NEW YORKRegimens based on cisplatin (Platinol), irinotecan
(Camptosar), and paclitaxel (Taxol) may provide a better alternative
than cisplatin and 5-fluorouracil (5-FU) in treating difficult cases
of gastric and esophageal cancers. Developing more effective
therapies has considerable public health importance because of the
high incidence and mortality rates of these cancers, commented Eileen
M. OReilly, MD, of Memorial Sloan-Kettering Cancer Center in
Gastric and esophageal cancers affect 33,800 per year. Mortality is
60% for gastric cancer and 90% for esophageal cancer. Dr.
OReilly spoke at a clinical investigators workshop
sponsored by the University of Texas M. D. Anderson Cancer Center and
As described by Dr. OReilly, the rationale for combining
irinotecan and cisplatin is based on the following: each is active as
a single agent; cisplatin induces DNA-cisplatin adducts; and
irinotecan blocks DNA repair mechanisms by inhibiting
Phase I studies using cisplatin at 30 mg/m² plus irinotecan at
65 mg/m² found manageable toxicity and produced seven partial
responses among 30 evaluable patients with varied cancers. This was
followed by a phase II study in 38 patients with metastatic or
unresectable esophageal cancer. Cisplatin 30 mg/m² and
irinotecan 65 mg/m² were cycled weekly, with a 4 weeks on, 2
weeks off schedule.
Complete and Partial Responses
The primary endpoint was response rate, and secondary
end-points were dysphagia relief, quality of life, toxicity, and
survival, Dr. OReilly said.
Cisplatin/irinotecan produced partial responses in 52% of patients
(18/34) and complete responses in 5% of patients (2/34), for an
overall response rate of 57% (20/34). The median response duration
was 4.2 months, and median survival was 14.6 months. Responses
occurred in 52% of adenocarcinomas and in 66% of squamous cancers.
Dysphagia relief was a major secondary endpoint. Dr. OReilly
reported that dysphagia resolved in 70% of patients (14/20), improved
in 20%, and worsened or was unchanged in 10%.
The most serious toxicities were grade 3 or 4 neutropenia in 46% of
patients, grade 3 anemia in 31%, and grade 3 diarrhea in 11%. A
number of patients required delay or shortening of the treatment
cycles, mostly due to failure to meet white blood cell and neutrophil
recovery requirements in weeks 3-4, Dr. OReilly said.
This regimen is now being studied in a confirmatory multicenter
community-based phase II trial in metastatic or unresectable
esophageal cancer. Patients will be cycled 2 weeks on and 1 week off
in an effort to limit toxicity.
Gastric Cancer Results
Results with cisplatin/irinotecan in gastric cancer have been
less encouraging than those in esophageal cancer, Dr.
OReilly acknowledged. There were 33% partial responses and no
complete responses. In addition, 38% of doses had to be delayed, and
23% of doses could not be given, even though G-CSF was used in 59% of
patients. One third of patients had outright disease
progression despite treatment, and one third had to be hospitalized,
mainly for neutropenia or diarrhea, Dr. OReilly said.
Phase I trials now underway are testing weekly irinotecan plus
radiation therapy, biweekly irinotecan/cisplatin, and weekly
paclitaxel plus irinotecan/cisplatin in locally advanced upper
gastrointestinal cancers. Dr. OReilly said that preliminary
data from a phase I study of radiation therapy plus
irinotecan/cisplatin in locally advanced esophageal cancer found
pathological complete remission in two of three evaluable patients at
the 40 mg/m² irinotecan dose level and that five of six patients
showed improvement on barium swallow after induction. The phase I
trial of weekly paclitaxel plus irinotecan/cisplatin has enrolled 16
patients with upper GI tumors and has so far shown partial remission
in five of eight patients with esophageal cancer (all previously
treatment-naive) and in two of three patients with gastric cancer.
Paclitaxel plus irinotecan/cis-platin is an active treatment in
esophageal cancer and offers an alternative to cisplatin/5-FU,
Dr. OReilly concluded. It is potentially an active
regimen to develop for esophageal and for gastric cancers.