Although the incidence of gastric cancer has been gradually declining in the United States and Western Europe, the disease remains among the most common tumor types and has a dismal prognosis in the advanced stage. Four out of five patients who undergo extensive surgery with curative intent ultimately relapse locoregionally or develop systemic metastases, and the 5-year survival for patients with advanced gastric cancer is still only 5% to 15%.[1,2]
Several antitumor compounds have clinical activity in gastric cancer. Among the most active are fluorouracil (5-FU), mitomycin (Mutamycin), doxorubicin (Adriamycin), and cisplatin (Platinol), all with objective response rates of more than 20%. Somewhat less effective but still active are methotrexate and etoposide (VePesid).[3-7] However, given that responses following single-agent therapy are usually short-lived and complete responses are rare, a variety of combination-chemotherapy regimens have been clinically evaluated. Most of these combinations contain 5-FU (Table 1). Although initial phase II studies in highly selected patients yielded encouraging response rates of up to 60%, with more than 10% complete responses, survival has remained largely unchanged at only 6 to 10 months.
At present, only a small number of randomized prospective studies of combination regimens have been completed. When compared with either fluorouracil/Adriamycin/mitomycin (FAM) or FAM/carmustine, single-agent 5-FU was as effective with regard to response rate and survival, but it was less toxic.[8,9] Similarly, phase III trials comparing combination-chemotherapy regimens have failed to demonstrate a clear survival advantage for any specific regimen.[10-12] However, some regimens were accompanied by severe toxicityspecifically, myelosuppressionand an unacceptably high percentage of toxic deaths.[10-16]
The lack of effective and tolerable treatment options for patients with advanced gastric cancer represents a pressing need for development of new treatment strategies. This review summarizes the clinical experience with tegafur and uracil (UFT) in the treatment of gastric cancer and outlines perspectives for the future development of this compound.
Most early clinical studies of single-agent UFT were conducted by Japanese investigators, and several forms have been evaluated. In an early phase II study of UFT in the treatment of various tumor types, Kikuchi and Wakui observed partial responses in 2 patients with advanced gastric cancer. Malik et al reported 1 partial response among 16 patients treated with UFT and concluded that UFT is convenient for patients and should be considered a therapeutic option in the palliative setting. A summary of survival and response data for single-agent UFT from Japanese studies is provided in Table 2.
Clinical studies with UFT-containing combination regimens, both in neoadjuvant and palliative settings, have been conducted mostly by investigators in Japan. Most combination regimens, including UFT, also contain mitomycin and cisplatin, with or without doxorubicin. Further, in the large majority of studies, the specific contribution of UFT to the overall efficacy of the trial regimen remains unclear, as many studies comprise either small numbers of patients or are case reports indicative of clinical activity. Representative results of larger studies are summarized in Table 3.
Recent evidence indicates that inhibition of thymidylate synthase in gastrectomy specimens is enhanced if UFT and leucovorin are combined for administration prior to surgery, but, overall, available information about the combination is limited (Table 4).
In one clinical phase II trial, Kim et al used UFT (480 mg/m2/d in a divided dose) in conjunction with leucovorin (25 mg/m2/d) as palliative therapy for advanced gastric cancer. Among 14 evaluable patients, 1 patient achieved a complete response and 3 patients had partial responses. The median duration of survival for all patients was 25 weeks, with 18% of patients surviving after 1 year. The main toxicities observed were diarrhea and oral mucositis.
The European Organization for Research and Treatment of Cancer/Early Clinical Studies Group also has recently activated a phase II study with UFT/leucovorin. UFT will be administered at a dose of 300 mg/m2/day for 28 days, with leucovorin 90 mg/day. Both agents will be given in 3 divided daily doses, and therapy will be followed by a 7-day rest period.
In an attempt to develop an oral regimen for treatment of advanced gastric cancer, Feliu et al combined UFT, leucovorin, and etoposide. To increase the tetrahydrofolate pools, an initial dose of leucovorin 500 mg/m2 was given as an IV bolus administration. Of the 46 patients included, 4 (9%) developed a complete response and 12 (26%) developed a partial response, yielding an overall objective response rate of 35% (95% confidence interval, 22% to 51%). The median duration of response was 10 months, and the median overall survival was 9 months. One patient died from neutropenic sepsis. The authors concluded that this oral regimen is well tolerated and convenient.
In their most recent study, these same investigators replaced etoposide with epirubicin (75 mg/m2), administered intravenously on day 1. Based on pharmacologic considerations, the use of a leucovorin loading dose may be important, but the practice has not been used by other investigators, and its clinical efficacy will need further evaluation.
Only two randomized phase III studies of UFT-containing chemotherapy regimens have been published (Table 5). Although results indicate that UFT-based regimens are at least as active as non-UFT regimens, the statistical power of these studies suffers from small sample size. Thus, definitive conclusions as to the superiority of UFT-based regimens are not yet possible.
Sasagawa et al have conducted a randomized study comparing mitomycin/5-FU and mitomycin/UFT in patients with advanced gastric cancer. Although 3 of 13 (23%) evaluable patients responded to the UFT-containing regimen, only 1 of 15 patients (6.7%). showed a partial response in the 5-FU-containing regimen. In addition, the authors reported that quality of life was higher in the UFT group.
Kurihara et al[30,31] performed a randomized study comparing mitomycin/tegafur with mitomycin/UFT in patients with advanced gastric cancer and reported a statistically significant increase in response rate and survival for the mitomycin/UFT group.
In a pilot study of patients with hepatic metastases, Yonemura et al used a combination of regional infusional mitomycin and cisplatin and oral UFT. They reported local partial responses in 9 out of 12 evaluable patients. However, the relative importance of the individual components of this treatment is unclear, as is any contribution of UFT to the gastrointestinal and bone marrow toxicity observed.
UFT-Containing Regimens as Neoadjuvant Treatment
In a pilot trial of PMUE in 8 patients with inoperable gastric cancer, Kato et al administered between 1 and 5 courses of PMUE as an intra-arterial, intravenous, or intraperitoneal infusion, achieving partial responses in seven patients (88%). Subsequent surgery performed on 5 patients showed no tumor in 2 and residual tumor in 3 patients. Subsequent to surgery, PMUE was continued as adjuvant therapy in the 5 patients, but no definitive conclusions can be drawn from this study, except that PMUE appears to be a highly active regimen.
In a randomized comparative trial, Yonemura et al compared neoadjuvant and adjuvant administration of PMUE in patients with stage IV gastric cancer and measurable lesions. In this study, 29 patients received PMUE as neoadjuvant therapy followed by surgery, whereas 26 patients underwent primary surgery followed by adjuvant chemotherapy. The authors reported a higher response rate (62% vs 35%). and improved survival in the neoadjuvant group. While this study demonstrates that PMUE is an active regimen and indicates that neoadjuvant chemotherapy may be important in improving the outcome for patients with unresectable gastric cancer, the specific contribution of UFT remains unclear.
In an attempt to correlate clinical antitumor effects with the extent of thymidylate synthase inhibition, Tanaka et al administered cisplatin combined with UFT to 24 patients prior to surgery. In this study, a correlation was found between thymidylate synthetase inhibition and antitumor effect. Although these data are in agreement with preclinical results, larger studies are required to define the value of thymidylate inhibition for monitoring therapy.
UFT Containing Regimens as Adjuvant Treatment
Japanese investigators also have integrated UFT into adjuvant treatment strategies following complete surgical resection of gastric cancer. Arima et al reported a randomized study involving 210 evaluable patients with ³ stage II gastric cancer. In stage IV patients, treatment with mitomycin (20 mg on the day of surgery, 10 mg day 1 post-surgery, and then 10 mg every 3 months) was compared with mitomycin plus UFT (600 mg daily in a divided dose). The authors found a statistically significant increase in 5-year survival for the patient cohort receiving UFT. In addition, patients with poorly differentiated adenocarcinoma had a prolonged survival when treated with UFT.
Because UFT is an oral medication and patients with gastric cancer often must undergo extensive bowel surgery, the issue of drug bioavailability is of potential importance. Addressing this issue, Suda et al have measured serum concentrations of UFT, 5-FU, and uracil and have correlated the results with the type of surgery performed. As would be expected, a rather rapid increase in serum UFT concentrations was seen in patients following total gastrectomy. In contrast, emptying of the gastric contents was delayed in patients with a Billroth I resection, and, consequently, the rise in serum concentrations of UFT, 5-FU, and uracil also were delayed.
Maehara et al conducted a comparative pharmacokinetic study in patients with early-stage disease patients before and after various surgical procedures. It was determined that the area under the concentration-time curves of 5-FU and uracil, but not of tegafur, decline temporarily after surgery. Only 3 months after surgery, however, serum concentrations of 5-FU and uracil had returned to preoperative values. The authors concluded that dose adjustments might be necessary in the immediate postoperative period for patients treated with UFT. Although differences in resorption certainly may affect antitumor activity and the pattern of toxicity, large clinical studies have not yet incorporated stratification of surgical procedures.
The issue of patient compliance also must be addressed if oral antitumor agents are administered. A report by Ohsawa et al indicates that in patients treated with UFT, patient compliance may be monitored via determination of urine concentrations of 5-FU and tegafur, though not of uracil. Alternatively, serum concentrations of tegafur and 5-FU also may be used to monitor patient compliance.
UFT has been shown to be a safe and well-tolerated compound in the treatment of gastric cancer, as well as several other tumor types with potential sensitivity to 5-FU. However, the optimal dose and treatment duration have not yet been clearly identified. In addition, a number of other issues deserve continuing clinical evaluation. First, the optimal means of combining UFT with other agents needs to be characterized. Second, the value of UFT-containing combinations in the neoadjuvant setting warrants further research. At present, the specific contribution of UFT to clinical activity is unclear. Third, available evidence suggests that UFT might have a place in adjuvant chemotherapy for locally advanced gastric cancer, but further trials are necessary to unequivocally demonstrate the actual value of the agent in this situation. Finally, it will be necessary to demonstrate that combination UFT/leucovorin is clinically equivalent to combination 5-FU/leucovorin. Studies to address these questions are currently under way.
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