ABSTRACT: Locally advanced or metastatic adenocarcinoma of the stomach still carries a poor prognosis, with 5-year survival rates of < 15%. Palliative chemotherapeutic regimens for this disease are largely 5-FU–based. We have investigated the clinical activity of an oral combination of uracil and tegafur (UFT) with calcium folinate (Orzel), in patients with measurable metastatic disease. Thirty-six patients received a total of 94 courses of daily UFT 300 mg/m² plus calcium folinate 90 mg for 28 consecutive days followed by a 7-day rest. Planned treatment doses were maintained in 83% of all evaluable courses. Main toxicities included diarrhea (21 patients) and nausea and vomiting (20 patients). Other side effects were asthenia, malaise, stomatitis, and myelosuppression. At present, 26 patients are evaluable for response. Of these, one achieved a complete response and three achieved partial remissions. In addition, six patients reached stable disease, yielding an overall response rate of 27%. We conclude that the combination of UFT and calcium folinate is a feasible outpatient regimen that warrants further clinical evaluation. [ONCOLOGY 7(Suppl 3):61-63, 1999]
Adenocarcinoma of the stomach is one of the leading causes of cancer-related death in Japan, Eastern Europe, and South America. There has been, however, a significant decrease in incidence in the United States and Western Europe.[1,2] The prognosis for patients remains extremely poor with 5-year survival rates ranging from 5% to 15%.
Despite surgical efforts, gastric carcinoma resection as a “curative” approach yields dismal results, and at least 80% of patients develop recurrent and metastatic disease. Single drugs with reported response rates between 20% and 36% are 5-fluorouracil (5-FU),[3,4] mitomycin C (Mutamycin), doxorubicin (Adriamycin), and cisplatin (Platinol).[6,7] Complete responses, however, are uncommon and in general, responses are of brief duration without a significant impact on survival.
In order to improve response rates and increase survival, combination regimens have been developed, including FAM (5-FU, Adriamycin, mitomycin C),[4,8] FAP (5-FU, Adriamycin, Platinol), PFU (Platinol, 5-FU), EAP (etoposide [VePesid], Adriamycin, Platinol),[11-14] ELF (etoposide, leucovorin [Leucovorin Calcium, Wellcovorin], 5-FU), FAMTX (5-FU, Adriamycin, methotrexate [Folex, Mexate]),[16,17] and ECF (5-FU, epirubicin, cisplatin). In initial phase II studies, response rates with these combinations have reached 40% to 60% and complete responses of 2% to 15% have been reported. However, there has been no improvement in median duration of survival (which remained at 6 to 10 months).
At present, only protocols with FAM or FAM associated with BCNU have been compared to single-drug 5-FU chemotherapy. These studies failed to demonstrate a significant increase in response[19,20] or survival rates.[4,19,20] Phase III trials conducted to compare polychemotherapy regimens have also not shown a reproducible significant advantage over any other regimen.[14,17,18] Moreover, some of these protocols were associated with a significant increase in toxicity. The EAP, and to a lesser extent FAMTX, regimens induced severe toxicity (consisting mainly of myelotoxicity).[11-14,16-18]
Uracil and tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) in a molar ratio of 4:1 comprise the compound UFT. Tegafur is converted to 5-FU in vivo. The coadministration of uracil in the form of UFT/oral calcium folinate has been shown to enhance the concentration of 5-FU in tumors and the resulting antitumor activity of tegafur. In vivo studies showed that UFT/oral calcium folinate resulted in 5 to 10 times greater accumulation of 5-FU in tumors than in normal tissue. UFT/oral calcium folinate is the first member of the second generation of 5-FU prodrugs that has been previously evaluated for metastatic gastric carcinoma in Japan.[22,23] Recently, this agent became available for clinical trials in Europe and North America based on promising initial results indicating a single-agent overall response rate of 27.7%.[22,23]
Eligible adult patients had histologically proven gastric cancer with measurable distant metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status £ 2, and a life expectancy > 3 months. They could not have received chemotherapy or radiotherapy for 4 weeks prior to study entry. Adequate organ function was required. Patients had to give written informed consent before entering the trial.
A clinical history and physical examination was recorded for each patient. Preinclusion staging included abdominal computed tomographic scans and scans from other fields depending on the site of the metastatic disease. Laboratory parameters such as a complete blood count and differential, electrolytes, and renal and liver function tests were determined. All patients had a baseline electrocardiogram.
UFT was administered orally at a dose of 300 mg/mg² daily for 28 consecutive days. The total daily dose was divided and administered every 8 hours (each dose equaled about 100 mg) with calcium folinate given concurrently at 90 mg daily for 28 days. A 7-day rest followed and the next cycle was scheduled to begin on day 36.
Intracycle or intercycle dose modification was allowed depending on toxicities as graded by the Common Toxicity Criteria (CTC).
If a CTC grade 3 toxicity for granulocytes or platelets was noted during any cycle of treatment, UFT/calcium folinate administration was suspended until granulocytes rose to ³ 1.5 × 109/L and the platelet count reached ³ 100 ×109/L. Following recovery, the UFT dose was reduced by 50 mg/m²/d. Where there was nonhematologic toxicity CTC grade ³ 2, with the exception of untreated anemia, inadequately treated nausea or vomiting, alopecia, and asthenia, UFT/oral calcium folinate therapy was discontinued until the toxic event completely resolved or returned to baseline. Therapy was resumed at the same dose level if toxicity was CTC grade £ 2. For CTC grade 3 or 4 toxicities, therapy was resumed at a UFT dose reduced by 50 mg/m²/d or 100 mg/m²/d, respectively. The days therapy was withheld because of toxicity were counted as treatment days. UFT/oral calcium folinate therapy was discontinued on day 28 of each cycle, regardless of any interruptions.
Before the start of the next cycle of treatment, dose adjustments were made based on the maximal toxicity observed during the previous cycle of treatment. The initiation of a new cycle of treatment was delayed until recovery of neutrophil count to ³ 1.5 × 109/L and platelet count to ³ 100 × 109/L. Nonhematologic toxicities had to return to baseline or CTC grade 1.
Evaluation of Treatment
Response was assessed every 10 weeks. The work-up was identical to the initial pretreatment evaluation.
From July 1997 to December 1997, 38 patients with metastatic gastric carcinoma were entered into the trial. All patients but two, who died before starting treatment because of progressive disease, were assessable for toxicity. Twelve patients were considered unassessable for tumor response: two died before receiving treatment and no final information was available from 10 patients. Median age of participants was 64 years (range, 43 to 76). Most patients had an ambulatory performance status: 13 patients (34.2%) had an ECOG performance status of 0, 20 (52.6%) had a status of 1, and five (13.2%) had a performance status of 2.
Administration of Treatment
Thirty-six patients received a total of 94 courses of treatment. Seventy-eight courses were administered at the planned UFT dose. In 16 courses (17%), the dose had to be decreased to 250 mg/m²/d.
Toxicities encountered were evaluated according to the CTC grading system. The main toxicities were diarrhea (21 patients), nausea and vomiting (20), asthenia, malaise (8), and stomatitis (6). Thirty-two grade 3 and 4 events (34%) were reported among 94 courses of treatment. They were predominantly diarrhea (grade 3, seven; grade 4, two), nausea (grade 3, four), vomiting (grade 4, three), asthenia (grade 3, one; grade 4, two) and neutropenia (grade 3, four; grade 4, one). Six patients had to discontinue because of excessive toxicity.
Response to Treatment and Survival
At the time of analysis, of 26 evaluable patients one achieved a complete response and three achieved partial responses. Six patients had stable disease.
Our preliminary data indicate that UFT/oral calcium folinate provides moderate activity in patients with metastatic gastric cancer. The more frequent toxicities were diarrhea, nausea, vomiting, and asthenia, with the main CTC grade 3 and 4 toxicities being diarrhea, nausea, and vomiting. The efficacy and limited toxicity seen in this trial confirm the rationale for continuing UFT/oral calcium folinate testing in metastatic gastric cancer patients.
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