Experience With UFT in Japan
The selective antineoplastic effect of tegafur and uracil (UFT) is attributed to its preferential enhancement of fluorouracil concentration in tumor tissues compared with that in normal tissues. The result of this effect is evident in the clinical benefit and lower toxicity associated with UFT compared with other fluorinated pyrimidines. Beginning with preclinical studies in the 1980s, significant therapeutic advantages of UFT have been reported in numerous trials conducted in Japan, including phase I dose-finding studies, phase II multicenter studies, comparative studies, and combination-chemotherapy studies. In phase II studies conducted at 211 institutions, for example, it was shown that the response rate was over 30% in patients with head/neck, bladder, or breast cancer, and the survival rate was superior to that previously reported in Japanese studies. Two comparative studies suggested that UFT was more effective than single-agent tegafur, and a number of combination-chemotherapy studies have shown that it has an advantage in terms of toxicity, response, and/or survival. UFT is also useful for postoperative adjuvant therapy, as well as therapy for advanced disease in a variety of neoplasms. UFT holds considerable promise and future trials should continue the evaluation and refinement of its role in the treatment of cancer.[ONCOLOGY 11(Suppl 10):30-34, 1997]
ABSTRACT: The selective antineoplastic effect of tegafur and uracil (UFT) is attributed to its preferential enhancement of fluorouracil concentration in tumor tissues compared with that in normal tissues. The result of this effect is evident in the clinical benefit and lower toxicity associated with UFT compared with other fluorinated pyrimidines. Beginning with preclinical studies in the 1980s, significant therapeutic advantages of UFT have been reported in numerous trials conducted in Japan, including phase I dose-finding studies, phase II multicenter studies, comparative studies, and combination-chemotherapy studies. In phase II studies conducted at 211 institutions, for example, it was shown that the response rate was over 30% in patients with head/neck, bladder, or breast cancer, and the survival rate was superior to that previously reported in Japanese studies. Two comparative studies suggested that UFT was more effective than single-agent tegafur, and a number of combination-chemotherapy studies have shown that it has an advantage in terms of toxicity, response, and/or survival. UFT is also useful for postoperative adjuvant therapy, as well as therapy for advanced disease in a variety of neoplasms. UFT holds considerable promise and future trials should continue the evaluation and refinement of its role in the treatment of cancer.[ONCOLOGY 11(Suppl 10):30-34, 1997]
Introduction
Tegafur and uracil (UFT), an oral formulation containing uracil and ftorafur (tegafur:1-(2-tetrahydrofuryl)-5-fluorouracil) in a 4:1 molar ratio, shows a selective antineoplastic effect, because biochemical modulation by uracil enhances fluorouracil (5-FU) concentration more specifically within tumor tissues than it does in normal tissues. This manifests in good clinical response and fewer side effects than seen with other fluorinated pyrimidine series.
Ftorafur, synthesized by Hiller et al,[1] becomes effective by gradual conversion to 5-FU, primarily by liver enzyme P450. Thymidine phosphorylase and spontaneous metabolism are also involved. Transformation of 5-FU into active metabolites occurs via the anabolic pathway: 5-fluorodeoxyuridine monophosphate inhibits DNA synthesis, and 5-fluorouridine-triphosphate causes RNA dysfunction. On the other hand, 5-FU also takes a catabolic pathway, being degraded into fluoroacetate, fluoro-b-alanine, urea, carbon dioxide, and ammonia, a process that is regulated by dihydrouracil dehydrogenase. Fluoroacetate and fluoro-b-alanine cause the cardiotoxicity and neurotoxicity linked with 5-FU administration. Although the clinical investigation of injectable ftorafur, developed in the 1970s and 1980s in the United States, was discontinued due to its neurotoxicity, similar efficacy was observed compared with intravenous 5-FU. In Japan, ftorafur was developed as an oral formulation based on its good bioavailability and was given on a daily-dosing schedule as chemotherapy for advanced disease and as adjuvant therapy for gastrointestinal, breast, and lung cancers.
Uracil is a natural pyrimidine compound found in nucleic acid. Fujii et al[2] found that the coadministration of uracil enhanced the 5-FU concentration in tumors and consequently enhanced the antitumor activity of ftorafur in a dose-dependent manner. In in vitro studies, uracil was degraded by dihydrouracil dehydrogenase, competitively inhibiting 5-FU catabolism. Uracil does not interfere with the anabolism of 5-FU under the same conditions, however. In vivo studies conducted in Japan show that although UFT and ftorafur administration resulted in comparable distributions of 5-FU in blood and normal tissues, UFT resulted in a 5 to 10 times greater concentration of 5-FU in tumors.
Clinical Pharmacology
Based on data from preclinical studies, clinical studies using combination ftorafur and uracil were begun in Japan in the early 1980s.[3,4] A fixed single dose of ftorafur 300 mg was administered with various doses of uracil. Ftorafur: uracil molar ratios included 1:0, 1:2, 1:4, 1:5, and 1:10. As the 5-FU concentrations in blood and tissues were enhanced in proportion to each increase in the higher molar ratio of uracil, 5-FU tumor-to-blood and tumor-to-normal tissue partition coefficients (T/B, T/N) were examined to discover which molar ratio resulted in the highest T/B and T/N of 5-FU. Results from these studies showed that the optimal ratio was 1:4.[3,4]
In patients with various neoplasms, comparative studies were undertaken to measure the concentration of 5-FU in blood after administration of ftorafur or UFT. The administered dose was 300 mg ftorafur in both the ftorafur and UFT groups.[5] The 5-FU concentration in blood after the ftorafur administration was Cmax 0.018 ± 0.0009 µg/mL, compared with a Cmax of 0.210 ± 0.094 µg/mL 30 minutes after UFT. The 5-FU concentration then decreased rapidly, to 0.05 ± 0.019µg/mL 3 hours after and 0.012 ± 0.06 µg/mL 24 hours after UFT administration. The Cmax of 5-FU after UFT was 11.7 times greater than that after ftorafur. The 5-FU concentration in various tumor tissues was measured 2, 4, 6, 8, and 10 hours following oral administration of UFT, and proved to be 2 to 10 times higher in tumor tissues than in blood. Notably, these concentrations were maintained for more than 12 hours in 6 of 8 patients.
Phase I Studies
Phase I studies showed that the maximum tolerated dose of UFT in the single-dose trial was ³ 1,200 mg, and 600 mg/day in 2 or 3 divided doses in the long-term daily dosing trial. Dose-limiting toxicity in the daily dosing trial was generally gastrointestinal, and hematologic toxicity was usually mild and reversible. The daily dosage of UFT recommended for phase II studies was thought to be 400 to 600 mg/day, given in 2 or 3 doses.
Phase II Study
A Japanese phase II study of UFT was conducted at 211 institutions. Eligibility criteria included histologically confirmed and measurable carcinoma, no prior exposure or full recovery from previous chemotherapy, and adequate liver, renal, and bone marrow function. Total UFT doses ranged from 300 to 600 mg in 2 or 3 divided doses given daily until tumor progression or the advent of dose-limiting toxicity. Patients received UFT in various formulations: 563 received UFT capsules, 49 received UFT fine granules, and 87 received enteric-coated granules. Table 1 presents efficacy data by disease site. Overall, 699 patients were evaluable for response, which ranged from over 30% for patients with cancers of the head and neck, breast cancer, or bladder cancer, to 14.7% in those with prostate cancer and 8.7% in lung cancer patients. The main side effects were gastrointestinal, including anorexia, nausea and vomiting, diarrhea, and stomatitis (Table 2). Hematologic toxicity was infrequent and mild in severity. Other treatment-related adverse events included pigmentation, malaise, and, rarely, hepatic dysfunction.
Of the 699 patients enrolled in this phase II trial, 288 were evaluable for survival (Table 3).[6] In general, survival for patients treated with UFT in this trial was superior to data previously reported in Japan.
Comparative Studies
UFT Vs Ftorafur
A historical comparative phase II study[6] was performed to evaluate UFT 300 to 600 mg in 2 or 3 divided doses and ftorafur 600 to 1,400 mg, given orally. Clinical efficacy was compared by pooling data from the same institutions. UFT yielded a higher response rate than ftorafur for cancers of the stomach, pancreas, colon/rectum, and breast. A comparative analysis of the side effects of both drugs included 551 patients receiving UFT and 1,502 patients taking ftorafur at the standard daily dose of 800 to 1,200 mg. Although the side effects profile of UFT resembled that of ftorafur, UFT was associated with fewer gastrointestinal and neurologic toxicities than ftorafur (35.6% of patients vs 40.5% and 1.8% vs 4.1%, respectively).
A double-blind study compared the efficacy of oral UFT (400 mg ftorafur) with that of oral ftorafur (800 mg) in patients with advanced breast cancer.[7] Of the 60 patients enrolled in the study, 56 were evaluable for response (28 in each group). The overall response rates were 39% (95% confidence interval [CI], 22% to 59%) in the UFT group and 21% (95% CI, 8% to 41%) in the ftorafur group. A trend in time to relapse was seen in favor of UFT (median, 37 weeks vs 28 weeks) and median survival times were 47 months for UFT and 34 months for ftorafur. Patients and investigators assessments of adverse effects were similar for both treatment groups. Taken together, results from these two comparative studies indicate that UFT is more effective than single-agent ftorafur.
Combination Chemotherapy Including UFT
Combination chemotherapy consisting of mitomycin-C (MMC) and oral ftorafur is regularly used in the management of advanced stomach cancer. To compare the efficacy of ftorafur plus MMC vs UFT plus MMC for patients with stomach cancer, a multi-institutional randomized study[8] was undertaken. (Results are detailed in Kurihara et al, pages 106-108). Combination MMC plus UFT yielded a significantly higher response rate, no marked differences in adverse events, and a significant survival advantage. Based on these encouraging results, several other combination trials that include UFT are now under way in patients with stomach cancer.
Combination cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin), and 5-FU (CAF) is a standard treatment regimen in advanced breast cancer, prompting an ongoing comparison of CAF vs CA plus UFT. A similar randomized trial was conducted in the Philippines,[9] which employed cyclophosphamide 500 mg/m2 and 50 mg/m2 doxorubicin administered intravenously on day 1 in both treatment arms. In the CAF arm, 5-FU 500 mg/m2 was administered intravenously on days 1 and 8, and UFT 350 mg/m2 was administered orally on days 1 to 14 in the CA plus UFT arm. Of the 65 patients enrolled, 31 were evaluable for response and toxicity in each group. Responses to CA plus UFT were higher than CAF, although no statistical difference was evident (CA plus UFT, 48.4%; CAF, 35.5%). Both combinations were well tolerated and their toxicity profiles were similar, but anemia and stomatitis were judged to be significant in the CAF arm. These results show that CA plus UFT has similar efficacy and lower toxicity than conventional CAF in patients with advanced breast cancer.
UFT has also demonstrated clinical efficacy at other disease sites. The combination of cisplatin (Platinol) and UFT shows comparative efficacy and less bone marrow toxicity than other cisplatin-based therapies and is described in detail by Ichinose et al elsewhere in this supplement (pp 103-105). Combination regimens of MMC and UFT [10] and UFT and leucovorin are currently under study against colorectal cancer in Japan. Endocrine therapy is the primary therapy for prostate cancer, and UFT shows efficacy in this region. Several randomized trials of endocrine therapy vs endocrine therapy with UFT have been conducted, and preliminary results indicate a survival benefit for combination therapy with UFT.
Postoperative Adjuvant Chemotherapy Including UFT
In Japan, ftorafur has been widely used for postoperative adjuvant chemotherapy in various neoplasms, and UFT is also used for this purpose. Several randomized trials with UFT have been performed, but definitive results are not yet available. Several of these postoperative adjuvant trials with UFT are discussed elsewhere in this supplement, including UFT in rectal cancer (pp 58-68), non-small cell lung cancer[11] (pp 98-105), colorectal disease (pp 35-57), and breast cancer (pp 69-85).
Conclusion
UFT is a new antineoplastic agent. Its formulation was based on biochemical modulation therapy (Figure 1), such that biochemical modulation by uracil specifically enhances 5-FU concentration in tumor tissues. Thus, UFT demonstrates both tumor selectivity and broad-spectrum anticancer effects. It has yielded therapeutic benefits in the treatment of various cancers in both advanced disease and in the adjuvant setting. UFT has been used without leucovorin in most Japanese trials. Future trials should continue to evaluate and refine the role of UFT in the treatment of cancer.
References:
1. Hiller SA, Juk RA, Lidak MYU, et al: Analogs of pyrimidine nucleosides. Dokl Akad Nauk SSSR 176:332-335, 1967.
2. Fujii S, Ikenaka K, Fukushima M, et al: Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann 69:763-772, 1978.
3. Taguchi T, Nakano H, Jikuya H, et al: Effect of uracil on the antitumor activity of Ftorafur. Jpn J Cancer Chemother 5:1161-1165, 1978.
4. Taguchi T, Furue H, Koyama Y, et al: Phase I study of UFT. Jpn J Cancer Chemother 7:966-972, 1980.
5. Nakajima O, Ihara K, Isoda T, et al: Phase I and II studies on mixture of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil. Jpn J Cancer Chemother 7:1558-1568, 1980.
6. Ota K, Taguchi T, Kimara K, et al: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988.
7. Tashiro H, Nomura Y, Ohsaki A, et al: A double blind comparative study of tegafur (FT) and UFT (a combination of tegafur and uracil) in advanced breast cancer. Jpn J Clin Oncol 24:212-217, 1994.
8. Kurihara M, Izumi T, Yoshida S, et al: A comparative randomized study of tegafur plus mitomycin C vs combined tegafur and uracil plus mitomycin C in the treatment of advanced gastric cancer. Jpn J Cancer Res 82:613-620, 1991.
9. Villano AH, De Guzman LMB, Samson MCL, et al: A comparative, randomized trial of UFT and 5-fluorouracil in combination with cyclophosphamide and doxorubicin in the treatment of advanced breast cancer patients in The Philippines General Hospital. Oncology 54(suppl 1):2-6, 1997.
10. Ikeda E, Kodaira S, Teramoto T, et al: Optimal dosage of UFT + MMC combination chemotherapy for advanced colorectal cancer: Phase I/II study of combination chemotherapy of MMC with 2-week intervals and intermittent UFT administration. Jpn J Cancer Chemother 23:1291-1298, 1996.
11. Wada H, Hitomi S, Teramatsu T, et al: Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 14:1048-1054, 1996.
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