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(Drug information on 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(Drug information on 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 topoisomerase I.[18,19]
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 treatment alone.
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 entry.
Exclusion criteria included previous treatment with irinotecan or topotecan(Drug information on 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 £ grade 1.
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.