Using oral tegafur/uracil (UFT) plus leucovorin as adjuvant chemotherapy in stage II colorectal cancer: a propensity score matching study from Taiwan.

BACKGROUND: Early-stage colorectal cancer had excellent outcomes after curative resection, typically. However, a perplexing survival paradox between stage II and stage III was noted. This paradox could be influenced by the administration of routine postoperative adjuvant chemotherapy and the presence of high-risk factors in stage II CRC. The objective of the study was to investigate the influence of high-risk factors on patients with stage II CRC and assess the efficacy of oral tegafur/uracil (UFT) plus leucovorin as adjuvant chemotherapy for stage II CRC patients. METHODS: A retrospective study was conducted using propensity score matching at a single medical institution. A total of 1544 patients with stage II colorectal cancer who underwent radical surgery between January 2004 and January 2009 were included. The intervention used was tegafur/uracil plus leucovorin as adjuvant chemotherapy. The main outcome measures were disease-free survival and overall survival. RESULTS: After propensity score matching, 261 patients were included in three groups: no-treatment, half-year treatment, and one-year treatment. The clinical characteristics of each group tended to be more consistent. The Cox proportional hazard models showed that tegafur/uracil treatment or not was a significant independent factor for oncological outcome. Kaplan-Meier analysis also showed significantly better disease-free survival and overall survival. Further investigation revealed that tegafur/uracil duration was an independent factor for oncological outcome. While the survival curve did not reach statistical significance, the one-year UFT treatment group demonstrated the best treatment trend. CONCLUSIONS: This study suggests that tegafur/uracil plus leucovorin is a feasible adjuvant chemotherapy regimen for patients with stage II colorectal cancer after curative surgical treatment. Prolonged tegafur/uracil plus leucovorin treatment for 12 months showed a trend towards better outcomes in patients with stage II colorectal cancer.

Prognostic factors in patients with high-risk stage II colon cancer after curative resection: a post hoc analysis of the JFMC46-1201 trial.

PURPOSE: The goal of the current study was to identify prognostic factors for disease-free survival (DFS) and overall survival (OS) in high-risk stage II colon cancer. METHODS: The subjects were patients with histologically confirmed stage II colon cancer undergoing R0 resection who met at least one of the following criteria: T4, perforation/penetration, poorly differentiated adenocarcinoma, mucinous carcinoma, and < 12 examined lymph nodes. Patients self-selected surgery alone or a 6-month oral uracil and tegafur plus leucovorin (UFT/LV) regimen. Serum CEA mRNA at ≥ 24 h after surgery and < 2 weeks after registration was also examined as a potential prognostic factor for stage II colon cancer. This study is registered with UMIN-CTR (protocol ID: UMIN000007783). RESULTS: 1880 were included in the analysis to identify prognostic factors for DFS and OS in patients with high-risk stage II colon cancer. In multivariate analyses, gender, depth of tumor invasion, extent of lymph node dissection, number of examined lymph nodes, and postoperative adjuvant chemotherapy (POAC) emerged as significant independent prognostic factors for DFS. Similarly, multivariate analysis showed that age, gender, depth of tumor invasion, perforation/penetration, extent of lymph node dissection, number of examined lymph nodes, and POAC were significant independent prognostic factors for OS. Univariate analyses showed no significant difference in DFS or OS for CEA mRNA-positive and mRNA-negative cases. CONCLUSION: This study showed that gender, depth of tumor invasion, extent of lymph node dissection, number of examined lymph nodes, and lack of use of POAC were significant independent prognostic factors in stage II colon cancer.

Comparable efficacy and safety of COVID-19 vaccines for patients receiving tegafur-uracil as postoperative adjuvant chemotherapy.

PURPOSE: Many effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed, but a weaker response in individuals undergoing anticancer treatment has been reported. This study evaluates the immunogenic status and safety of SARS-CoV-2 vaccines for patients with non-small-cell lung cancer (NSCLC), receiving tegafur-uracil (UFT) as postoperative adjuvant chemotherapy. METHODS: The subjects of this prospective study were 40 patients who underwent surgery for NSCLC and received SARS-CoV-2 vaccines postoperatively. We compared the antibody titers of SARS-CoV-2 vaccines and the adverse events between patients who received adjuvant UFT and patients who did not. RESULTS: The mean anti-S1 IgG titers were not significantly different between the UFT and without-UFT groups (mean optimal density, 0.194 vs. 0.205; P = 0.76). Multivariate analysis identified the period after the second vaccination as an independent predictor of anti-S1 IgG titer (P = 0.049), but not the UFT status (with or without-UFT treatment; P = 0.47). The prevalence of adverse events did not differ significantly between the groups, and no severe adverse events occurred. CONCLUSIONS: The efficacy and safety of the SARS-CoV-2 vaccines for NSCLC patients who received postoperative adjuvant UFT chemotherapy were comparable to those for NSCLC patients who did not receive postoperative adjuvant UFT chemotherapy. CLINICAL TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN) in Japan (UMIN000047380).

Predictive marker for exposure-driven haematological toxicity of tegafur-uracil and proposed modified-dosage regimen by pharmacometric approach in rats.

Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5­fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required.Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts.Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively.Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.

Randomized phase II study of tegafur-uracil/leucovorin versus tegafur-uracil/leucovorin plus oxaliplatin after curative resection of high-risk stage II/III colorectal cancer (SOAC-1101 trial).

PURPOSE: This randomized phase II trial compared tegafur-uracil/leucovorin (UFT/LV) plus oxaliplatin (TEGAFOX) to UFT/LV as adjuvant chemotherapy for patients with high-risk stage II/III colorectal cancer. METHODS: From 2010 to April 2015, 159 patients who underwent curative resection were randomly assigned to receive TEGAFOX (85 mg/m2 oxaliplatin on days 1 and 15, 300 mg/m2/day UFT and 75 mg/day LV on days 1-28, every 35 days for five cycles) or UFT/LV. The primary study endpoint was disease-free survival. RESULTS: The 3-year disease-free survival rate was 84.2% in the TEGAFOX arm, versus 62.1% for UFT/LV. The stratified hazard ratio for disease-free survival for TEGAFOX compared to UFT/LV was 0.338 (P < 0.01). The incidence of any-grade adverse events was significantly higher in the TEGAFOX arm (96.1%) than in the UFT/LV arm (76.6%; P < 0.01). The rates of any-grade neutropenia, thrombocytopenia, aspartate aminotransferase/alanine aminotransferase elevation, and peripheral sensory neuropathy were higher in the TEGAFOX group, whereas the incidence of grade ≥ 3 adverse events did not differ between the groups. CONCLUSIONS: TEGAFOX is an additional adjuvant chemotherapy option for high-risk stage II/III colorectal cancer. TRIAL REGISTRATION: UMIN ID: 000007696, date of registration: April 10, 2012.

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

BACKGROUND: Adjuvant 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. METHODS: Patients 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. RESULTS: From 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. CONCLUSIONS: This 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.

MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression.

BACKGROUND: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. PATIENTS AND METHODS: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. RESULTS: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. CONCLUSION: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).

PURPOSE: Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection. METHODS: The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints. RESULTS: Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (-9.06%, 90% confidence interval -17.06 to -1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK. CONCLUSIONS: As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS.

Efficacy and short-term outcomes of preoperative chemoradiotherapy with intermittent oral tegafur-uracil plus leucovorin in Japanese rectal cancer patients: a single center experience retrospective analysis.

BACKGROUND: Various types of preoperative chemoradiotherapy (CRT) have been established for rectal cancer; thus, Physicians will need to refine the selection of appropriate preoperative CRT for different patients since there are various treatment regimens. Oral tegafur-uracil (UFT) plus leucovorin (LV) is commonly used to treat rectal cancer in Japan. Oral chemotherapy offers patients many potential advantages. Since 2008, we have been performing preoperative CRT with intermittent oral UFT plus LV in locally advanced rectal cancer patients to prevent postoperative local recurrence. Here, in a retrospective analysis, we evaluated the efficacy and short-term outcomes of preoperative CRT with intermittent oral UFT plus LV. METHODS: We analyzed data from 62 patients with locally advanced rectal cancer, including 31 patients who underwent preoperative CRT between 2009 and 2013 (the CRT group) and 31 patients who were treated with surgery alone between 2001 and 2008 (the non-CRT group). Clinicopathologically, both groups included patients with rectal cancer at clinical tumor stages III-IV or clinical node stages 0-III. In the CRT group, curative operations were performed ≥8 weeks after CRT. Patients were concomitantly treated with 2 cycles of oral UFT (300 mg/m2/day, days 1-14 and 29-42) plus LV (75 mg/day, days 1-14 and 29-42) and 45 Gy of radiotherapy. Chemotherapy was repeated every 28 days, followed by a 2-week break. RESULTS: The completion rate of CRT was high at 94% (n = 29/31). The downstaging rate of CRT was 61% (n = 19/31). The pathological complete response rate was 6.5% (n = 2/31). Significant differences were observed in the 3-year local recurrence rate between the two groups (P < 0.05). CONCLUSIONS: Preoperative CRT with intermittent oral UFT plus LV appears to be a tolerable and effective treatment for Japanese patients with rectal cancer. A further investigation of a diversification of preoperative CRT for Japanese rectal cancer patients is required.

Feasibility Trial of Oral UFT after Platinum-based Adjuvant Chemotherapy in Patients with Resected Non-small Cell Lung Cancer.

We evaluated the feasibility of maintenance treatment using UFT (a combination of tegafur and uracil) after adjuvant platinum-based chemotherapy in patients with resected lung cancer. A prospective feasibility trial was conducted. Between 2010 and 2014, UFT was administered for 2 years sequentially after platinum-based adjuvant chemotherapy in 24 patients with resected Stage IIA-IIIA non-small cell lung cancer. The safety of UFT and the rate of treatment completion were then evaluated. The prior platinum-based chemotherapy regimens consisted of cisplatin+vinorelbine in 16 patients, carboplatin+paclitaxel in 5 and carboplatin+S-1 in one. During the subsequent UFT administration, a total of 3 patients required a dose reduction because of Grade 1 blood-stained sputum, Grade 2 numbness, and Grade 2 constipation, in one patient each. Eleven patients underwent the planned 2-year UFT administration, but 12 patients could not because of the recurrence of lung cancer in 5 patients, metachronous malignancy in one, and toxicities in 6. The completion rate for UFT administration was 64.7% (11/17). The most common type of toxicity was gastrointestinal toxicities. All of the toxicities were grade 1 or 2, and no severe toxicities were observed. UFT treatment after platinum-based chemotherapy was revealed to be feasible.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

N2 Lymph Node Metastasis Is a Useful Predictor of Recurrence in Patients With Stage III Rectal Cancer Undergoing Adjuvant Chemotherapy Using Tegafur-uracil/leucovorin.

BACKGROUND/AIM: Fluoropyrimidine therapy or oxaliplatin combination therapy is recommended for patients with stage III colorectal cancer as adjuvant chemotherapy (AC). However, the criterion for selecting these regimens is still unclear in patients with stage III rectal cancer (RC). In order to select an appropriate regimen of AC for such patients, it is needed to identify characteristics associated with tumor recurrence. PATIENTS AND METHODS: The records of 45 patients with stage III RC undergoing AC using tegafur-uracil/leucovorin (UFT/LV) were retrospectively reviewed. The cut-off value of characteristics was determined using a receiver operating characteristic curve for recurrence. Univariate analyses using Cox-Hazard model for predicting recurrence were performed with clinical characteristics. Survival analysis was performed using Kaplan-Meier method and log-rank test. RESULTS: Thirty patients (66.7%) completed AC using UFT/LV. Fifteen patients (33.3%) did not complete AC because of adverse events, tumor recurrence and others. Sixteen patients (35.6%) had recurrence. Univariate analyses revealed that lymph node metastasis (N2/N1) (p=0.002) was associated with tumor recurrence. Survival analysis showed that lymph node metastasis (N2/N1) could stratify recurrence-free survival (p<0.001). CONCLUSION: N2 lymph node metastasis can predict tumor recurrence in patients with stage III RC undergoing AC using UFT/LV.

Comparison of neoadjuvant oral chemotherapy with UFT plus Folinic acid or Capecitabine concomitant with radiotherapy on locally advanced rectal cancer.

AIM: To evaluate the differences in treatment response and the impact on survival with both oral agents (UFT and Capecitabine) as neoadjuvant chemotherapy administered concomitantly with radiotherapy. BACKGROUND: There are still no studies comparing the use of neoadjuvant oral chemotherapy either with UFT plus Folinic acid or Capecitabine concomitant with radiotherapy in locally advanced rectal cancer (LARC). MATERIALS AND METHODS: A set of 112 patients with LARC were treated preoperatively. GROUP 1 - 61 patients underwent concomitant oral chemotherapy with Capecitabine (825 mg/m(2) twice daily). GROUP 2 - 51 patients submitted to concomitant oral chemotherapy with UFT (300 mg/m(2)/d) + Folinic acid (90 mg/d) and radiotherapy. 57.1% of patients were submitted to adjuvant chemotherapy. RESULTS: GROUP 1: acute toxicity - 80.3%; pathological complete response (pCR) - 10.5%; tumor downstaging (TD) - 49.1%; nodal downstaging (ND) - 76.5%; loco-regional response (LRR) - 71.9%; toxicity to adjuvant chemotherapy - 75%. GROUP 2: acute toxicity - 80.4%; pCR - 28%; TD - 62%; ND - 75.6%; LRR - 78%; toxicity to adjuvant chemotherapy - 56%. There was no difference in survival nor loco-regional control between the groups. CONCLUSIONS: Patients treated with neoadjuvant oral UFT + Folinic acid had a higher rate of pathologic complete response than patients treated with Capecitabine concomitant with radiotherapy. There were no differences in downstaging, LRR, toxicity, survival or loco-regional control between both groups. There was a trend to a higher rate of toxicity to adjuvant chemotherapy in the Capecitabine group.

Effects of bolus injection of 5-fluorouracil on steady-state plasma concentrations of 5-fluorouracil in Japanese patients with advanced colorectal cancer.

OBJECTIVES: The irinotecan (CPT-11) + 5-fluorouracil (5-FU)/leucovorin (LV) + UFT/LV chemotherapy, in which repetitive oral administration of UFT/LV replaces the infusion of 5-FU/LV in the FOLFIRI regimen, has been proposed previously. In this study, five of 10 patients were injected with a bolus of 5-FU and the other were not injected with it in order to examine the effect of omitting it in terms of pharmacokinetics of 5-FU. METHODS: The treatment consisted of the intravenous infusions of CPT-11 at 100 mg/m(2 )and l-LV at 15 mg/m(2), and the injection of a bolus of 5-FU at 500 mg/m(2) on day 1, and the repetitive oral administration of UFT/LV (300 mg/m(2)/day as tegafur + 75 mg/day of LV) on days 1-5. A total of 13 measurements of the plasma concentrations of uracil, 5-FU and tegafur were made per patient within 48 hr after the start of chemotherapy and the value of area under the concentration-time curve (AUC(0-48)) was evaluated. The plasma concentration was also determined at 2 weeks to assess long-term exposure to 5-FU. RESULTS: The plasma concentrations of 5-FU at 24 hr after the start of treatment were 27.4 ng/mL and 9.4 ng/mL in the patients with and without the bolus injection, respectively. At 48 hr, they were 31.3 ng/mL and 10.4 ng/mL with the AUC(0-48) values of 22.16 mg h/L and 0.65 mg h/L, respectively. The 5-FU was detected in the plasma at 226 hr after the last administration of UFT/LV for the patients with the bolus injection, but not for those without. CONCLUSION: A bolus of 5-FU on day 1 provided long-term exposure to 5-FU.

S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Oral drugs in the treatment of metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common forms of cancer, with an estimated 1.36 million new cases and almost 700,000 deaths annually. Approximately 21% of patients with CRC have metastatic disease at diagnosis. The objective of this article is to review the literature on the efficacy and safety of oral drugs available for the treatment of metastatic colorectal cancer (mCRC). Several such drugs have been developed, and fluoropyrimidines are the backbone of chemotherapy in this indication. They exert their antitumour activity by disrupting the synthesis and function of DNA and RNA. Oral fluoropyrimidines include prodrugs capecitabine, tegafur, eniluracil/5-fluorouracil, tegafur/uracil, tegafur/gimeracil/oteracil and trifluridine/tipiracil (FTD/TPI). Oral drugs offer several advantages over injectable formulations, including convenience, flexibility, avoidance of injection-related adverse events (AEs) and, in some circumstances, lower costs. However, oral drugs may not be suitable for patients with gastrointestinal obstruction or malabsorption, they may result in reduced treatment adherence and should not be co-administered with drugs that interfere with absorption or hepatic metabolism. Oral fluoropyrimidines such as capecitabine, as monotherapy or in combination with oxaliplatin, irinotecan or bevacizumab, are as effective as intravenous 5-fluorouracil (5-FU) in first-line treatment of mCRC. Other oral fluoropyrimidines, such as FTD/TPI, are effective in patients with mCRC who are refractory, intolerant or ineligible for 5-FU. In addition, oral fluoropyrimidines are used in adjuvant treatment of mCRC. Regorafenib is an oral multikinase inhibitor used in patients in whom several previous lines of therapy have failed. Frequent AEs associated with oral drugs used in the treatment of CRC include hand-foot syndrome and gastrointestinal and haematological toxicities.

Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG1001.

BACKGROUND: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. METHODS: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1-14 and 29-42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). RESULTS: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). CONCLUSIONS: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial.

BACKGROUND: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.