NEW YORKThe cisplatin/irinotecan combination produces
responses among patients with gastric and esophageal cancers, David H. Ilson,
MD, PhD, reported at the Vanderbilt University Symposium. Dr. Ilson is
assistant attending physician in the Department of Gastrointestinal Oncology,
Memorial Sloan-Kettering Cancer Center, New York.
Irinotecan (Camptosar) has demonstrated efficacy in
gastric/esophageal cancer cell lines and in xenografts. Both cisplatin
(Platinol) and irinotecan are active as single agents against gastric and
esophageal cancer, Dr. Ilson noted. Cisplatin induces DNA/cisplatin adducts,
and irinotecan blocks cellular repair mechanisms by inhibiting topoisomerase I.
Together, cisplatin and SN-38, the active metabolite of irinotecan, have shown
synergistic activity in vitro. This includes reduced removal of DNA cross links
and growth inhibition with simultaneous delivery.
The cisplatin/irinotecan combination for gastric cancer has
been most widely studied in Japan. As related by Dr. Ilson, Japanese phase I/II
studies have shown response rates of 27% to 42%. Dose-limiting toxicities have
mainly been neutropenia or diarrhea.
Dr. Ilson and colleagues at Memorial Sloan-Kettering Cancer
Center conducted a phase I study of weekly low-dose irinotecan 65 mg/m2 plus
cisplatin 30 mg/m2, 4 weeks on, 2 weeks off. "Surprisingly, toxicity was
minimal in this phase I trial, and dose-limiting toxicity was
neutropenia," Dr. Ilson said. "We saw responses in a number of upper
GI cancers, in particular esophageal cancer, and this led to a phase II trial
in 35 patients with esophageal cancer.
The primary study endpoint was response rate. Secondary endpoints were
dysphagia relief, quality of life, toxicity, and survival.
"The overall response rate was 57%, including two complete
responses (5%), 18 partial responses (52%), with a median response duration of
4.2 months, and median actuarial survival of 14.6 months," Dr. Ilson
Dysphagia relief was notable. Among the 20 patients with
evaluable dysphagia at baseline, 70% had complete resolution of dysphagia, and
another 20% had improvement. "So 90% of patients had significant
improvement of swallowing problems with chemotherapy alone," Dr. Ilson
Toxicity in this phase II trial was manageable. About half of
patients had grade 3/4 neutropenia; 31% had grade 3 anemia; 11% had grade 3
diarrhea; and 6% had grade 3 nausea/vomiting. Dr. Ilson said that only 17% of
patients were hospitalized for complications of therapy, most commonly
neutropenia or diarrhea.
A confirmatory community-based phase II trial of this regimen
in esophageal cancer will soon be enrolling patients with metastatic or
unresectable disease. The treatment regimen is cisplatin 30 mg/m2 and
irinotecan 54 mg/m2, cycled 2 weeks on and 1 week off. Primary endpoints are
response rate and dysphagia relief.
Investigators at M. D. Anderson Cancer Center in Houston have
conducted a similar trial in 39 patients with gastric and gastroesophageal
junction cancers. There were significant delays of therapy in this trial38%
of doses were delayed and 23% were canceled. Granulocyte colony stimulating
factor (G-CSF) was used in 59% of patients, and 36% were hospitalized for
neutropenia or diarrhea. One patient died. This experience has reinforced the
change to a 2-week-on, 1-week-off schedule.
In a Memorial Sloan-Kettering trial of cisplatin/irinotecan in
18 patients with gastric cancer, the partial response rate was 33%. Dr. Ilson
said that 44% of patients had grade 3/4 neutropenia and 22% had grade 3
diarrhea. "This was almost a doubling of the diarrhea rate in the previous
study," Dr. Ilson said.
Other initial trials have included:
tests of single-agent irinotecan at 125 mg/m2/wk in
esophageal and gastric cancer
irinotecan 125 mg/m2 plus
fluorouracil (5-FU) plus folinic acid in gastric and gastroesophageal
comparison of irinotecan 200 mg/m2 plus cisplatin 60
q3 wks to irinotecan 80 mg/m2 plus folinic acid 500 mg/m2 plus 5-FU 2
6 wks on, 1 off in esophageal and gastric cancer.
Dr. Ilson added that phase I trials in development at Memorial
Sloan-Kettering include weekly irinotecan/cisplatin plus concurrent
radiotherapy, weekly paclitaxel (Taxol), or weekly fluorouracil.
A phase I study of weekly paclitaxel or 5-FU plus
irinotecan/cisplatin in patients with esophageal, gastric, or pancreatic
cancers produced "responses in previously treated pancreatic and gastric
cancer," Dr. Ilson stated. Figure 1 shows an example of a response to
5-FU, irinotecan, and cisplatin, in gemcitabine (Gemzar)-resistant pancreatic
cancer.) "Due to reduced toxicity, most of us have accepted the 2 weeks
on/1 week off schedule used in this trial as our standard approach."
There are 33,800 new cases of esophageal and gastric cancers in
the United States each year, Dr. Ilson noted, and 25,100 deaths, accounting for
4% of American cancer deaths. "Mortality is 90% for esophageal cancer and
60% for gastric cancer," he said.