Although the incidence of gastric carcinoma has fallen in most Western countries, it is still one of the most important causes of cancer mortality in the world and its treatment remains a challenge. Considering that the majority of patients have metastatic disease either at presentation or later, the development of better systemic chemotherapeutic treatments is mandatory to improve clinical outcome for patients with gastric carcinoma. Given the predominantly palliative intent of advanced gastric carcinoma therapies, regimens with both low toxicity and acceptable activity should be chosen for patients in this category.
Tegafur1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU)is a prodrug of 5-FU that undergoes metabolic activation mainly in the liver. Fujii et al reported that oral administration of combination tegafur and uracil (UFT) significantly increased 5-FU levels in tumor compared with tegafur alone. The mechanism for this biochemical modulation is thought to be the inhibitory effect of uracil on the degradation of 5-FU through competition with 5-FU for dihydropyrimidine dehydrogenase. An advantage of long-term oral administration of UFT is that it might mimic the effects of protracted infusions of 5-FU.
Although there are not enough data to support the beneficial advantage by biochemical modulation of tegafur by leucovorin, the possible modulation of UFT by leucovorin is of interest. A recent study of UFT plus leucovorin showed clinical responses among patients with gastric carcinoma who had been treated with a 5FUcontaining regimen, with no change in either the pharmacokinetic or toxicity pattern of UFT. As a result of these drug-combination studies, as well as reports of effective treatment of colorectal carcinoma patients with UFT and leucovorin and a study showing that UFT has superior antineoplastic action against gastric carcinoma compared with 5-FU or tegafur, we initiated a phase II study to assess the response rate and toxicity of oral UFT plus leucovorin in patients with advanced gastric carcinoma. Following up on our previous preliminary report, we now have long-term results and have expanded our series to include 39 patients treated with this regimen.
Between September 1993 and December 1996, 39 patients seen at the Korea University Guro Hospital entered the study. All patients had locally unresectable or disseminated adenocarcinoma of the stomach confirmed by biopsy, with measurable or evaluable disease. Eligibility requirements included age older than 20 years and a life expectancy of at least 4 weeks. Required prestudy laboratory parameters included a white blood cell count greater than 4,000/mm3, platelets greater than 100,000/mm3, and bilirubin and creatinine values of less than 2.0 mg/dL. Patients who had received prior 5-FU or other chemotherapeutic agents were eligible for the trial. Of the 39 patients who entered the study, two patients who were lost to follow-up after the first cycle were inevaluable for response; they were, however, included in the evaluation of toxicity. All patients provided informed consent.
A course of therapy comprised 21 consecutive days of treatment followed by a 7-day treatment-free interval. The total daily dose of UFT was divided into three doses administered orally every 8 hours, beginning with an initial dose of 360 mg/m2/day. UFT was supplied in the form of 100-mg capsules (that is, 100 mg tegafur plus 225 mg uracil). Leucovorin was supplied as 5-mg tablets and administered orally, with the total dose divided into four doses. If a patient had a body surface area of 1.7 m2, the total daily leucovorin dose was 40 mg (eight tablets). In subsequent courses the daily dose of UFT was increased by 100 mg/day if toxicity was absent or mild at the 360-mg/m2 dose level. The leucovorin doses, however, remained at 25 mg/m2/day.
On the next course the daily dose of UFT was reduced by 100 mg/day in patients who experienced grade 3 or 4 toxicity, based on World Health Organization criteria. Courses were repeated every 4 weeks until tumor progression or the development of treatment intolerability. Treatment was interrupted if the patient developed World Health Organization grade 3 or 4 hematologic and nonhematologic toxicity that did not resolve with dosage reduction. Treatment was reinstituted after hematologic abnormalities returned to baseline levels and clinical symptoms resolved.
All patients were examined clinically prior to entry into the study. Baseline investigations included a complete blood count and estimation of serum electrolytes, urea, creatinine, calcium, phosphate, bilirubin, alkaline phosphatase, aspartate aminotransferase, total proteins and albumin, carcinoembryonic antigen, and alpha-fetoprotein. Upper gastrointestinal endoscopy, double contrast upper gastrointestinal radiographs, abdominal computed tomographic scan, and other appropriate procedures were also performed. Patients were evaluated clinically at 2-week intervals using routine blood tests and evaluation of carcinoembryonic antigen blood levels. Unless disease had progressed unequivocally or the patient had dropped out of the study due to drug toxicity, disease status was re-evaluated radiologically at 2-month intervals. Standard World Health Organization response criteria were used to assess response to treatment. Toxicity was also reported using World Health Organization criteria. The time to disease progression was calculated from the date therapy was initiated to the date that progressive disease was first observed. Survival duration was calculated from the first day of treatment to death or the last follow-up.
Thirty-nine consecutive patients entered this trial. Patient and disease characteristics are listed in Table 1 and Table 2. Only half of the patients had a relatively good performance status of grade 1, while eight patients were evaluated as grade 3. The median age of patients was 64 years, with a range of 32 to 79. Four patients had been treated previously with bolus 5-FU-containing chemotherapy [two had received pinorubin (Pirarubicin)/5-FU/cisplatin (Platinol), one 5-FU/doxorubicin (Adriamycin)/mitomycin (Mutamycin), and one etoposide (VePesid)/leucovorin/5-FU]. Of the 39 patients, 25 had metastatic disease at the start of treatment and 14 had locally advanced unresectable disease (Table 2).
Response to Chemotherapy
After the first cycle of treatment, the UFT dose was increased by 100 mg/day in eight patients whose toxicity did not exceed grade 2. When four of these eight patients experienced grade 3 or greater toxicity after the second cycle of treatment, their dosage was returned to the starting dose level for subsequent courses. Another three patients tolerated one dose-level elevation for one, four, and six cycles. One patient tolerated one dose-level elevation for one cycle, followed by two dose-level elevations for two cycles. After the second cycle, however, that patient developed grade 3 diarrhea and was returned to treatment at one dose-level elevation. Six patients developed grade 3 toxicity with the first cycle of treatment and so received a reduction of one dose level for subsequent cycles (Table 3). Cumulative toxicity was not observed with long-term treatment.
With 10 of 37 evaluable patients responding, the overall objective response rate was 27.0% (95% confidence interval, 15.4% to 42.9%), including two (5.4%) complete remissions. Of the 19 patients with measurable disease, five (26.3%) responded to treatment, and, of the 18 patients with evaluable disease, another five (27.7%) showed responses. One patient who had failed to respond to a previous FAM (5-FU/Adriamycin/mitomycin) regimen achieved a complete response and has no evidence of disease with over 88 weeks of follow-up. Other patients who had received previous chemotherapy did not respond to this therapy. After a median follow-up of 57 weeks, the median survival time was 30 weeks (range, 8 to 111 weeks) for 37 patients (Table 4, Figure 1).
The main toxicities encountered with oral UFT and leucovorin were diarrhea and oral mucositis (Table 5). Seven patients experienced grade 3 diarrhea, which was severe enough to require temporary cessation of treatment, and three of these patients were hospitalized due to severe diarrhea. Grade 3 or greater stomatitis occurred in six patients; treatment was discontinued in one patient due to grade 4 toxicity and that patient was admitted to the hospital. World Health Organization grades 2 and 3 nausea and vomiting were observed in 12.8% and 15.4% of the patients, respectively. The toxic reactions resolved on cessation of treatment. Only grade 1 hematologic toxicity was observed in five patients. Alopecia was not detected, and no severe infection or treatment-related death occurred.
Our results suggest that oral UFT plus leucovorin has a role as palliative treatment of locally advanced or metastatic gastric carcinoma when more toxic chemotherapies are not suitable. In our study, 10 of the 37 evaluable patients with advanced gastric carcinoma responded to oral UFT plus leucovorin, resulting in a response rate of 27%. Even though our result is not superior to previous results reported for 5-FU or UFT alone, this regimen appears to have some advantages in managing patients with advanced gastric carcinoma.
As Table 1 shows, the median age of our study population is relatively older than that of other reported series. Fourteen patients (36%) were older than 70 years. Such elderly patients were not included in other studies. The performance status of our patients also was relatively poor compared with other studies, and many of these patients had underlying diseases that could be an obstacle to administering other, more toxic chemotherapy. Two patients had liver cirrhosis, one had a history of myocardial infarction, another had a hemiparesis due to a previous cerebrovascular accident, and one patient had chronic lung empyema with continuous discharge from a cutaneous fistula.
The median survival of our evaluable patients was 30 weeks. This result appears to be better than the survival observed in untreated patients with metastatic or unresectable gastric carcinomas, among whom the reported median survival times range from 2 to 4 months.[12,13] Further, side effects of this regimen were tolerable and controllable. Because of its minimal hematologic toxicity, this regimen can be administered on an outpatient basis without disrupting daily life. With the oral treatment regimen, treatment could be temporarily discontinued if toxicity such as diarrhea, mucositis, nausea, or vomiting worsens. In addition, no hair loss was associated with this treatment, a benefit patients appreciated.
Considering these facts, the UFT plus leucovorin regimen seems to be a reasonable alternative to other highly myelosuppressive and toxic chemotherapy regimens for treating gastric cancer. This regimen may provide an option for patients whose poor performance status or age contraindicates toxic chemotherapy.
Oral UFT plus leucovorin provides an effective form of palliative treatment for patients with advanced gastric carcinoma. Further study in a large patient population is warranted to determine the usefulness of this regimen in groups of patients with better performance status and, eventually, in neoadjuvant settings. In the future, combination therapy with UFT and oral etoposide or methotrexate, which have no overlapping toxicities and have proven activity against gastric carcinoma, warrants investigation in these patients.
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