NEW YORK-A new regimen
combining intravenous (IV) cisplatin
(Platinol) and irinotecan (CPT-11,
Camptosar) given before surgery
and intraperitoneal (IP) floxuridine
(FUDR)/cisplatin after surgery produced
promising responses in locally
advanced gastric cancer. Howard
Hochster, MD, of New York University
School of Medicine, presented these
findings at the 6th University of Texas
M. D. Anderson Cancer Center Investigators'
Irinotecan/cisplatin induction chemotherapy
(Figure 1) was of interest
because previous studies showed neoadjuvant
therapy can be delivered in
this setting and can induce tumor
downstaging, improve "R0" resectability
rates, and identify patients with
subclinical metastases. The IP adjuvant
approach is attractive for preventing
local recurrence because it provides direct treatment at high-risk
sites, produces higher drug concentrations,
provides longer contact between
the drug and the tumor cell,
and allows for treatment of liver metastases
caused by portal absorption.
"The background for this trial is
that the majority of phase III trials
have shown no significant survival
benefit," Dr. Hochster said. "The
Intergroup 0116 study was the first
large phase III trial to show survival
benefit with adjuvant chemoradiation,
and only patients with curative 'R0'
resections were eligible. Three-year
disease-free survival was 48% vs 31%,
and median survival was 36 vs 27
months, for a 35% risk reduction in
Endpoints for the NYU study of 34
patients with biopsy-proven locally
advanced gastric cancer were response
(pretreatment clinical vs postoperative
pathologic), disease-free survival
(including analysis of sites of recurrence),
and overall survival.
Ability to deliver the planned dose
is often an issue in this type of trial. A
total of 86% received the planned dose
of irinotecan (600 mg/m2), and 78%
received the planned dose of cisplatin
(200 mg/m2). "These patients were
somewhat malnourished and presented
a treatment challenge to begin with,
but we did manage to get in approximately
80% of both drugs as planned,"
reported Dr. Hochster.
Nearly all of the 32 evaluable patients
had some type of grade 3/4 hematologic
toxicity after induction chemotherapy.
Thirteen patients had
grade 3 neutropenia, and three patients
had grade 4 neutropenia, but there
were only four cases of grade 3/4 febrile
Catheter complications were a
problem in 24 patients. They included
one case of peritonitis, one instance in
which the catheter broke, and one
infection at the port site.
A total of 29 patients underwent
surgical resection, and 25 had complete
clearing with a negative surgical
margin (R0). The median number of
lymph nodes removed was 28. During
the 30 days after surgery, 2 patients
died, and 10 patients had complications,
including three reoperations,
one anastomotic leak, four cardiac or
respiratory problems, and five wound
problems. The median postoperative
length of stay was 9 days.
There were 1 pathologic complete
response (CR) to induction chemotherapy;
18 partial responses (PR),
many of which were microscopic residual
disease; 6 cases of stable disease
(SD); and 7 cases of disease progression.
Dr. Hochster concluded that irinotecan-
based neoadjuvant therapy and
postoperative IP therapy could be delivered
safely and with acceptable toxicity
in this patient population. No
increase in surgical morbidity was seen
in the postchemotherapy gastric resections,
and 85% of patients achieved
an R0 curative resection. "Pathologic
response was a bit disappointing to
us," Dr. Hochster admitted. "We saw
evidence of downstaging, mostly of
the primary tumor, in over 50% of
patients, but most patients still had
microscopic nodal involvement."
Sixteen patients remain with no
evidence of disease at a median follow-
up of 15.9 months, three patients
are alive with disease, and three died
of other causes. The main sites of recurrence
have been intra-abdominal,
including the liver (five patients) and
distant metastases (five patients).
There have been no local recurrences.
Mean overall survival is 37.5
months, at a mean follow-up of 28
months in surviving patients. "Preliminary
survival data are encouraging,
and at present, median survival is
comparable to that in the treatment
arm of INT 0116," Dr. Hochster said.
Longer follow-up is needed to determine
the ultimate impact.
This study raises two specific questions:
First, should neoadjuvant therapy
be used routinely in the treatment
of patients with gastric cancer? Second,
would results with IP therapy
equal those of radiotherapy in the adjuvant
setting? Further study is required
to answer these questions, Dr.