UFT Group Research Articles

Risk of cardiovascular disease among different fluoropyrimidine-based chemotherapy regimens as adjuvant treatment for resected colorectal cancer.

BackgroundPatients with colorectal cancer (CRC) are more likely to develop cardiovascular disease (CVD) than those without cancer. Little is known regarding their CV risk after operative chemotherapy. We aimed to compare the risk of CV disease among different fluoropyrimidine derivatives.MethodsWe assembled a nationwide cohort of patients with newly diagnosed CRC between 2004 and 2015 who received fluoropyrimidine-based adjuvant chemotherapy for resected CRC by linking the Taiwan Cancer Registry (TCR), National Health Insurance Research Database (NHIRD), and Taiwan Death Registry (TDR). All eligible patients were followed from CRC diagnosis (index date) until a CV event, death, loss to follow-up, or December 31st 2018, whichever came first. CV outcomes included acute myocardial infarction (AMI), life-threatening arrhythmia (LTA), congestive heart failure (CHF), and ischemic stroke (IS). We used stabilized inverse probability of treatment weighting using propensity score (SIPTW) to balance all covariates among the three chemotherapy groups: tegafur-uracil (UFT), non-UFT, and mixed. In addition, survival analysis was conducted to examine the association between study outcomes and chemotherapy groups.ResultsFrom 2004 to 2015, 10,615 (32.8%) patients received UFT alone, 14,511 (44.8%) patients received non-UFT, and 7,224 (22.3%) patients received mixed chemotherapy. After SIPTW, the UFT group had significantly lower all-cause mortality and cancer-related death rates than the other two chemotherapy groups. However, the UFT group had significantly higher rates of cancer death, ischemic stroke, and heart failure than those of the other two chemotherapy groups. The UFT group also had a significantly higher AMI rate than the mixed group. There was no significant difference in LTA among the three groups. Similar findings were observed in the subgroup analysis (stage II and age <70 years, stage II and age ≥70 years, stage III and age <70 years, stage III and age ≥70 years) as the overall population was observed.ConclusionHigher heart failure and ischemic stroke rates were found in the UFT group than in the other two chemotherapy groups, especially those with stage III CRC and ≥70 years of age. Careful monitoring of this subset of patients when prescribing UFT is warranted.

Type of 5-fluorouracil and risk of cardiovascular events in early-stage colon cancer.

e15596 Background: Older patients with colorectal cancer are at increased risk of developing cardiovascular (CV) disease. 5-FU-based chemotherapy was found to increase CV morbidity; however, whether CV risks differ among different fluorouracil types, including infusional 5-FU, capecitabine, and tegafur-uracil (UFT), remains unclear. We aimed to assess the association between CV morbidities, including myocardial infarction and heart failure, and different 5-FU types in patients with colorectal cancer. Methods: We evaluated patients from Taiwan Cancer Registry linked with national health insurance research database with stage I to III colorectal cancer between January 1, 2004, and December 31, 2014. A multivariate Cox proportional model with age as the time scale was conducted for comparison. UFT alone was set as the control group. Results: In the cohort of 29176 patients (median [interquartile range] age, 65 [43-79] years), 2241 (7.6%) received UFT, 25181 (86.3%) received infusional 5-FU or capecitabine, 1754 (6%) received mixed. Overall, 290 patients were diagnosed with myocardial infarction (1.78 per 1000 person-years) during a median (interquartile range) follow-up of 5.5 years. Compared with those received UFT, those using infusional 5-FU or capecitabine showed no increased risk of myocardial infarction (weighted hazard ratio [HR], 0.84; 95% CI, 0.57-1.24). There were 376 patients diagnosed with heart failure, corresponding to 2.3 per 1000 person-years. The risks of heart failure between the UFT group and infusional 5-FU/capecitabine were similar (weighted HR, 0.9; 95% CI, 0.62-1.31). Conclusions: In this study, we did not observe any increased CV risk using infusional 5-FU or capecitabine compared with UFT alone use.

Adjuvant tegafur-uracil (UFT) or S-1 monotherapy for advanced gastric cancer: a single center experience

BackgroundAdjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur-uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable. The real-world data of adjuvant UFT has less been investigated.MethodsPatients with pathological stage II-IIIB (except T1) gastric cancer receiving adjuvant UFT or S-1 monotherapy after D2 gastrectomy were included. Usage of UFT or S-1 was based on reimbursement policy of the Taiwanese healthcare system. The characteristics, chemotherapy completion rates, and 5-year recurrence-free survival (RFS) and overall survival (OS), were compared between these two groups.ResultsFrom 2005 to 2016, 86 eligible patients were included. Most tumor characteristics were similar between the UFT group (n = 37; age 59.1 ± 13.9 years) and S-1 group (n = 49; age 56.3 ± 10.7 years), except there were significantly more Borrmann type III/IV (86.5% versus 67.3%; p = 0.047) and T4 (56.8% versus 10.2%; p < 0.001) lesions in the UFT group than in the S-1 group. The chemotherapy complete rates were similar in the two groups. The 5-year RFS was 56.1% in the UFT group and 59.6% in the S-1 group (p = 0.71), and the 5-year OS was 78.3% in the UFT group and 73.1% in the S-1 group (p = 0.48). The hazard ratio of adjuvant chemotherapy (S-1 versus UFT) on RFS was 1.25 (95% confidence interval = 0.53-2.94) when Borrmann type and T and N stages were adjusted.ConclusionsThis small cohort study showed adjuvant UFT, and S-1 monotherapy had a comparable long-term outcome for pathological stage II-IIIB gastric cancer following D2 gastrectomy.

Metronomic chemotherapy with tegafur-uracil following radical resection in stage II colorectal cancer

Stage II colorectal cancer has a relatively good prognosis. Adjuvant chemotherapy following surgery is the standard treatment for stage III colorectal cancer but is not routinely recommended for all stage II colorectal cancer patients. We aimed to evaluate the clinical outcomes, treatment results, and prognostic factors in stage II colorectal cancer patients who underwent curative surgery with/without oral tegafur-uracil (UFT). We included stage II colorectal cancer patients who underwent curative surgery and were followed up for at least 5 years after surgery at the National Taiwan University Hospital between January 2008 and December 2012. Excluding patients receiving neoadjuvant therapy, adjuvant therapy other than UFT, and those lost follow-up, patients treated with UFT (UFT group) and those without adjuvant therapy (surgery alone group) were analyzed for their clinical outcomes and prognostic factors. A total of 233 patients were recruited. Of these, 104 (44.64%) underwent only surgery while 129 (55.36%) received adjuvant chemotherapy with oral UFT following surgery. Recurrence or death occurred within 5 years in 60 patients (25.75%), with a significant difference between the surgery alone (36/104, 34.62%) and UFT groups (24/129, 18.61%) (p=0.007). The UFT group demonstrated significantly superior 5-year disease-free (p=0.003) and overall survival rates (p=0.001), respectively. Patient age of ≤35.3 or ˃72.7 years, UFT duration of <486.8 days, 7.1cm<tumor size ≤13.2cm, number of harvested lymph nodes ≤13.5, and mucinous adenocarcinoma were associated with poorer 5-year overall survival. The present data suggest that UFT following curative surgery may be associated with lower recurrence and improved survival in patients with stage II colorectal cancer.

A randomised-controlled trial of 1-year adjuvant chemotherapy with oral tegafur–uracil versus surgery alone in stage II colon cancer: SACURA trial

BackgroundEfficacy of adjuvant chemotherapy in patients with stage II colon cancer is still controversial. The SACURA trial is a randomised-controlled study evaluating the superiority of 1-year adjuvant treatment with oral tegafur–uracil (UFT) to surgery alone for stage II colon cancer. MethodsPatients were randomly assigned to the surgery-alone group or UFT group (UFT at 500–600 mg/day for 5 days, followed by 2-day rest, for 1 year). The primary end-point was disease-free survival (DFS). Target sample size was 2000, determined with one-sided alpha of 0.05, power of 0.9 and assumed hazard ratio (HR) 0.729. ResultsA total of 1982 patients (997 in the surgery-alone group and 985 in the UFT group) were analysed. Median follow-up was 69.5 months, median age was 66 years and for stage IIA/IIB/IIC, the distribution was 84%/13%/3%.The 5-year DFS rate was 78.4% in the surgery-alone group and 80.2% in the UFT group. The HR for DFS was 0.91 (95% confidence interval [CI], 0.75–1.10; p = 0.31); superiority of UFT was not demonstrated. Approximately 9% of patients experienced second cancers, which consist 40.7% of the DFS events. The 5-year relapse-free and overall survival rates of the surgery-alone and UFT group were 84.6% and 87.2% (HR, 0.82; 95% CI, 0.65–1.04) and 94.3% and 94.5% (HR, 0.93; 95% CI, 0.66–1.31), respectively. Subgroup analysis failed to disclose superiority in prognosis of adding UFT to the patients with risk factors for recurrence. ConclusionsSuperiority of 1-year adjuvant UFT over surgery alone was not demonstrated in stage II colon cancer. Patients with risk factors for recurrence did not benefit from UFT. Trial registrationClinicalTrials. Gov. #NCT00392899.

A Multicenter Randomized Controlled Study ofPaclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy inResected Non-Small Cell Lung Cancer.

We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC. In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (armA) or a group receiving orally administered UFT (250mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively. Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63-76] in arm A versus 73% (95% CI: 66-78) in arm B (hazard ratio= 0.92, 95% CI: 0.55-1.41, p= 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio= 0.92, 95% CI: 0.63-1.34, p= 0.50]). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]). As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810).

Randomized phase III trial comparing surgery alone to UFT\u2009+\u2009PSK for stage II rectal cancer (JFMC38 trial)

BackgroundWe conducted a randomized phase III trial comparing tegafur/uracil (UFT) and Polysaccharide-K (PSK) to surgery alone in curatively resected stage II rectal cancer patients.MethodsPatients were randomly assigned to receive either UFT and PSK or surgery alone in a 1:1 ratio with a minimization method to balance the treatment allocation. The primary end point of this study was the disease-free survival (DFS). The secondary end point was the overall survival (OS).ResultsFrom October 2011 to February 2013, 111 patients were registered from 62 institutions. The study was prematurely closed due to poor accrual after reaching 20% of its goal. The patients’ characteristics were similar between the UFT and PSK group and the surgery-alone group. The DFS rate was 76.0% at 3 years and 65.1% at 5 years in the UFT and PSK arm and 84.0% at 3 years and 77.2% at 5 years in the surgery-alone arm. The DFS was slightly worse in the UFT + PSK arm than in the surgery-alone arm, but the difference did not reach statistical significance (log rank p = 0.102). The OS rate was 100% at 3 years and 97.9% at 5 years in the UFT + PSK arm, while that was 100% at 3 years and 93.4% at 5 years in the surgery-alone arm. The OS was similar in the UFT + PSK arm and surgery-alone arm (p = 0.533).ConclusionThe present study suggests that UFT and PSK are not attractive candidates to advance to the next phase III study because the DFS was slightly worse in the UFT and PSK arm than in the surgery-alone arm.

Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial.

e15155 Background: The SACURA trial is a phase III study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer. Superiority of adjuvant treatment with UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). In an additional translational study, we assessed microsatellite instability (MSI) status of cancer tissues and prospectively examined the association of MSI with prognosis in stage II colon cancer patients. Methods: Formalin-fixed, paraffin-embedded samples were prospectively collected from 1026 patients enrolled in the SACURA trial. MSI was evaluated using 5 markers; BAT25, BAT26, D2S123, D5S346, and D17S250. MSI-high (MSI-H) was defined as the presence of instability in more than 20% of the markers. Median follow-up time was 69.6 months. Results: MSI-H, MSI-low (MSI-L) and microsatellite-stable (MSS) was observed in 74 (7.2%), 24 (2.3%), and 928 (90.5%) samples, respectively. Patients with MSI-H was significantly frequent in female, right-sided colon cancers, &gt; 5cm tumors, poor histological type, and elevated CEA. Relapse rate for MSI-H patients (4.1%) was significantly lower than that for MSI-L/MSS cancer (13.4%, p = 0.02). Relapse free survival (RFS) in MSI-H patients was significantly better than in MSI-L/MSS patients (hazard ratio: 0.40, 95%CI: 0.17-0.98, p = 0.045), as well as adjusted results by prognostic factors. The 5-year RFS rates in MSI-H and MSI-L/MSS patients were 92.9% and 84.1%, respectively. Although there was no statistical significance, the 5-year RFS rate in MSI-H patients was tended to be better than that in MSI-L/MSS patients in the surgery alone group (94.3% vs. 83.1%, p = 0.086) as well as in the UFT group (91.7% vs. 85.1%, p = 0.233). Conclusions: MSI was an independent prognostic factor in stage II colon cancers. By considering their favorable RFS, adjuvant chemotherapy for stage II colon cancer patients with MSI-H may be unnecessary. Clinical trial information: NCT00392899.

Recurrence risk factors and outcome stratification in stage II colon cancer patients: A subanalysis of the SACURA trial.

3611 Background: Efficacy of adjuvant chemotherapy for stage II colon cancer is still controversial. We conducted the SACURA trial, a phase III study which evaluated the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone in stage II colon cancer. However, survival benefit of 1-year UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). We herein aimed to identify risk factors for recurrence in the stage II patients “without adjuvant chemotherapy”, and to stratify the prognosis by using these factors. Methods: Among a total of 982 patients without adjuvant chemotherapy enrolled to the SACURA trial, we extracted the factors correlated to recurrence using a univariate and multivariate Cox proportional hazard model. 943 and 935 patients in the surgery alone group and UFT group were divided to subgroups according to the number of risk factors, and the recurrence rate in each subgroup was evaluated. Results: Among the conventional clinicopathological characteristics, the multivariate analysis identified pT4, elevated CEA, and examined lymph nodes less than 12 as significant risk factors for recurrence. The rate of patients with 0, 1, 2, and 3 risk factors were 45.0%, 42.4%, 11.5%, and 1.1%, respectively. The recurrence rate for each subgroup was shown in the table: the recurrence rate increased with number of risk factors, while 10.2% of patients without any risk factors developed recurrence. Difference in the recurrence rate between the treatment groups was significant in patients without risk factor, marginal in patients with 1 risk factor, and none in patients with &gt;1 factors. Conclusions: pT4, elevated CEA, and examined lymph nodes less than 12 were identified as risk factors for recurrence in stage II colon cancer patients. The recurrence rate was divided by the number of these risk factors, but we could not extract the very-low risk group in whom adjuvant therapy is unnecessary. Induction of novel risk factors other than conventional clinicopathological characteristics is recommended. Clinical trial information: NCT00392899. [Table: see text]

Preoperative chemoradiotherapy for advanced lower rectal cancer using SOX+Bev regimen.

708 Background: We have performed preoperative CRT for advanced lower rectal cancer patients using S-1 or UFT. To improve response rate, we are performing phase 2 trial of preoperative CRT using S-1/ Oxaliplatin /Bevacizumab (SOX+Bev) regimen. In this study, we show the results of the trial and the promising predictive factor. Methods: Twenty-five patients (SOX+Bev) and 59 patients (S-1 or UFT) were included in this study. S-1(80mg/m2), UFT(300mg/m2) were administered orally every day on radiation therapy, and S-1(80mg/m2,Oxaliplatin(40-60mg/m2),Bevacizumab(5mg/kg) were administered in SOX+Bev group. Total dose of radiation was 40Gy with four field technique. As a predictive factor, we measured miR-223 with real-time PCR using pre CRT biopsy specimens. Results: Clinical response by RECIST were as follows: SOX+Bev group: CR/PR/SD/PD = 1/21/3/0, S-1/UFT group: CR/PR/SD/PD = 1/32/26/0. Clinical response rate were 88% in SOX+Bev group, higher than 56.0% in S-1/UFT group. Pathological response grade were as follows: SOX+Bev group: 1a/1b/2/3 = 5/4/10/6,S-1/UFT group :1a/1b/2/3 = 13/16/27/3. Pathological response rate was 64% in SOX+Bev group, 51% in S-1/UFT group and there was no significant difference. The pCR rate was 24% in SOX+Bev group, significantly higher than 5% in S-1/UFT group (p &lt; 0.05)B In S-1 group, miR-223 in responder group tended to be higher than non-responder group (p = 0.06). And in SOX+Bev group, miR-223 in Grade 3 group(8.89±9.41) was significantly higher than other group (3.19±4.64) (p = 0.05). Conclusions: Preoperative CRT with SOX+Bev regimen can improve response rate and bring high pCR rate. miR-223 may be promising predictive factor and useful to perform order made therapy. Clinical trial information: 13267.

P1.05-052 An Exploratory Analysis of Postoperative Adjuvant Chemotherapy with Tegafur-Uracil on Survival for Lung Adenocarcinoma

The Eighth Edition of the TNM Classification (TNM 8th) for non-small cell lung cancer (NSCLC) proposes a more detailed classification of primary tumor diameter (T). Tegafur-uracil (UFT) improves survival in patients with stage I adenocarcinoma of the lung based on the results of Japan Lung Cancer Research Group (JLCRG: Kato H, et al. N Engl J Med. 2004). However, it is controversial whether the effect of UFT on survival in each T category be the same when TNM 8th is adopted. This exploratory analysis was performed on the subgroup of 979 eligible patients in JLCRG study. The hazard ratio and the 95% confidence interval (CI) for overall survival in each T category of TNM 8th were estimated using stratified Cox proportional hazards models, stratified by sex and age. The overall survival in each T category was estimated by the Kaplan-Meier method. The UFT group and the observation group were reanalyzed based on the new classifications of T category defined by TNM8th, T1a (T, ≤1 cm), T1b (T, >1 to ≤2 cm), T1c (T, >2 to ≤3 cm), T2a (T, >3 to ≤4 cm), T2b (T, >4 to ≤5 cm), and T3 (T, >5 to ≤7 cm). The major prognostic factors did not differ significantly between these two groups in each T category. The benefits of UFT on overall survival varied in each T category (Table 1). UFT tended to improve survival in each T category defined by TNM 8th, except for T1b, when compared to surgery alone.

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.

Prediction of response to preoperative chemoradiotherapy and establishment of individualized therapy in advanced rectal cancer.

Preoperative chemoradiotherapy (CRT) has become the standard treatment for patients with locally advanced rectal cancer. However, no specific biomarker has been identified to predict a response to preoperative CRT. The aim of the present study was to assess the gene expression patterns of patients with advanced rectal cancer to predict their responses to preoperative CRT. Fifty-nine rectal cancer patients were subjected to preoperative CRT. Patients were randomly assigned to receive CRT with tegafur/gimeracil/oteracil (S-1 group, n=30) or tegafur-uracil (UFT group, n=29). Gene expression changes were studied with cDNA and miRNA microarray. The association between gene expression and response to CRT was evaluated. cDNA microarray showed that 184 genes were significantly differentially expressed between the responders and the non‑responders in the S-1 group. Comparatively, 193 genes were significantly differentially expressed in the responders in the UFT group. TBX18 upregulation was common to both groups whereas BTNL8, LOC375010, ADH1B, HRASLS2, LOC284232, GCNT3 and ALDH1A2 were significantly differentially lower in both groups when compared with the non-responders. Using miRNA microarray, we found that 7 and 16 genes were significantly differentially expressed between the responders and non-responders in the S-1 and UFT groups, respectively. miR-223 was significantly higher in the responders in the S-1 group and tended to be higher in the responders in the UFT group. The present study identified several genes likely to be useful for establishing individualized therapies for patients with rectal cancer.

Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: A randomized controlled trial

Recurrence of hepatocellular carcinoma (HCC) after surgery is frequent, and is an important factor adversely influencing the long-term survival of patients. This prospective study evaluated whether adjuvant chemotherapy with oral tegafur/uracil (UFT) reduces the recurrence rate of HCC. In addition, expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were investigated in resected tumors and nontumorous tissues, and the relationship between their expression and the effectiveness of UFT was examined. A total of 117 patients who underwent curative hepatic resection for HCC were randomly allocated to UFT 400mg/d (n=24, UFT group) or surgery alone (n=56, control group). The primary endpoint was the recurrence-free survival rate, and the secondary endpoint was the overall survival rate. Expression of the DPD and TS genes were quantified with TaqMan reverse transcription-polymerase chain reaction assay using β-actin as an internal standard. The cut-off value was set at the mean value of TS and DPD expression. Among the 61 patients in the UFT group, 37 patients (60.6%) discontinued UFT within 1 month. Recurrence-free survival (p=0.16) and overall survival (p=0.29) were similar in the two groups. In the UFT group, recurrence-free survival did not differ significantly between high-TS (TS>3.6) and high-DPD (DPD>8.9; n=10), and low-TS (TS≤3.6) and low-DPD (DPD≤8.9; n=9) groups. However, there was a significant difference between the two groups in overall survival (p=0.04). Peroral UFT administration fails to prolong the recurrence-free rates and overall survival rates, in comparison with surgery alone. However, oral administration of UFT may improve the survival of HCC patients when the levels of TS and DPD mRNA are low in the tumor tissue.

Oral Adjuvant Chemotherapy with S-1 or Uracil-tegafur versus Surgery Alone in Patients with Biliary Tract Cancer

Abstract Objective: We compared the influence of postoperative adjuvant chemotherapy with oral anticancer drugs (S-1 or uracil-tegafur [UFT]) and the influence of surgery alone on overall survival (OS) and disease-free survival (DFS) in patients with biliary tract cancer. Methods: This retrospective study included 108 patients with gallbladder cancer (n=22) or bile duct cancer (n=86), who underwent curative resection. The patients were divided into surgery alone (n=58), UFT (n=39; 400 mg/m2/day), and S-1 groups (n=11; 80 mg/m2, days 1–28, twice daily), and outcomes and adverse effects were compared. Results: The 2-year DFS rate was significantly higher in the S-1 group than in the surgery alone group for all patients (72.7% vs. 32.8%, p=0.046). For the patients with gallbladder cancer, the 2-year OS and DFS rates were significantly higher in the UFT group than in the surgery alone group (36.4% vs.0%, p=0.033 and 27.4% vs. 0% p=0.032, respectively; log-rank test). For patients with lymph node metastasis, the 2-year OS and DFS rates were significantly higher in the S-1 group than in the surgery alone group (71.4% vs. 18.2%, p=0.039 and 71.4% vs. 18.2%, p=0.026, respectively) Conclusion: Postoperative adjuvant chemotherapy might improve both the OS and DFS rates, particularly in patients with gallbladder cancer and those with biliary tract cancer and lymph node metastasis.

Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial

The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. Epidemiological and Clinical Research Information Network.

Immunochemoradiotherapy for Patients with Oral Squamous Cell Carcinoma: Augmentation of OK-432-Induced Helper T Cell 1 Response by 5-FU and X-ray Irradiation

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Adjuvant chemotherapy with S-1 after curative treatment in patients with head and neck cancer (ACTS-HNC).

6004 Background: To establish the efficacy of adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) after curative treatment in patients with advanced squamous cell carcinoma of the head and neck (SCCHN), we conducted a randomized phase III study to investigate whether S-1 is superior to UFT (uracil/tegafur). Methods: Patients with SCCHN who had received curative treatment and were confirmed to be tumor-free were randomly assigned to receive UFT (300 or 400 mg/day for 1 year) or S-1 (80, 100, or 120 mg/day for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were overall survival (OS), relapse-free survival (RFS), and safety. We estimated that 500 patients were needed to establish the primary end point. Results: From April 2006 through November 2008, a total of 526 patients (262 assigned to UFT; 264 assigned to S-1) were enrolled. The 3-year DFS rate was 66.0% in the UFT group and 64.1% in the S-1 group (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.66 to 1.16; [log-rank], P = .34). The 3-year OS rate was 75% in the UFT group and 82.9% in the S-1 group (HR, 0.64; 95% CI, 0.44 to 0.94; [log-rank], P = .022). The 3-year RFS rate was 63.6% in the UFT group and 68.2% in the S-1 group (HR, 0.81; 95% CI, 0.60 to 1.09; [log-rank], P = .16). There were no significant differences in 3-year DFS or RFS; however, the 3-year OS was significantly better in the S-1 group. The incidence of the following grade 3 or 4 events was significantly higher in the S-1 group: oral mucositis/stomatitis (2.4%), leukopenia (5.2%), neutropenia (3.6%), and thrombocytopenia (5.0%). Conclusions: S-1 was not demonstrated to be superior to UFT in terms of 3-year DFS; however, 3-year OS was significantly better with S-1 than with UFT. Clinical trial information: NCT00336947.

959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (III)1 Apr 2013959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER Katsuhiro Fukuta, Hiromichi Naruyama, Masahito Hirose, Hiroki Kubota, Noriyasu Kawai, Keiichi Tozawa, Kenjiro Kohri, and Kenjiro Kohri Katsuhiro FukutaKatsuhiro Fukuta yatomi, Japan More articles by this author , Hiromichi NaruyamaHiromichi Naruyama yatomi, Japan More articles by this author , Masahito HiroseMasahito Hirose yatomi, Japan More articles by this author , Hiroki KubotaHiroki Kubota yatomi, Japan More articles by this author , Noriyasu KawaiNoriyasu Kawai nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa nagoya, Japan More articles by this author , Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.540AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel-based systemic chemotherapy has been shown to be useful for the management of castration-resistant prostate cancer (CRPC). However, reports on drug therapy for docetaxel-refractory prostate cancer are scarce. We evaluated the effectiveness of UFT (a prodrug of 5-fluorouracil [5-FU]), cisplatin, plus dexamethasone in patients with docetaxel-refractory prostate cancer. METHODS Fifty-six patients with CRPC whose serum prostate-specific antigen (PSA) levels had increased on 3 consecutive measurements during docetaxel-based treatment were included in the analysis. Twenty-five patients received oral UFT and dexamethasone plus intravenous cisplatin (UFT-P therapy) and control group (thirty-five patients) were continued docetaxel therapy. PSA levels were measured once a month to evaluate the treatment response. UFT-P therapy related adverse events and overall survival were also assessed. RESULTS The average age was 72.4 years (range, 51-86 years). The mean initial PSA was 720 ng/ml (range, 1.84-9700). Forty-two patients had bone metastases (UFT group had twenty patients, and control group had thirty-five patients) and sixteen patients had lymph node metastases at the start of therapy. The previous treatment was full extraction in fifteen patients and radiotherapy in six patients. The mean observation periods was 592 days (range, 65-1380 days). During UFT-P therapy, PSA levels decreased in 14 of 25 patients (56%). PSA doubling time (PSADT) decreased in 7 of 11 patients, although their PSA levels were increasing. Including these latter patients, the response rate to UFT-P therapy was 84% (21 of 25 patients). The median survival of UFT-P group and control group (docetaxel continued) was 34 and 21 months, respectively. The median time to PSA progression of UFT-P group and control group were 14 and 6 months, respectively. The adverse events of UFT-P therapy were mild diarrhea (20%), general fatigue (100%), and anorexia (44%). However there were not pancytopenia, and adverse events were all grade 1. Treatment by UFT-P could be continued in all patients. Tumor shrinkage during UFT-P therapy was minimal on imaging studies, although hydronephrosis with lymph node metastasis improved in one patient. CONCLUSIONS Our results suggest that UFT-P therapy is effective against docetaxel-refractoly prostate cancer, with minimal adverse events. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e393 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katsuhiro Fukuta yatomi, Japan More articles by this author Hiromichi Naruyama yatomi, Japan More articles by this author Masahito Hirose yatomi, Japan More articles by this author Hiroki Kubota yatomi, Japan More articles by this author Noriyasu Kawai nagoya, Japan More articles by this author Keiichi Tozawa nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 versus UFT to rectal cancer for personalized therapy (UMIN ID: 000001704).

499 Background: Preoperative chemoradiotherapy (CRT) in rectal cancer reduces the local recurrence rate after operation and preserves the anus, but it is difficult to predict the effects of CRT. Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 vs UFT for rectal cancer was conducted to compare the toxicity and efficacy of CRT using oral DPD-inhibitory fluoropyrimidines (UFT versus S-1, (UMIN ID: 000001704)) in patients with locally advanced rectal cancer. Methods: In this randomized phase II study, during April 2008 to October 2010, rectal cancer patients (n=59) who underwent preoperative CRT were randomly divided into two groups; S-1 group (n=30, 80 mg/m2/day, 5 days/w x 4 w), and UFT (n=29, 300 mg/m2/day, 5 days/w x 4 w). Both groups were combined with 40Gy radiotherapy (2 Gy ×5 days/w × 4 weeks,total 40 Gy). The pathological response rate, clinical response rate by RECIST, and frequency of adverse events of CRT were compared between S-1 group and UFT group. Results: Response to CRT determined by histopathologic examination of surgically resected specimens and RECIST were as follows: responders (grade 2 or 3) were 60% (S-1) and 52% (UFT) (p=0.52). S-1 group showed 54% of response rate in pathological response, whereas UFT group showed 45% (p=0.43). In adverse events, frequence of Grade 2 and 3 diarrhea was significantly higher in S-1 group compared with UFT group. There was no difference between the two groups in compliance (S-1group: 83%, UFT group: 97%). Conclusions: Both S-1 and UFT were safely used for preoperative CRT. S-1 tended to show higher response rate than UFT, although diarrhea in S-1 was higher than in UFT. Clinical trial information: 000001704.