Adjuvant Chemotherapy With UFT/LV Versus UFT/LV Plus PSK in Stage II/III Colorectal Cancer.

BACKGROUND/AIM: Uracil-tegafur+leucovorin (UFT/LV), an oral adjuvant therapy for stage II/III colorectal cancer, is non-inferior to standard weekly fluorouracil and folinate. Although polysaccharide K (PSK) has been evaluated as a postoperative adjuvant colorectal cancer drug, its efficacy remains unclear. This randomized phase II trial compared UFT/LV+PSK with UFT/LV as adjuvant chemotherapy. PATIENTS AND METHODS: Between April 2011 and August 2016, 186 patients who underwent radical resection randomly received 6 months of UFT/LV (Group A: 300 mg/m2/day UFT and 75 mg/day LV, every 35 days for five cycles), 6 months of UFT/LV+PSK (Group B: standard UFT/LV regimen and daily administration of 3 g/day of PSK), or 12 months of UFT/LV+PSK (Group C). The primary endpoint was the 3-year disease-free survival. RESULTS: Groups A, B, and C consisted of 37, 75, and 74 patients, of which treatment was completed by 33 (89.2%), 63 (84.9%), and 53 (70.4%) patients, respectively (p=0.0279). Adverse event incidence for all grades were 59.5%, 52.1%, and 59.2%, and for grade ≥3 were 13.5%, 9.6%, and 9.9%, respectively. The 3-year disease-free survival rates were 72.5%, 82.2%, and 74.2%, respectively, with no significant differences. The preoperative lymphocyte ratio did not significantly differ between groups. CONCLUSION: UFT/LV+PSK is comparable to UFT/LV therapy in terms of prognostic efficacy and reduced adverse effects. Thus, UFT/LV+PSK is a useful adjuvant chemotherapy option for patients with high-risk stage II/III colorectal cancer.

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.

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.

A prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged ≥ 80 years after curative resection of colorectal cancer, the HiSCO-03 study.

PURPOSE: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥ 80 years. We conducted a prospective multi-institutional phase II study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. PATIENTS AND METHODS: Patients with stage III CRC aged ≥ 80 years who underwent curative resection were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1-28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. RESULTS: Sixty-nine patients were enrolled between 2013 and 2021. Of the 69 patients, 65 were included in the analysis. There were 32 males and 33 females with a median age of 82 years (range 80-88 years). In the primary endpoint, administration completion rate was 67.3% (95% confidence interval 54.9-77.6%), and the lower limit of the 95% confidence interval was below the threshold of 60%. 21 patients discontinued treatment because of adverse events (AEs) and refused treatment. The median relative dose intensities were 84% (range 4-100%) for UFT, and 100% (range 4-100%) for LV. Incidence of grade three or higher AEs were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). CONCLUSIONS: The indications for adjuvant UFT/LV therapy for elderly CRC aged ≥ 80 years were considered limited. It is necessary to clarify the background of patients in whom drug administration is discontinued and investigate their impact on long-term prognosis.

Clinical T2N0 Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy plus Local Excision.

INTRODUCTION: Total mesorectal excision is the standard treatment for clinical T2 (cT2) rectal cancer; however, this procedure can result in postoperative dysfunction, decreased quality of life, and stoma creation in some patients. We investigated neoadjuvant chemoradiotherapy (nCRT) plus local excision (LE) as an alternative treatment strategy for patients with cT2N0 rectal cancer. METHOD: Fifty-six patients with cT2N0M0 rectal cancer who exhibited the following characteristics (an anal verge of ≤8 cm, tumor size of <30 mm, well- or moderately differentiated adenocarcinoma on biopsy) underwent LE following nCRT. Chemoradiotherapy was administered at 40 or 45 Gy in 20-25 fractions with concurrent oral UFT (tegafur/uracil; 400 mg/m2) or S-1 (tegafur/gimeracil/oteracil; 80 mg/m2). RESULTS: Fifty-five patients (98%) completed nCRT as planned. Histologically, the excision margin was negative in all patients, and four patients with ypT3 disease underwent total mesorectal excision. Recurrence was observed in 15 patients (27%), local recurrence in 7 (13%), and distant recurrence in 10 (18%). The salvage surgery was possible for the local recurrence group. The 5-year disease-free and overall survival rates were 68.4% and 84.9%, respectively. Multivariate analysis showed that only the tumor regression grade (TRG) was an independent risk factor for recurrence (p = 0.025). Although 7 (26%) out of 27 patients with a TRG of 3 or 4 developed local recurrence and 6 (22%) had distant metastasis, 25 patients with a TRG of 1 or 2 did not exhibit local recurrence, and only 1 (4%) experienced distant metastasis. CONCLUSION: nCRT plus LE may be an alternative treatment for patients with cT2N0 rectal cancer who achieved a TRG of 1 or 2. However, additional treatment was required in patients who achieved a TRG of 3 or 4.

A case of hepatocellular carcinoma with long-term survival by multidisciplinary treatment for cranial and skeletal muscle metastases.

We report a case in which multidisciplinary treatment was effective for hepatocellular carcinoma (HCC) with cranial and skeletal muscle metastases. A 55-year-old male with HCC received sorafenib for lung metastases. He was admitted to our hospital due to the skull metastasis detected by fluorodeoxyglucose positron emission tomography (FDG-PET). The patient underwent resection for skull metastasis. After the surgical treatment, he was treated with sorafenib again. Eight months after craniectomy, FDG-PET showed FDG uptake in the semimembranosus and semitendinosus muscles. Histopathological examination of the muscle biopsy revealed HCC muscle metastasis. Sorafenib treatment was discontinued. The investigational new drug (tegafur-gimeracil-oteracil) and tegafur-uracil were used for the treatment. These treatments proved to be ineffective as the lung metastases enlarged and new metastases appeared on the mediastinal lymph nodes and dura cava. The patient was unable to walk due to the enlarged thigh muscle metastases. Sorafenib was re-administered, which reduced the enlargement of the lung and mediastinal lymph nodes. Dural metastases were treated with resection and radiotherapy. Additional radiation therapy to the thigh muscles relieved the patient from pain experienced during walking. Sorafenib treatment was continued for the next 3 years. The patient survived for 4 years after the skull resection.

[A Case of UFT/LV-Induced Acute Liver Failure after Surgery for Sigmoid Colon Cancer].

Oral uracil and tegafur plus Leucovorin(UFT/LV)therapy is one of the standard adjuvant chemotherapies for colorectal cancer, and is widely used without any serious adverse events. Herein, we describe a case of UFT/LV-induced acute liver failure in a 75-year-old woman who underwent laparoscopic sigmoidectomy for sigmoid colon cancer. She was diagnosed with advanced colon cancer and lymph node metastasis by postoperative histopathological analysis, and adjuvant chemotherapy was initiated. After 30 days of commencing the therapy, the patient visited our hospital with complaints of severe diarrhea and difficulty in food intake. The apparent cause of these symptoms was unclear on computed tomography(CT), and mild liver damage was revealed in blood test results. The hepatic disorder gradually progressed after the hospitalization, and the condition was diagnosed as acute hepatic insufficiency. Additionally, obvious atrophy of the liver parenchyma and significant ascites were confirmed on CT. Two months later, the platelet count decreased markedly, but fortunately, no bleeding occurred. There has been no recurrence since 2 years after the surgery without any additional adjuvant therapy.

[A Case Report for Peritoneal Recurrences by Laparoscopic Surgery after Colorectal Cancer Resection].

We report a cases report of colorectal cancer who underwent repeated resection for peritoneal recurrences by laparoscopic surgery. In 2013, a 70-year-old woman diagnosed with an ascending colon cancer underwent laparoscopic right hemicolectomy. The pathological diagnosis was tub2, pT4aN1M0, Stage Ⅲb. Postoperative adjuvant chemotherapy(uracil and tegafur/Leucovorin)was administered. PET-CT performed at 25 months after the surgery because of CEA elevation. It revealed a peritoneal recurrence in the pouch of Douglas. The following peritoneal recurrences were removed by laparoscopic Hartmann's procedure. Chemotherapy(5-fluorouracil/levofolinate/oxaliplatin/bevacizumab)was administered 11 courses and after that chemotherapy(5-fluorouracil/levofolinate/bevacizumab)was administered 6 courses. PET-CT performed 37 months after the second surgery revealed a peritoneal recurrence near the right ovary in the pouch of Douglas. The following peritoneal recurrences was removed. Chemotherapy(tegafur/gimeracil/oteracil/bevacizumab)was administered 11 courses. The long-term survival has been continued for 7 years and 7 months after first operation. It was considered that laparoscopic surgery for peritoneal recurrence in colorectal cancer is contributed to one of the surgical procedures in selected patients.

Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

High L-Type Amino Acid Transporter 1 Levels Are Associated with Chemotherapeutic Resistance in Gastric Cancer Patients.

INTRODUCTION: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. METHODS: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. RESULTS: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). CONCLUSION: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment.

Nutritional impact of active hexose-correlated compound for patients with resectable or borderline-resectable pancreatic cancer treated with neoadjuvant therapy.

Active hexose-correlated compound (AHCC) is a standardized extract from cultured Lentinula edodes mycelia, used as a potent biological response modifier in cancer treatment. We evaluated the nutritional effect of AHCC, given during neoadjuvant therapy, to patients with pancreatic ductal adenocarcinoma (PDAC). Thirty patients with resectable or borderline-resectable PDAC received neoadjuvant therapy with gemcitabine plus S-1. We compared, retrospectively, the outcomes of 15 patients who received AHCC combined with neoadjuvant therapy with those of 15 patients who did not receive AHCC combined with neoadjuvant therapy. The median changes of the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) were significantly better in the AHCC group. The relative dose intensity of neoadjuvant therapy was also significantly higher in the AHCC group. Thus, AHCC may improve the nutritional status during neoadjuvant therapy of patients with pancreatic ductal adenocarcinoma. To validate these results and examine the long-term impact of AHCC, a prospective phase II study for PDAC is ongoing.

[Choroidal metastasis from gastric cancer 8 years after surgery].

A man in his 50s underwent total gastrectomy with D2 lymphadenectomy for gastric cancer 8 years ago. The pathological stage was pT3N3bM0, pStage IIIC. He took tegafur, gimeracil, and oteracil potassium (S-1) as adjuvant chemotherapy for the next 3 years at his own request. No recurrence was observed for 8 years after surgery, but then a recurrent lesion near the anastomosis and multiple metastases were detected on abdominal computed tomography. He started treatment with S-1 plus oxaliplatin. One month later, he experienced right-sided visual disturbance. Ophthalmological tests revealed a tumor on his choroid. Three months later, the recurrent tumor and metastatic lesions shrank, and his visual symptoms improved. Therefore, we diagnosed choroidal metastasis from gastric cancer. Choroidal metastasis from the gastrointestinal tract is extremely rare. We discuss this case along with the relevant literature.

Uracil-tegafur vs fluorouracil as postoperative adjuvant chemotherapy in Stage II and III colon cancer: A nationwide cohort study and meta-analysis.

ABSTRACT: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; P = .349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2 = 0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer.

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.

Clinical Impact of the Prognostic Nutritional Index as a Predictor of Outcomes in Patients with Stage II/III Gastric Cancer: A Retrospective Cohort Study.

BACKGROUND: The Japanese Gastric Cancer Treatment Guidelines recommend S-1 and S-1 plus docetaxel as postoperative chemotherapy for pathological stage II and III gastric cancer (GC). There is currently no strategy for using chemotherapy to treat high-risk recurrent pathological stage II/III. Previous studies reported that the several nutritional, immunological, and inflammatory markers examined the association with clinical outcomes after surgery for GC. METHODS: Ninety patients with GC (stage II, n = 48; stage III, n = 42) for whom gastrectomy was performed at our institution between November 2009 and September 2018 were examined. Nutritional, immunological, and inflammatory markers were calculated from blood samples within 1 week before surgery. RESULTS: The prognostic nutritional index (PNI) status correlated with the pathological stage and disease recurrence after surgery (p = 0.015 and p < 0.0001, respectively). Thirty-three patients had disease recurrence after gastrectomy (stage II, n = 11; stage III, n = 22). The PNI was significantly lower in the recurrent group than in the non-recurrent group (p = 0.0003). The PNI correlated with overall survival and recurrence-free survival after gastrectomy (p = 0.0021 and p = 0.0001, respectively). A multivariate analysis identified the PNI as an independent prognostic factor (p = 0.006). CONCLUSION: The PNI may be useful for predicting the outcomes of patients with pathological stage II/III GC and may contribute to the selection of an appropriate adjuvant chemotherapy regimen.

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.

Administration Method of Adjuvant Tegafur-Uracil and Leucovorin Calcium in Patients with Resected Colorectal Cancer: A Phase III Study.

LESSONS LEARNED: The 3-year disease-free survival rate of the twice-daily regimen was not inferior to that of the conventional three-times-daily regimen, and the twice-daily regimen did not lead to an increase in adverse events. The effectiveness of the twice-daily regimen highlights an increased number of treatment options for patients. This will facilitate personalized medicine, particularly for elderly or frail patients who may experience more severe side effects from the combination therapy. BACKGROUND: Tegafur-uracil (UFT)/leucovorin calcium (LV) is an adjuvant chemotherapy treatment for colorectal cancer. We conducted a multicenter randomized trial to assess the noninferiority of a twice-daily compared with a three-times-daily UFT/LV regimen for stage II/III colorectal cancer in an adjuvant setting. METHODS: Patients were randomly assigned to group A (three doses of UFT [300 mg/m2 per day]/LV [75 mg per day]) or B (two doses of UFT [300 mg/m2 per day]/LV [50 mg per day]). The primary endpoint was 3-year disease-free survival. RESULTS: In total, 386 patients were enrolled between July 28, 2011, and September 27, 2013. The 3-year disease-free survival rates of group A (n = 194) and B (n = 192) were 79.4% and 81.4% (95% confidence interval, 72.6-84.4-74.5-85.9), respectively. The most common grade 3/4 adverse events in group A and B were diarrhea (3.9% vs. 7.3%), neutropenia (2.9% vs. 1.6%), increase in aspartate aminotransferase (4.0% vs. 3.9%), increase in alanine aminotransferase (6.2% vs. 6.8%), nausea (1.7% vs. 3.4%), and fatigue (1.1% vs. 2.3%). CONCLUSION: Group B outcomes were not inferior to group A outcomes, and adverse events did not increase.

Randomized phase II study comparing the efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer (KSCC1301).

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

A Study on the Effect and Mechanism of Xiaoaiping (XAP) Injection and S-1 Combination Therapy in Inhibiting the Invasion and Metastasis of Human GC Cells.

BACKGROUND: This study aimed to determine the effect and mechanism of Xiaoaiping (XAP) injection combined with S-1 in inhibiting the invasion and metastasis of human GC cells. METHODS: BGC-823 and MGC-803 cells were incubated in vitro, and the effects of treatment on the cytotoxicity and proliferation of BGC-823 and MGC-803 cells were evaluated by MTT assay. Cell adhesion tests and Transwell assays were used to detect the effects of Xiaoaiping injection combined with S-1 on the metastatic ability of BGC-823 and MGC-803 cells. The expression of VEGF, Metalloproteinases (MMPs) and proteins related to the Epithelial-Mesenchymal Transition (EMT) were detected by Western blotting. Meanwhile, a tumour model was established in nude mice, and the effect of XAP combined with S-1 on BGC-823 cells in vivo was studied. RESULTS: Compared with the single drug group, the combination of XAP with S-1 increased the inhibition rate (P<0.05). The adhesion test showed that the combination group significantly inhibited the adhesion of BGC-823 and MGC-803 cells (P<0.05). The combination of XAP with S-1 reduced the migration and invasion potential of human GC BGC-823 and MGC-803 cells. Western blotting showed that the expression of VEGF, MMP-9, Ncadherin and vimentin was decreased and E-cadherin expression was increased in the combination group compared with these expression values in either the XAP or S-1 alone group (P<0.05). In vivo, we found that XAP combined with S-1 had a significant inhibitory effect on the growth of tumours compared with XAP or S-1 alone. Immunohistochemistry showed that XAP combined with S-1 was able to enhance the levels of E-cadherin and downregulate N-cadherin and vimentin. CONCLUSION: The combination of XAP with S-1 can enhance the inhibitory effect of a single drug on proliferation, invasion and metastasis. The mechanism may be related to the decrease in the expression of VEGF and MMP-9 proteins and the effect on EMT.

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

PURPOSE: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes. METHODS: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status. RESULTS: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02). CONCLUSIONS: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.