Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

IgA Vasculitis as a Potential Complication of Fourth-Line Chemotherapy with Tegafur/Gimeracil/Oteracil (S-1) in Advanced Non-Small Cell Lung Cancer: A Case Report.

BACKGROUND Immunoglobulin A (IgA) vasculitis is a systemic vasculitis that involves the small vessels. It is mainly characterized by skin symptoms such as purpura, arthritis/arthralgia, abdominal symptoms, and nephropathy, which are caused by IgA adherence to the vessel walls. Herein, we report the case of an advanced non-small cell lung cancer (NSCLC) and a purpuric skin rash of the legs that developed during fourth-line chemotherapy with tegafur/gimeracil/oteracil (S-1). CASE REPORT A 68-year-old man diagnosed with NSCLC 2 years ago was undergoing S-1 as fourth-line chemotherapy when he developed purpura and edema on the lower extremities. Biopsy renal specimens were consistent with IgA vasculitis. Considering his medical history, both IgA vasculitis induced by S-1 and a paraneoplastic syndrome were considered, although the exact cause could not be identified. Subsequently, chemotherapy was discontinued because of his deteriorating general condition, and he received optimal supportive care. The purpura spontaneously disappeared; however, his ascites and renal function deteriorated. Systemic steroids improved renal function, but the ascites did not resolve. One month after being diagnosed with IgA vasculitis, the patient died due to deterioration of his general condition. CONCLUSIONS This case emphasizes the occurrence of IgA vasculitis during lung cancer treatment and its potential impact on the disease course of lung cancer. Moreover, the possible causes of IgA vasculitis in this case were paraneoplastic syndrome or S-1 adverse effects, but further case series are needed to gain a more comprehensive understanding. Refractory, steroid-unresponsive ascites may occur as an abdominal manifestation of IgA vasculitis.

Paeonia × suffruticosa Andrews leaf extract and its main component apigenin 7-O-glucoside ameliorate hyperuricemia by inhibiting xanthine oxidase activity and regulating renal urate transporters.

BACKGROUND: Hyperuricemia is an important pathological basis of gout and a distinct hazard factor for metabolic syndromes and cardiovascular and chronic renal disease, but lacks safe and effective treatments currently. Paeonia × suffruticosa Andrews leaf effectively reduced serum uric acid in gout patients; however, the material foundation and the mechanism remain unclear. PURPOSE: To determine the primary active components and mechanism of P. suffruticosa leaf in hyperuricemic mice. METHODS: The chemical constituents of P. suffruticosa leaf was identified using high-performance liquid chromatographic analysis. The anti-hyperuricemic activity of P. suffruticosa leaf extract (12.5, 25, 50, 100, and 200 mg/kg) and its components was evaluated in hyperuricemic mice induced by a high purine diet for 14 days. Then, the urate-lowering effects of apigenin 7-O-glucoside (0.09, 0.18, and 0.36 mg/kg) were assessed in another hyperuricemic mice model built by administrating potassium oxonate and adenine for 4 weeks. The inhibitory effect of apigenin 7-O-glucoside on uric acid production was elucidated by investigating xanthine oxidase activity in vitro and in serum and the liver and through molecular docking. Immunofluorescence and western blot analyses of the expression of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), and ATP-binding cassette G member 2 (ABCG2) proteins elucidated how apigenin 7-O-glucoside promoted uric acid excretion. RESULTS: Six compounds were identified in P. suffruticosa leaf: gallic acid, methyl gallate, oxypaeoniflorin, paeoniflorin, galloylpaeoniflorin, and apigenin 7-O-glucoside. P. suffruticosa leaf extract significantly attenuated increased serum uric acid, creatinine, and xanthine oxidase activity in hyperuricemic mice. Apigenin 7-O-glucoside from P. suffruticosa leaf reduced uric acid, creatinine, and malondialdehyde serum levels, increased superoxide dismutase activity, and partially restored the spleen coefficient in hyperuricemic mice. Apigenin 7-O-glucoside inhibited xanthine oxidase activity in vitro and decreased serum and liver xanthine oxidase activity and liver xanthine oxidase protein expression in hyperuricemic mice. Molecular docking revealed that apigenin 7-O-glucoside bound to xanthine oxidase. Apigenin 7-O-glucoside facilitated uric acid excretion by modulating the renal urate transporters URAT1, GLUT9, OAT1, and ABCG2. Apigenin 7-O-glucoside protected against renal damage and oxidative stress caused by hyperuricemia by reducing serum creatinine, blood urea nitrogen, malondialdehyde, and renal reactive oxygen species levels; increasing serum and renal superoxide dismutase activity; restoring the renal coefficient; and reducing renal pathological injury. CONCLUSION: Apigenin 7-O-glucoside is the main urate-lowering active component of P. suffruticosa leaf extract in the hyperuricemic mice. It suppressed liver xanthine oxidase activity to decrease uric acid synthesis and modulated renal urate transporters to stimulate uric acid excretion, alleviating kidney damage caused by hyperuricemia.

Doxifluridine versus Tegafur/Gimeracil/Oteracil (S-1) as adjuvant chemotherapy for patients with gastric cancer after gastrectomy: A propensity score-matched analysis.

INTRODUCTION: Doxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer. METHODS: We retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group. RESULTS: There was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors. CONCLUSION: There was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival.

Hypouricemic effect of gallic acid, a bioactive compound from Sonneratia apetala leaves and branches, on hyperuricemic mice.

As a tropical medicinal plant, Sonneratia apetala is mainly distributed in the southeast coastal areas of China. Recently, the hypouricemic effect of Sonneratia apetala leaves and branches (SAL) has been reported, but the active compound and its mechanism are unclear. Thus, this study aims to explore the effective fraction of SAL and the mechanism of its active compound on uric acid formation and excretion. SAL was extracted with ethyl acetate and concentrated to obtain solvent-free extracts (SAL-EA). The remains fraction (SAL-E) and the supernatant fraction (SAL-S) of SAL resulting from water extraction and alcohol precipitation were collected and dried. The effects of different fractions were explored on hyperuricemic mice. SAL-S showed excellent activities in decreasing the levels of uric acid (UA), blood urea nitrogen (BUN), and creatinine (CRE) in serum and in attenuating kidney damage. Then, the active compound gallic acid (GA) identified by HPLC was assayed for its mechanism of regulating uric acid metabolism in hyperuricemic mice. The hypouricemic effect of GA was probably associated with the downregulation of URAT1 and GLUT9, upregulation of ABCG2 and decreased activities of adenosine deaminase (ADA) and xanthine oxidase (XOD). Moreover, GA suppressed the level of MDA, IL-6, IL-1ß, TNF-α, TGF-ß1, COX-2 and cystatin-C (Cys-C), and enhanced the activities of SOD, GSH-Px, CAT, and Na+-K+-ATPase (NKA) in the kidneys. These results indicated that GA protects against hyperuricemia-induced kidney injury via suppressing oxidative stress and inflammation as well as decreasing the serum levels of UA by regulating urate transporters.

The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

Addition of sintilimab to nanoparticle albumin-bound paclitaxel and S-1 as adjuvant therapy in stage IIIC gastric cancer.

The prognosis of stage III gastric cancer (GC) is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and efficacy of sintilimab in GC. A combination of Nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. The aim of this article is to describe the design of this prospective Dragon-VII trial, conducted to evaluate the safety and efficacy of the combination of Nab-PTX, S-1 and sintilimab. Clinical trial registration: NCT04781413.

Lay abstract The prognosis of stage IIIC gastric cancer is poor and the treatment for it is not satisfying. This is a clinical trial that aims to explore a more effective therapy in gastric cancer patients of stage IIIC. Patients with stage IIIC gastric cancer must meet all of the inclusion criteria and none of the exclusion criteria to be eligible for this trial. The eligible patients will be given eight cycles of combinatory therapy of albumin-bound paclitaxel, a chemotherapy (day 1 and day 8), and S-1, another chemotherapy (days 1 to 14), plus sintilimab, a type of immunotherapy called an immune checkpoint inhibitor (day 1) every 3 weeks and then sintilimab maintenance for up to 12 months.

Application of Evidence-Based Nursing Intervention in the Treatment of Advanced Squamous Cell Carcinoma of the Lung by Erlotinib Combined with Tegafur, Gimeracil, and Oteracil Potassium and Its Influence on Quality of Life.

Objective: To explore the application of evidence-based nursing intervention in the treatment of advanced squamous cell carcinoma of the lung by erlotinib combined with tegafur, gimeracil, and oteracil potassium (TS-1) and its influence on quality of life (QOL). Methods: Clinical data of 92 patients with advanced squamous cell carcinoma of the lung treated with erlotinib and TS-1 in our hospital (January 2017-January 2021) were retrospectively analyzed. Forty-six patients receiving conventional nursing were set as the control group (CG), and other 46 patients receiving evidence-based nursing intervention additionally were set as the study group (SG). The clinical observation indexes of the two groups were compared and analyzed. Results: No obvious difference in general data between both groups (P > 0.05). According to EORTC QLQ-C30, compared with the CG, the scores of role function, physical function, social function, cognitive function, and emotional function in the SG were remarkably higher (P < 0.05). After intervention, scores of VAS of patients were obviously lower than those before intervention (P < 0.05), and scores of VAS in the SG after intervention were obviously lower than those in the CG (P < 0.05). After intervention, scores of SAS and SDS were lower than those before intervention, and those of the SG were obviously lower than those of the SG (P < 0.05). Compared with the CG, incidences of adverse reactions such as diarrhoea, nausea and vomiting, erythra, pressure sores, and leukopenia in the SG were obviously lower (P < 0.05). Compared with the CG, "very satisfied" and total satisfaction in the SG were obviously higher (P < 0.05). Conclusion: Application of evidence-based nursing intervention in the treatment of advanced squamous cell carcinoma of the lung by erlotinib combined with TS-1 can help patients to relieve pain, improve their psychological state, reduce the incidence of adverse reactions, significantly improve the QOL, and also enhance the satisfaction of clinical nursing.

Oxaliplatin plus S-1 with intraperitoneal paclitaxel for the treatment of Chinese advanced gastric cancer with peritoneal metastases.

BACKGROUND: In this study, we tried to access the efficacy and safety of oxaliplatin plus S-1 with intraperitoneal paclitaxel (PTX) for the treatment of Chinese advanced gastric cancer with peritoneal metastases. PATIENTS AND METHODS: Thirty patients diagnosed with advanced gastric cancer underwent laparoscopic exploration and were enrolled when macroscopic disseminated metastases (P1) were confirmed. PTX was diluted in 1 l of normal saline and IP administered through peritoneal port at an initial dose of 40 mg/m2 over 1 h on day1,8, respectively. Oxaliplatin was administered intravenously at an initial dose of 100 mg/m2 on day1, and S-1 was administered orally at an initial dose of 80 mg/m2 for 14 days followed by 7 days rest, repeated by every 3 weeks. RESULTS: Of all these 30 patients, the median number of cycles was 6 (range 2-16) due to the limitation of hematotoxicity and peripheral neuropathy by oxaliplatin. There were 11 (36.7%) patients received conversion surgery. The median progression free survival (PFS) was 6.6 months (95% CI = 4.7-8.5 months) and the median overall survival (OS) was 15.1 months (95% CI = 12.4-17.8 months). The grade 3-4 hematological toxicities were leucopenia (23.3%), neutropenia (23.3%), anemia (16.7%), and thrombocytopenia (20%), respectively. The grade 3-4 non-hematological toxicities were tolerated, most of which were peripheral sensory neuropathy (40%) due to oxaliplatin, diarrhea (20%), nausea and vomiting (26.7%). CONCLUSIONS: SOX+ip PTX regimen was effective in advanced gastric cancer with peritoneal metastasis. Survival time was significantly prolonged by conversion surgery. Grade 3-4 toxicities were uncommon. Large scale clinical trial is necessary to get more evidence to identify its efficacy. TRAIL REGISTRATION: ChiCTR, ChiCTR-IIR-16009802 . Registered 9 November 2016.

Phase II feasibility study of adjuvant chemotherapy with docetaxel/cisplatin/S-1 followed by S-1 for stage III gastric cancer.

BACKGROUND: This study aimed to evaluate the feasibility, safety, and efficacy of postoperative adjuvant chemotherapy with docetaxel/cisplatin/S-1 (DCS) following S-1 therapy in patients with stage III gastric cancer after curative gastrectomy. METHODS: Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Adjuvant chemotherapy was initiated within 8 weeks of gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy (day 1-14), followed by a 7-day rest period. Cycles 2 and 3 consisted of the following: S-1 (day 1-14) administration, followed by a 14-day rest period, and an intravenous infusion of cisplatin and docetaxel on days 1 and 15. After two cycles, S-1 was administered for up to 1 year. RESULTS: Thirty patients were enrolled between 2014 and 2017. Febrile neutropenia of grade 3 or higher was the most common hematological toxicity with 4 patients (13.3%). Other hematological toxicities of grade 3 or higher were as follows: neutropenia in 3 (10.0%), leukopenia in 3 (10.0%), and anemia in 2 (6.7%) patients. Most frequent non-hematological toxicity of grade 3 was anorexia (n = 4, 13.3%) and general fatigue (n = 3, 10.0%); no grade 4 non-hematological toxicities were observed. Twenty-five patients (83.3%) completed two cycles of DCS treatment and 18 (60.0%) completed subsequent S-1 treatment for 1 year. The relative dose intensity of docetaxel and cisplatin was 0.86 and that of S-1 was 0.88. CONCLUSION: The DCS regimen can be acceptable as an adjuvant chemotherapy and offers an effective postoperative treatment option for stage III gastric cancer patients. TRIAL REGISTRATION NUMBER: UMIN000012785 . DATE OF REGISTRY: 08/01/2014.

Impact of Renal Function on S-1 + Radiotherapy for Locally Advanced Pancreatic Cancer: An Integrated Analysis of Data From 2 Clinical Trials.

OBJECTIVES: S-1 monotherapy with concurrent radiotherapy (RT) is a standard of care for patients with locally advanced pancreatic cancer (LAPC). Although renal dysfunction increases S-1 monotherapy toxicity, its effect in S-1 with concurrent RT remains unknown. We evaluated the effect of renal function on the safety of S-1 with RT for LAPC. METHODS: We performed an integrated exploratory post hoc analysis of data from 2 prospective studies (JCOG1106 and LAPC-S1RT), where patients with LAPC received RT (50.4 Gy/28 fraction for 5.5 weeks) and concurrent S-1 (40 mg/m2 per dose, twice daily on the day of irradiation). We split the patients into high creatinine clearance (CCr; ≥80 mL/min) and low CCr (<80 mL/min) groups and compared the findings to determine treatment safety. RESULTS: The high and low CCr groups showed a median of 97.5 (range, 80.0-194.6) and 64.4 (range, 50.0-78.3) mL/min, respectively. The low CCr group presented more adverse reactions (ARs) of grade 3 or higher and gastrointestinal ARs of grade 2 or higher than the high CCr group (30.8% vs 15.8% and 51.9% vs 36.8%). CONCLUSIONS: The incidence of ARs associated with concurrent S-1 and RT increases in patients with low CCr; therefore, ARs should be duly considered in such patients.

Survival Outcomes of Gemcitabine Plus S-1 Adjuvant Chemotherapy after Surgical Resection for Advanced Biliary Tract Cancer.

INTRODUCTION: The usefulness of adjuvant chemotherapy in biliary tract cancer (BTC) is poorly reported. This study aimed to evaluate the effectiveness and safety of adjuvant gemcitabine plus S-1 (GS) chemotherapy after curative surgical resection for BTC. METHODS: 225 BTC patients who underwent surgical resection between January 2006 and May 2019 were enrolled in this study. Twenty-seven patients received adjuvant chemotherapy with GS (GS group), whereas 67 patients underwent surgery alone (S group). Twenty-three matching pairs were derived through propensity score (PS) matching analysis. Patients received 12 cycles of adjuvant chemotherapy (70 mg/m2 oral S-1 for 7 consecutive days plus intravenous gemcitabine 1,000 mg/m2 on day 7). The primary end point was recurrence-free survival (RFS). The secondary end points were the 1-, 2-, and 3-year RFS and overall survival (OS) rates, tolerability, and frequency of grade 3/4 toxicity. RESULTS: The completion rate was 81.5%; no treatment-related deaths were observed. Grade 3/4 adverse events were seen in 40.7% of the patients. RFS (3-year RFS rate: 59.3% vs. 39.1%, p = 0.049) and OS (3-year OS rate: 71.7% vs. 53.4%, p = 0.008) were significantly better in the GS group than in the S group among PS-matched pairs. DISCUSSION/CONCLUSION: GS chemotherapy after curative surgery was well tolerated, showed better clinical benefit in the adjuvant setting, and can effectively reduce BTC recurrence.

Severe hypertriglyceridemia induced by S-1: Subsequent case series of four patients and further review of the literature.

OBJECTIVE: We previously reported a case where S-1, containing tegafur, gimeracil, and oteracil potassium, induced severe hypertriglyceridemia. After the case, we regularly monitored serum lipid levels and surprisingly observed an additional 4 cases within 1.5 years. We here report the treatment process. CASE REPORT: At least 3 patients exhibited hyperlipidemia at baseline; in 2 of them, this was caused by previous fluoropyrimidine treatment. One patient experienced grade 4 hypertriglyceridemia, and the other 3 grade 3 hypertriglyceridemia. One patient developed temporary serum triglyceride elevation during the S-1 administration period, and the 3 experienced persistent elevation. The severity of serum triglyceride level worsened with increasing administration and peaked in cycles 2 - 6. Fenofibrate 80 - 160 mg/day and S-1 dose reduction were effective, with some significantly and others gradually decreasing to grade 0 - 1. DISCUSSION: The summarized clinical features are as follows: (1) Severe hypertriglyceridemia tends to appear after several treatment cycles and worsens with increasing administration. (2) It tends to occur in patients with hyperlipidemia at baseline. (3) Patients previously affected with fluoropyrimidines-induced hypertriglyceridemia can experience S-1 symptoms. (4) In some cases, it might decrease after the S-1 suspension period. (5) Fibrates and S-1 dose reductions were effective. As the final fluoropyrimidine product is fluorouracil, its presence or that of its metabolizing enzymes and the genetic background of the patients might have affected the results. We should be aware of the risk of temporal and asymptomatic occurrence of S-1-induced hypertriglyceridemia for early detection with appropriate treatment.

Impact of Camellia japonica Bee Pollen Polyphenols on Hyperuricemia and Gut Microbiota in Potassium Oxonate-Induced Mice.

Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.

Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3).

BACKGROUND: The efficacy of modified FOLFIRINOX (mFOLFIRINOX) as a second-line chemotherapy treatment for metastatic pancreatic adenocarcinoma (mPAC), remains unclear. This multi-center randomised phase III trial aimed to elucidate the efficacy of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients with good performance status. PATIENTS AND METHODS: Eighty mPAC patients (age, 19-75 years) refractory to first-line gemcitabine-based chemotherapy were randomly selected to receive mFOLFIRINOX or S-1. mFOLFIRINOX comprised oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), and leucovorin (400 mg/m2) on day 1 and continuous 5-FU infusion (1000 mg/m2) over 24 h on days 1-2 every 2 weeks. S-1 comprised body surface area-dependent oral S-1, divided into two doses per day on days 1-28 every 6 weeks. RESULTS: Overall survival was the primary endpoint. The objective response and disease control rates were higher in the mFOLFIRINOX than in the S-1 group (15% versus 2%; p = .04 and 67% versus 37%; p = .007). The median progression-free survival rates were 5.2 and 2.2 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted hazard ratio [HR]: .4; 95% confidence interval [CI]: .2-.6; p < .001). The median overall survival rates were 9.2 and 4.9 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted HR: .4; 95% CI: .2-.7; p = .002). Grade 3-4 adverse events occurred in 56% and 17% of the patients in the mFOLFIRINOX and S-1 groups, respectively (p < .001). CONCLUSION: Administration of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients refractory to gemcitabine-based chemotherapy resulted in increased survival rates than S-1 treatment alone.

Comparison of S-1-based vs. capecitabine-based adjuvant chemotherapy for patients with gastric cancer: a systematic review and meta-analysis.

BACKGROUND: S-1-based and capecitabine-based adjuvant treatments are proved efficacious for patients with gastric cancer, but conventional meta-analyses of the direct comparisons between two alternative adjuvant regimens to resection of GC have not been attempted. AIM: The aim of this review was to compare the disease-free survival, overall survival and adverse events in patients receiving the S-1- and capecitabine-based adjuvant chemotherapies for treatment of gastric cancer (GC) patients undergoing resection. METHODS: A search of the academic literature was performed in PUBMED, SCOPUS, CENTRAL and EMBASE databases along with manual search in relevant journals for studies in English, to identify comparative studies comparing the effect of S-1-based chemotherapy and capecitabine-based adjuvant chemotherapy (AC), used in combination with surgical resection for treatment of gastric cancer. Both qualitative and quantitative analyses was carried out for all the included studies. The hazard ratios (HR) of disease-free survival (DFS) and overall survival (OS) were pooled using generic inverse variance method. The included studies were assessed for risk of bias using ROBINS-E (risk of bias in non-randomized studies of exposures) tool. RESULTS: Seven retrospective cohort studies, two prospective cohort studies and one randomized clinical trial were included. Both S-1- and capecitabine-based adjuvant chemotherapy for treatment of stage 2 or 3 gastric cancer had similar effects on the 3-year and 5-year DFS rates, overall survival and adverse events in the included studies. There was no difference in the adjusted hazard ratios (HR) of OS and DFS (0.86 95% CI (0.68, 1.09); p = 0.21 and 0.96 95% CI (0.75, 1.24), respectively). Oral mucositis was increasingly associated with S-1-based AC, while incidences of adverse events such as neutropenia, anaemia and thrombocytopenia were similar to those of capecitabine-based regimen. The quality of the included studies was found to be low to moderate. CONCLUSION: S-1- and capecitabine-based adjuvant chemotherapies can be used interchangeably as an adjuvant chemotherapeutic regimen postradical gastrectomy with D2 lymph node dissection.

Tolerability and safety of adjuvant chemoradiotherapy with S-1 after limited surgery for T1 or T2 lower rectal cancer.

BACKGROUND: Chemo-radiotherapy (CRT) after local excision for pT1 with high-risk features or pT2 rectal cancer is recommended as an optional treatment to achieve both curability and maintenance of quality of life. The aim of this study was to evaluate the short-term safety of combining limited surgery with adjuvant CRT for T1 or T2 lower rectal cancer. METHODS: This was a multicenter, single-arm, prospective phase II trial. Patients diagnosed with lower rectal or anal canal cancer (clinical T1 or T2 with a maximum diameter of 30 mm and N0 and M0) underwent local excision or endoscopic resection. Patients received CRT with S-1 (tegafur/gimeracil/oteracil) after confirmation of well- or moderately differentiated adenocarcinoma, and negative margins, and/or depth of submucosal invasion ≥ 1000 µm or muscularis propria, and/or positive lymphovascular invasion, and/or tumor budding grade of 2/3. The primary endpoint was relapse-free survival. Secondary endpoints included overall and local relapse-free survival, safety, anal sphincter preservation rate, and anal function. RESULTS: Pathological diagnosis was T1 in 36 patients and T2 in 16 patients. Serious complications after surgery were not reported. The CRT completion rate per protocol was 86.5% (45/52). Thirty-two patients developed 54 events of CRT-related adverse events, including only one patient with a grade 3 event (stomatitis). The most common CRT-related adverse event was diarrhea (n = 14). No patients showed deterioration of anal function at 3 years postoperatively. CONCLUSION: CRT with S-1 after limited surgery for T1 or T2 lower rectal cancer resulted in a low incidence of toxicities and maintenance of anal function.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Safety of alternate-day treatment with TS-1TM (tegafur/gimeracil/oteracil) in tumor-bearing dogs: a pilot study.

Tegafur is a prodrug of fluoropyrimidine 5-fluorouracil (5-FU), while TS-1TM is an oral fixed-dose combination of three active drugs, tegafur, gimeracil, and oteracil. This pilot study evaluated the safety of tegafur/gimeracil/oteracil in the treatment of cancers in dogs. Tegafur/gimeracil/oteracil was administered orally at a mean dose of 1.1 mg/kg twice daily on alternate days, Monday-Wednesday-Friday, every week to 11 dogs with tumors. Partial response and stable disease were observed in one dog each, whereas six exhibited progressive disease. Three dogs were not assessed. Adverse events, the most serious being grade 2, were noted in seven dogs. Adverse events were acceptable, and the drug was effective in some dogs. Therefore, tegafur/gimeracil/oteracil may be useful for treating malignant solid tumors in canines.

Safety and efficacy of S1 monotherapy or combined with nab-paclitaxel in advanced elderly pancreatic cancer patients: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. METHOD: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. RESULTS: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). CONCLUSION: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.