UFT Therapy Research Articles

The effect of epidermal growth factor receptor mutation on adjuvant chemotherapy with tegafur/uracil for patients with completely resected, non-lymph node metastatic non-small cell lung cancer (> 2cm): a multicenter, retrospective, observational study as exploratory analysis of the CSPOR-LC03 study.

The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03). Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1>2cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status. Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P=0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status. In pathologic stage I (>2cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed.

Retrospective study of efficacy of adjuvant chemotherapy using tegafur-uracil in patients with non-small cell lung cancer with primary tumor size of 4.1-5.0 cm.

The staging of patients with a tumor of diameter 4.1-5.0 cm and no lymphatic/distant metastases have been up-graded to stage IIA in the latest 8th edition of the TNM staging system. However, the efficacy of adjuvant tegafur-uracil (UFT) therapy in these patients, which has been recommended in the guideline issued by The Japan Lung Cancer Society, remains unclear. We evaluated the efficacy of adjuvant UFT therapy among a cohort by retrospective analyses of multicentric database. In 2005-2007, 130 patients with p-stage IB non-small cell lung cancer (NSCLC) (diagnosed according to the 7th edition of the TNM staging system) and tumor size of ≥3.1 cm underwent anatomic complete resection at nine of our affiliated hospitals. We retrospectively reviewed the clinicopathological characteristics and the outcomes among these patients. Ninety-eight patients had tumor size of 3.1-4.0 cm (T2a group), whereas 32 patients had tumor size >4.0 cm (T2b group). Overall, patients who received adjuvant UFT showed a tendency of better outcomes than patients who did not [hazard ratio (HR) 0.564; 95% confidence interval (CI), 0.257-1.238, P=0.147]. In subgroup analyses, patients who received adjuvant UFT also tended to show better outcomes than those who did not in both T2a group and T2b group (HR 0.504; 95% CI, 0.202-1.255, P=0.132 in T2a group and HR 0.855; 95% CI, 0.181-4.033, P=0.843 in T2b group, respectively). Our results suggest that adjuvant UFT therapy have the potential to improve postoperative outcomes even in patients with p-stage IIA disease, as classified according to the 8th edition of the TNM staging system.

Abstract A27: Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC)

Abstract Ras is a well-known oncogene, and patients with metastatic colorectal cancer that harbored activating mutations in KRAS and NRAS did not benefit from anti-epidermal growth factor receptor antibodies in previous clinical trials. However, the value of RAS mutations in stage III colorectal cancer has been controversial. NSAS-CC/RC studies consisting of two multicenter phase 3 randomized trials showed that postoperative adjuvant chemotherapy with uracil-tegafur (UFT) significantly improved relapse-free survival (RFS) and overall survival (OS) in patients with stage III colorectal cancer. Here, we performed an integrated analysis of two trials in order to evaluate the association of RAS (KRAS exons 2, 3, 4 and NRAS exons 2, 3) mutations with effectiveness of adjuvant UFT therapy. The analysis included 178 patients with colon cancer and 146 with rectal cancer. RAS mutations were detected by direct-sequencing with a polymerase chain reaction method and observed in 134/304 (44.0%) patients. In patients with RAS mutations, a significant survival benefit was associated with adjuvant UFT chemotherapy in terms of both RFS (HR = 0.49; p = 0.02) and OS (HR = 0.51; p = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS (HR = 0.89; p = 0.67) and OS (HR = 0.94; p = 0.83) between the surgery-alone group and surgery plus adjuvant UFT group. Therefore, we propose that KRAS/NRAS mutations are predictive indicators of the efficacy of adjuvant UFT chemotherapy. Thereafter, we performed a proteomic analysis of 73 tumors of the patients participating in this study by the system of 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL). The quantity of detected 2652 proteins was compared between RAS mutation group and RAS wild-type groups. Significant differences were observed in the expression of 36/2652 proteins. Moreover, we divided the patients treated with adjuvant UFT chemotherapy into an early-recurrence group (recurrence within 12 months after surgery) and a late recurrence/ no recurrence group. Among the 36 proteins, the quantities of 4 proteins (KRT3, CLU, C6orf70 and FBXW8) were significantly different between these groups. In conclusion, our study suggested that the KRAS/NRAS mutation is a biomarker to predict the benefit of adjuvant chemotherapy in stage III colorectal cancer. The benefit may be caused by differences in the expression of several proteins. Citation Format: Yusuke Sasaki, Yasuhide Yamada, Masahiro Kamita, Masaya Ono. Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A27.

Efficacy of tegafur–uracil (UFT) administration in castration-resistant prostate cancer patients with a history of both alternative antiandrogen therapy and estramustine phosphate sodium hydrate therapy

The purpose of this study was to evaluate the efficacy of tegafur-uracil (UFT) administration as a fourth-line therapy in patients with castration-resistant prostate cancer (CRPC) who had already received combined androgen blockade (CAB) therapy (first-line), alternative antiandrogen therapy (second-line), and estramustine phosphate sodium hydrate (EMP) therapy (third-line), in order to determine who would benefit from UFT therapy. UFT was administered at a daily dose of 300 mg/m(2) to 26 patients, and the response to UFT 4 weeks after its induction and its toxicity were evaluated. A reduction in the serum prostate-specific antigen (PSA) value was observed in 12 patients (46.2 %), while two cases (7.7 %) achieved more than 50 % reduction in PSA. Two patients (7.7 %) required discontinuation of UFT administration because of side effects (grade 2 exanthema in one patient and grade 2 nausea in one patient). A PSA response to UFT was observed, especially in patients older than 75 years and/or whose Gleason score was 8 or less. Our data indicate that UFT administration as a fourth-line therapy was tolerable and effective to some degree in patients with CRPC who had already received CAB therapy, alternative antiandrogen therapy, and EMP therapy. It can be used, even in patients aged more than 75 years old, without any loss of efficacy or effect on their activities of daily life, and can be regarded as a treatment option for patients with advanced prostate cancer.

Significance of Uracil/Tegafur for Preventing Intravesical Recurrence of Non-Muscle Invasive Urothelial Carcinoma of the Bladder

Background: The objective of this study was to assess the role of uracil/tegafur (UFT) and its metabolite γ-butyrolactone (GBL), a potent inhibitor of angiogenesis, in the prevention of intravesical recurrence in patients with non-muscle invasive urothelial carcinoma of the bladder (NMIUCB). Patients and Methods: This study included 48 patients with NMIUCB following complete transurethral resection who were randomly divided into 27 receiving UFT therapy (group A) and 21 without any adjuvant therapies (group B). Serum levels of GBL, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor and interleukin-8 were measured. Results: There was no significant difference in the intravesical recurrence-free survival between groups A and B. Despite the lack of significant differences in serum levels of vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor and interleukin-8, serum GBL in group A was significantly greater than in group B. Multivariate analysis identified tumor size as an independent predictor of intravesical recurrence irrespective of the other factors examined. Conclusions: Despite the significant induction of GBL, adjuvant UFT therapy failed to show a preventive effect on intravesical recurrence of NMIUCB. Therefore, we should consider enhancing the anti-angiogenic effect of GBL using an alternative administration schedule of UFT.

Protective effects of water-soluble low-molecular-weight β-(1,3-1,6)D-glucan purified from Aureobasidium pullulans GM-NH-1A1 against UFT toxicity in mice

5-Fluorouracil and its derivatives are widely used in the treatment of a variety of tumours. However, their use is associated with gastrointestinal toxicity, myelotoxicity and immune toxicity. In this study, we examined the protective effects of low-molecular-weight beta-glucan isolated from Aureobasidium pullulans GM-NH-1A1 against toxicity of UFT (combination of tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) and uracil) in mice bearing colon 26 tumours. UFT was administered orally at 50 mg/kg once daily for 14 days alone or with orally administered low-molecular-weight beta-glucan, 25, 50 and 100 mg/kg twice daily. Tumour growth was inhibited equally in all treatment groups. Onset of diarrhoea, which started on day 9 of UFT administration, was delayed by concomitant administration of the beta-glucan (50 and 100 mg/kg twice daily). Histological analysis showed that damage to small-intestine villi by UFT was inhibited by the orally administered beta-glucan. Oral administration of low-molecular-weight beta-glucan prevents gastrointestinal mucositis associated with UFT therapy without interfering with its anti-tumour activity.

Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil

The study present the results of the dose-setting study of concomitant weekly administration of paclitaxel and tegafur·uracil (UFT) for metastatic breast cancer. Eligible patients who entered the study underwent two or more courses of weekly paclitaxel + UFT therapy as the protocol therapy. The initial dose (level 1) was paclitaxel, 80 mg/m(2) and UFT, 400 mg/day. At level 2, paclitaxel remained the same, but UFT was increased to 600 mg/day. At level 3, only paclitaxel was increased to 90 mg/m(2). Twelve patients were enrolled in this study between September 2000 and September 2002. Three patients were assigned to level 1. Grade 3 liver dysfunction (increased aspartate aminotransferase and alanine aminotransferase) was noted in one patient and grade 4 neutropenia was noted in one patient, showing that dose-limiting toxicity was detected in 2/3 patients. In accordance with the protocol, UFT was fixed at 400 mg/day and paclitaxel was decreased to 60 mg/m(2) at level -1, and then increased to 70 mg/m(2) at level 0. The overall effective rate after completion of two courses was 33% (3/9) including one case of complete response and two cases of partial responses. The remaining patients presented with stable diseases and no patient had progressive disease. In this study, weekly paclitaxel with concomitant UFT was administered. The recommended doses of paclitaxel and UFT were determined to be 70 mg/m(2) and 400 mg/day, respectively. As the toxicity profile shows, the highest toxicity level of this regimen was neutropenia and liver dysfunction, and dose-limiting toxicity was neutropenia.

The effect of neoadjuvant therapy on the 5-fluorouracil metabolic and relative enzymes of oral squamous cell carcinoma

To assess the effect of neoadjuvant therapy using tegafur/uracil (UFT) and radiation therapy on the 5-fluorouracil (5-FU) metabolic and relative enzymes, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in oral squamous cell carcinoma (OSCC), we examined the mRNA expression and immunohistochemical staining status of these enzymes using 17 surgical specimens. Seven patients did not receive any neoadjuvant therapy and 10 were treated with UFT and local irradiation therapy. Our result showed that the mRNA expression of these enzymes in neoadjuvant group was not significantly different from that of non-treated group using real-time quantitative PCR. To confirm the protein expression, we also carried out immunohistological staining of TS and DPD two key enzymes in the 5-FU metabolism, using the same specimens. Immunohistological staining status did not correspond to the results of mRNA analysis completely, though no significant difference between the groups was observed. Furthermore, no significant relationship between the UFT administration period and mRNA expression of the 5-FU metabolic enzymes was observed in neoadjuvant therapy group and also the distribution of the enzyme mRNA expression levels was similar to that of non-treated group. The results suggested that the neoadjuvant therapy of OSCC might not affect the expression status of 5-FU metabolic and relative enzymes in surgical tumor samples and the tumor tissues might serve as a useful specimen source to analyze the expression status of the 5-FU metabolic and relative enzymes and to determine the prospective efficiency of 5-FU-based adjuvant chemotherapy.

Cost-effectiveness of adjuvant chemotherapy with uracil–tegafur for curatively resected stage III rectal cancer

Recently, the National Surgical Adjuvant Study of Colorectal Cancer in Japan, a randomised controlled trial of oral uracil–tegafur (UFT) adjuvant therapy for stage III rectal cancer, showed remarkable survival gains, compared with surgery alone. To evaluate value for money of adjuvant UFT therapy, cost-effective analysis was carried out. Cost-effectiveness analysis of adjuvant UFT therapy was carried out from a payer's perspective, compared with surgery alone. Overall survival and relapse-free survival were estimated by Kaplan–Meier method, up to 5.6 years from randomisation. Costs were estimated from trial data during observation. Quality-adjusted life-years (QALYs) were calculated using utility score from literature. Beyond observation period, they were simulated by the Boag model combined with the competing risk model. For 5.6-year observation, 10-year follow-up and over lifetime, adjuvant UFT therapy gained 0.50, 0.96 and 2.28 QALYs, and reduced costs by $2457, $1771 and $1843 per person compared with surgery alone, respectively (3% discount rate for both effect and costs). Cost-effectiveness acceptability and net monetary benefit analyses showed the robustness of these results. Economic evaluation of adjuvant UFT therapy showed that this therapy is cost saving and can be considered as a cost-effective treatment universally accepted for wide use in Japan.

UFT and its metabolite γ-butyrolactone (GBL) inhibit angiogenesis induced by vascular endothelial growth factor in advanced cervical carcinoma

The aim of this study was to evaluate the potential role of UFT and its metabolite gamma-butyrolactone (GBL) for inhibition of angiogenesis induced by vascular endothelial growth factor (VEGF) in advanced cervical carcinoma by the determination of serum GBL and VEGF, and by immunohistochemical staining to assess VEGF protein expression, before and after UFT therapy. The subjects were 35 patients with an advanced cervical carcinoma and five healthy volunteers between 2002 and 2003 at Hiroshima University Hospital, under informed consent. The patients received two courses of oral fluoropyrimidine (UFT) therapy at a dose of 600 mg/day for 5 and 2 days off treatment. Serum GBL and VEGF was measured before and after UFT therapy by the gas chromatography mass spectrometry and ELISA-kit in 22 patients and five healthy volunteers, respectively. Immunohistochemical detection of VEGF protein was done in 35 cervical cancers. Results The mean serum GBL level before and after UFT therapy was 21.9 +/- 2.3 and 79.3 +/- 6.2 ng/ml, respectively, and it was significantly increased after UFT administration (P < 0.0001). The mean serum VEGF level before and after UFT therapy was 95.3 +/- 28.1 and 67.5 +/- 11.2 pg/ml, respectively, and it was decreased by UFT administration. In 20 out of 33 (66.6%) patients who were detected with VEGF protein, VEGF protein expression was decreased by UFT therapy. The Delta GBL value (GBL after UFT--GBL before UFT therapy) showed a significant inverse correlation with Delta VEGF value (VEGF after therapy--VEGF before therapy) (r2 = 0.940). Our findings suggest that UFT and its metabolite GBL inhibit angiogenesis induced by VEGF to have an antitumor effect on cervical cancer.

Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.

Contrasting effects of extended low dose versus standard dose shorter course UFT chemotherapy on microscopic versus macroscopic established tumors: Implications for optimal postoperative adjuvant chemotherapy

Given such differences as relative tumor burden, the optimal dose and schedule for postoperative adjuvant chemotherapy of microscopic disease might be expected to differ significantly from therapy of advanced higher volume disease. We investigated this hypothesis by determining the optimal dose and schedule of the 5-FU pro-drug, UFT, for treatment of early versus later stage disease models of the Lewis lung carcinoma (LLC). Postoperative adjuvant therapy of early stage disease was modeled by intravenous injection of LLC cells and initiating therapy one day later, thus simulating the presence of micrometastases at the time of surgery. As a model of 'late' stage disease, a LLC fragment was implanted subcutaneously and UFT therapy was initiated when the tumor was firmly established and had grown to >5 mm in size. A number of UFT dosing protocols were evaluated such as short-term (daily, for 7 days) maximum tolerated dosing (MTD), e.g. 31 mg/kg/day, or a much longer-term (e.g., daily, for up to 60 days) repetitive dosing using doses such as 24 mg/kg/day (the MTD) or lower. The long-term consecutive administration of UFT at relatively low minimally toxic dose levels is a superior dosing regimen in the postoperative adjuvant chemotherapy model; in contrast, the short-term higher dose protocols were superior for treatment of more advanced, established cancer. In addition, the efficacy of UFT in an adjuvant setting is more effective when drug administration is continued for longer periods and when treatment is initiated at progressively earlier time points, after disease establishment.

Adjuvant UFT therapy does not increase survival in people with resected stage 1 non-small cell lung cancer

Adjuvant UFT therapy does not increase survival in people with resected stage 1 non-small cell lung cancer

Clinical outcome of oral uracil/tegafur (UFT) therapy for patients with hormone refractory prostate cancer

There is no standard therapeutic strategy for advanced hormone refractory prostate cancer after the initial hormonal therapy fails. The objective of this study was to retrospectively evaluate the clinical outcome of the oral anticancer agent, uracil/tegafur (UFT) for patients with hormone refractory prostate cancer. This study included 68 patients with hormone refractory prostate cancer treated by oral administration of UFT (300-600 mg/day). All patients had previously received maximum androgen blockade (MAB) which failed. In this series, response was defined as more than 50% decrease from the baseline prostate specific antigen (PSA) value at the start of second line therapy. Upon initiating administration of UFT, a reduction in PSA value was observed in 41 of the 68 patients (60.3%), among whom 13 (19.1%) were regarded as responders; however, PSA value continued to increase in the remaining 27 (39.7%). Median duration of PSA response was 7 months (range 1-22 months). During the observation period, there were no severe side effects due to UFT administration, but 7 patients transiently presented appetite loss. Patients without bone metastasis at the initial diagnosis or whose serum PSA value at the start of UFT therapy was less than 2.0 ng/ml showed a significantly higher incidence of PSA response to UFT; however, other factors examined had no significant impact on PSA response to UFT. Furthermore, cause-specific survival in responders to UFT therapy was significantly better than that in non-responders. These findings suggest that administration of UFT after the failure of initial MAB therapy can achieve a comparatively favorable PSA response without severe side effects; therefore, it may be worthy to consider administering UFT to patients with hormone refractory prostate cancer.

P-498 Impact of third-line Tegafur/Uracil UFUR, UFT therapy on patientswith advanced non-small-cell lung cancer who had failed prior gemcitabine-CDDP and docetaxel regimen: A case series report of 36 patients in Taiwan

P-498 Impact of third-line Tegafur/Uracil UFUR, UFT therapy on patientswith advanced non-small-cell lung cancer who had failed prior gemcitabine-CDDP and docetaxel regimen: A case series report of 36 patients in Taiwan

Multicenter phase II study of pre-administrated uracil/tegafur (UFT) plus gemcitabine for unresectable/recurrent pancreatic cancer

4152 Background: Gemcitabine (GEM) remains the standard of care for advanced pancreatic cancer. The rationale to develop the pretreatment of 5-fluorouracil (5-FU) and GEM combination in pancreatic cancer is based on that 5-FU is a major mediator of GEM uptake. Our objective was to evaluate the efficacy and toxicity of pre-administration of UFT (uracil/tegafur: prodrug of 5-FU) and GEM combination therapy for unresectable/recurrent pancreatic cancer in outpatient setting. Methods: Major eligibility criteria: histologically or cytologically proven pancreatic adenocarcinoma, measurable disease, age 20–80 yrs, good performance status (50 -100 in KPS), normal renal, liver, and bone marrow function, capable oral intake, and written informed consent. UFT (250 mg/ m2/day) was orally administrated from day 1 through day 6 and from day 8 through 13, and GEM (800 mg/m2, div/30min) was administrated on day 7 and 14, and one week rest every 3 weeks based on the result of the previous phase I study. Results: 36 pts (24 male, 12 female) were enrolled (median age, 63.8 yrs). 24 pts were considered to be unresectable (15: liver metastasis, 2: lymph node, 7: locally advanced). 12 pts were recurrent pancreatic cancer after curative surgery (7: liver metastasis, 3: lung metastasis, 2: local reccuremce). 32 pts were evaluable for efficacy and were treated at outpatient clinic. Median KPS was 90 (range 100 - 50). Median number of courses administrated was 4 (range 1–20). There were 8 partial responses (25%), 18 pts (56%) had stable disease, and 6 pts (19%) had a progression. Reduced CA19–9 level less than a half of that at starting time was observed in 11 pts (34%). Median progression-free survival time was 6.7 months (range 1–21). Median survival time was 8.3 months (range 1.5–26). Grade 3 toxicities were leucopenia (19%), neutropenia (12%), thoronbocytopenia (3%), nausea (3%), and liver dysfunctions (3%). There was no Grade 4 toxiciety. Conclusion: Pre-administrated UFT plus GM is a promising treatment for unresectable/recurrent pancreatic cancer due to a favorable prognosis and less toxicity in outpatient setting. No significant financial relationships to disclose.

Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials.

The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials. We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy. Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild. This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.

A randomized trial of postoperative UFT therapy in p stage I, II non-small cell lung cancer: North-east Japan Study Group for Lung Cancer Surgery

Objective: A prospective randomized trial was performed to investigate the prognostic advantage of postoperative adjuvant chemotherapy in patients with resected stage I–II non-small cell lung cancer (NSCLC). Patients and methods: From March 1992 to December 1994, 221 patients with completely resected stage I–II primary NSCLC were enrolled and randomly assigned to two groups, as follows: 2-year oral administration of Uracil plus Tegafur (UFT) (adjuvant group, 109 patients), and surgical treatment alone (control group, 110 patients). Results: The overall 5-year survival rates were 79% for the adjuvant group and 75% for the control group, and there was no statistical significance. The 5-year disease-free survival rates were 78% for the adjuvant group and 71% for the control group, and there was also no statistical significance. There have been seen no severe complications in the adjuvant group. The mean total dosages of UFT were about 75% of maximum basic amount. Conclusions: The UFT regimen was feasible. However, we have not observed any survival benefit in the adjuvant group. Larger trials are needed to confirm the effect of UFT to patients with resected NSCLC.

Tumor dihydropyrimidine dehydrogenase activity in advanced cervical carcinoma

Patients with advanced cervical carcinoma were treated with oral fluoropyrimidine (UFT) as neoadjuvant chemotherapy and its antitumor effect was examined. The relationship between thymidylate synthase (TS) or dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue and apoptosis was also investigated. The subjects were 56 patients with advanced cervical carcinoma. The patients received two courses of therapy consisting of UFT at a dose of 600 mg/day for 5 days and 2 days off treatment. The TS and DPD activity in tumor tissue was measured before and after UFT administration by the FdUMP binding assay and a catalytic assay in 38 patients, respectively. Apoptosis was detected by the TUNEL method, and the apoptotic index (AI) was calculated. Tumor tissue activity of TS or DPD was unrelated to clinicopathologic factors or to the activity of the other enzyme. The mean tumor TS and DPD activity before UFT administration was 5.42+/-3.92 pmol/g tissue and 206.54+/-128.58 pmol/mg/min, respectively, and the levels of these enzymes in two patients showing an antitumor effect were below the mean values. The AI increased from 1.10+/-0.57% before UFT to 1.27+/-0.81% afterwards, and the DPD activity before UFT showed an inverse relationship with the AI after UFT (r=-0.6938). In patients with DPD activity below the median value (186.92 pmol/mg/min), UFT administration significantly caused an increase of the AI (p=0.0002). These results indicate that the DPD activity of advanced cervical carcinoma is a determinant of sensitivity to UFT, suggesting an association between UFT therapy and the induction of apoptosis.

Prolongation of survival period and improvement of cancer cachexia by long-term administration of UFT.

We assayed the antitumoral and anticachectic activity of an oral fluoropyrimidine, UFT using the Colon-26-bearing murine cachexia model in terms of the survival period and parameters corresponding to clinical symptoms. Tumor growth was inhibited by UFT dose-dependently at the dose range of 12.5-25.0 mg/kg per day. Although UFT did not show significant growth inhibition at 15.0 and 12.5 mg/kg to which UFT gave little toxicity, the survival period was shown to be superior to the case of maximum tolerated dose (25.0 mg/kg per day). Next, we compared the maximum increase of life span (ILS) value for an administration schedule of continuous 9 days and 5 weeks which mimics the clinical schedule and found that the ILS value in the latter group was superior to the former and UFT improved cachexia, in the same manner. In the following experiments, we have clarified that UFT decreased the level of both plasma interleukin-6 (IL-6) and tumorous prostaglandin E2 (PGE2) and it highly accelerated IL-6 production from Colon-26. These findings suggest that UFT therapy, in low-toxic dose, could be useful to cachectic patients with poor performance status.