Although the incidence of gastric carcinoma has declined in the
United States over the past 40 years, it remains the eighth leading cause of
cancer death. In addition, for reasons that are as yet unclear, the incidence of
gastroesophageal and esophageal carcinoma (particularly adenocarcinoma) appears
to be increasing. Smoking has recently been implicated, but the evidence
appears weak.[2,3] Fifty percent of patients with upper gastrointestinal (GI)
malignancies present with unresectable locally advanced or metastatic cancer.
A recent approach for the treatment of locally advanced upper GI tumors is
multidisciplinary. However, patients with coincidental medical problems, elderly
patients, and those with a history of smoking and/or heavy alcohol consumption
may not be appropriate candidates for radical surgery. These patients especially
will need chemoradiotherapy for their upper GI tract tumors.
Irinotecan (Camptosar) is a plant alkaloid that was isolated
from Camptotheca acuminata. Irinotecan has strong anticancer activity in
vitro and in various experimental animal cancer models. Because it had
demonstrated minimal efficacy in early clinical trials and severe toxicity, this
chemotherapeutic agent was not popular in the United States.[8-13] There have
been many attempts to synthesize derivatives of camptothecin in order to
reinforce its anticancer activity and to decrease its toxicity.[14,15]
The water-soluble derivative of camptothecin,
7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (irinotecan)
has been shown to have high antitumor activity and low toxicity in murine
tumors.[7,16] Furthermore, Tsuruo et al have demonstrated that irinotecan is
effective against pleiotropic drug-resistant tumors in vitro and in vivo. It
appears that camptothecin and irinotecan strongly inhibit mammalian DNA
A phase I clinical study of irinotecan, in which the drug was
given intravenously in a weekly dose, has shown that leukopenia and
unpredictable diarrhea are dose-limiting toxicities, and that 100 mg/m2
is the maximum tolerated dose (MTD).[20,21] A partial response was observed in
patients with advanced non-small-cell lung cancer (NSCLC) who were treated
with 100 mg/m2 or more of irinotecan in this
phase I study.
A recent publication reports the outcome of the investigational
use of irinotecan to increase tumor radiosensitivity. Human lung tumor
xenografts were treated with either irinotecan 10 mg/kg intraperitoneally on
days 1, 5, and 9; single-dose radiation (10 Gy/leg) on day 1; or a combination
regimen of both treatments, with radiation given 1 hour after the first dose of
irinotecan. DNA flow cytometry studies were performed to define the cell cycle
changes following treatment for 1 to 12 hours with 0, 0.5, 2.0, or 8.0 ng/mL
SN-38, the major active metabolite of irinotecan. In the small-cell and
small-cell/large-cell carcinoma xenografts, combination treatment resulted in
significant tumor regression compared with the use of irinotecan or radiation
No severe weight loss or increased skin reaction was observed
following the combined treatment. Flow cytometry studies showed that the
proportion of cells in G2/M-phase, the most radiosensitive phase, increased
after 1-hour exposure to the lowest dose of SN-38 (0.5 ng/mL). These findings
suggest that irinotecan is a potent radiosensitizing agent, and that its
activity is related to the cell cycle.
Based on the preclinical data and a few phase I studies
indicating irinotecan to be an active chemotherapeutic agent as well as a
radiosensitizer for upper GI tumors, we conducted a phase I study to assess the
MTD of weekly irinotecan given with concurrent daily continuous radiotherapy for
upper GI tumors.
This phase I study was initiated in January 1998. Patients were
eligible after the histology of their tumors was confirmed. They were to have
advanced, unresectable gastric, gastroesophageal, or esophageal carcinoma.
Patients previously treated by chemotherapy without irinotecan or those with
recurrent unresectable tumors were eligible. Patients had to be 18 years of age
or older with a performance status of 0, 1, or 2 (Zubrod performance scale) and
a life expectancy of at least 12 weeks.
Additional eligibility requirements included a pretreatment
granulocyte count >1,500/mL, hemoglobin level ³ 9
g/dL, a platelet count ³ 100,000/mL, adequate renal
function as documented by serum creatinine £ 2.0
mg/dL, and adequate hepatic function as documented by a serum bilirubin level
< 1.5 mg/dL regardless of liver involvement secondary to tumor. In addition,
serum glutamic-oxaloacetic transaminase (SGOT) had to be £
3 times the institutional upper limit of normal (ULN) unless the liver was
invaded with tumor, in which case the SGOT had to be £
5 times the institutional ULN. Patients who had received up to two prior
regimens of systemic chemotherapy (excluding irinotecan) were eligible for study
Exclusion criteria included previous treatment with irinotecan
or topotecan (Hycamtin), or prior radiation therapy to the thorax or upper
abdomen. Also excluded were patients with any active or uncontrolled infection,
including known infection with human immunodeficiency virus, patients with
psychiatric disorders that would interfere with consent or follow-up, or
patients with a history of myocardial infarction within the previous 6 months or
congestive heart failure that required therapy. Patients with a history of prior
malignancy (except for adequately pretreated basal cell carcinoma, squamous cell
skin cancer in situ, or other cancer for which the patient was disease-free for
at least 5 years) were also barred from the study.
Baseline measurement of the tumor site and all known metastatic
disease had to be documented by computed tomography (CT) scans, x-ray, or other
radiographic assessments before treatment could be instituted, and an informed
consent form had to be signed by the patient before registration into the study.
At least three patients were treated at each irinotecan dose
level. Doses were escalated in sequential groups of three patients until the MTD
was established or the highest intended dose level was tested. Dose escalation
was not allowed for individual patients. All three patients at each dose level
were to receive all five doses of irinotecan before the next cohort was started
at the next higher dose level. Cohorts could be expanded to six patients as
necessary. The starting dose level of irinotecan was 30 mg/m2/wk
infused over 90 minutes. All patients were premedicated prior to irinotecan
dosing to prevent nausea and vomiting.
The following dose levels were employed: dose level 1, 30 mg/m2;
level 2, 40 mg/m2; level 3, 50 mg/m2;
level 4, 60 mg/m2; level 5, 70 mg/m2.
A weekly dose of irinotecan was given if the granulocyte count
was ³ 1,000/µL, the platelet count was ³
100,000/µL, and any other treatment-related toxicities were £
The treatment plan for radiation therapy was to give a total
tumor dose of 45-50.4 Gy in 1.8 Gy fractions for a total of 25-28 fractions,
delivered over 5 weeks. The dose was calculated at the midplane. All patients
were reassessed at 4 weeks after completion of chemoradiation therapy.
Irinotecan was administered 1 hour prior to administration of radiation therapy
on day 1 of each week of 5 treatment weeks.
The linear accelerator generated 6 MV or 18 MV photons. The
minimum target skin distance was 80 cm. Field placements were
anterior-posterior/posterior-anterior and anterior with two posterior obliques
to avoid high dosing to the heart. The two sharp posterior angles were used to
minimize the volume of the lung included within the irradiated fields. Target
volume was based on the size of individual tumors. The 2-cm lateral margin and
3-cm margin along the vertical axis of the target mass were used.
Radiation therapy was withheld on any planned treatment day on
which the patients exhibited grade 3 toxicity. A toxicity that delayed planned
radiation therapy for more than 2 weeks was considered dose-limiting for the
purpose of this study.
All patients were seen weekly in the Radiation Oncology
Department and every 2 weeks in the GI Center during chemoradiation therapy.
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