. Rothenberg commented. While some researchers elsewhere
use this method, others believe it is better to divide the cisplatin
dosage and give it with the irinotecan.
Dr. Rothenberg said research using irinotecan in pancreatic cancer is
also encouraging, and that phase III testing is the logical next
step. He noted that tumor response is probably not a very good
surrogate for survival in pancreatic cancer.
In a phase III comparative study, it may not be necessary, he said,
but in a phase II trial in which there is no control group, tumor
response measurement provides an objective way to observe whether the
drug in question is having any effect on the cancer.