A nomogram based on nutritional and inflammatory parameters to predict DMFS and identify beneficiaries of adjuvant chemotherapy in IVA-stage nasopharyngeal carcinoma.

OBJECTIVE: This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment and prediction for stage IVA NPC. Furthermore, it endeavors to pinpoint specific subgroups that may derive significant benefits from S-1 adjuvant chemotherapy. METHODS: A total of 834 patients diagnosed with stage IVA NPC were enrolled in this study and randomly allocated into training and validation cohorts. Multivariate Cox analyses were conducted to identify independent prognostic factors for constructing the nomogram. The predictive and clinical utility of the nomogram was assessed through measures including the AUC, calibration curve, DCA, and C-indexes. IPTW was employed to balance baseline characteristics across the population. Kaplan-Meier analysis and log-rank tests were utilized to evaluate the prognostic value. RESULTS: In our study, we examined the clinical features of 557 individuals from the training cohort and 277 from the validation cohort. The median follow-up period was 50.1 and 49.7 months, respectively. For the overall cohort, the median follow-up duration was 53.8 months. The training and validation sets showed 3-year OS rates of 87.7% and 82.5%, respectively. Meanwhile, the 3-year DMFS rates were 95.9% and 84.3%, respectively. We created a nomogram that combined PNI, NRI, and EBV DNA, resulting in high prediction accuracy. Risk stratification demonstrated substantial variations in DMFS and OS between the high and low risk groups. Patients in the high-risk group benefited significantly from the IC + CCRT + S-1 treatment. In contrast, IC + CCRT demonstrated non-inferior 3-year DMFS and OS compared to IC + CCRT + S-1 in the low-risk population, indicating the possibility of reducing treatment intensity. CONCLUSIONS: In conclusion, our nomogram integrating NLR, PNI, and EBV DNA offers precise prognostication for stage IVA NPC. S-1 adjuvant chemotherapy provides notable benefits for high-risk patients, while treatment intensity reduction may be feasible for low-risk individuals.

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.

[A Case of Adenocarcinoma of Pancreatic Head of Liver Disfunction after Pancreaticoduodenectomy with Celiac Artery Stenosis Treated by Urgent Median Arcuate Ligament Release].

This patient visited our hospital for the purpose of detailed examination of prostate cancer in his seventies. Abdominal contrast-enhanced computed tomography(CT)revealed a low-density mass of 2 cm in the pancreatic head. He was diagnosed with pancreatic cancer. Pancreaticoduodenectomy was performed after 2 courses of gemcitabine and S-1 therapy were performed as neoadjuvant chemotherapy. An intraoperative clamp test of the gastroduodenal artery showed that the pulsation of the common hepatic artery and the proper hepatic artery was weak but sufficient, so the gastroduodenal artery was cut and the operation was completed as planned. A blood test on the 1st day after the operation showed elevated levels of AST 537 U/L, ALT 616 U/L, and 7 hours later blood sampling showed further increases in AST 1,455 U/L, ALT 1,314 U/L. After a detailed review of the preoperative CT, celiac artery stenosis due to compression of the arcuate ligament was suspected, and urgent median arcuate ligament release was performed on the same day. Dissection of the arcuate ligament significantly improved the pulsation of the common hepatic artery and proper hepatic artery. Postoperatively, hepatic enzymes improved and ISGPS showed Grade B pancreatic juice leakage, but the patient was discharged from the hospital on the 49th postoperative day without any other complications. He took S-1 as adjuvant chemotherapy, and no signs of recurrence have been observed 9 months after the operation.

Efficacy of S-1 Adjuvant Chemotherapy for Resected Biliary Tract Cancer: A Retrospective Propensity-Matched Analysis.

INTRODUCTION: Surgical resection is considered an effective cure for biliary tract cancer (BTC); however, the prognosis is unsatisfactory despite improved surgical techniques and perioperative management. The recurrence rate remains high even after curative resection. The efficacy of adjuvant chemotherapy in pancreatic and gastric cancers has been previously reported, and the feasibility of adjuvant therapy with S-1 has recently been reported in patients with resected BTC. We aimed to retrospectively investigate the effects of adjuvant chemotherapy with S-1 on resected advanced BTC. METHODS: We included data from 438 BTC patients who underwent resection between 2001 and 2020. After excluding patients with pTis-pT1 (n = 112) and other exclusion criteria, 266 patients were included in the analysis. RESULTS: After propensity score matching, 48 patients received S-1 adjuvant chemotherapy (S-1 group), and 48 patients received non-S1 adjuvant chemotherapy or underwent surgery alone (Non-S-1 group). The patients in the S-1 group had significantly better overall survival (OS) than those in the non-S-1 group (MST 51 vs 37 months, hazard ratio [HR]:.54, 95% confidence interval [CI]:.30-.98, P = .04). The S-1 group had a significantly better recurrence-free survival (RFS) than the non-S-1 group (94 vs 21 months, HR: .57, 95% CI: .33-.97, P = .03). Subgroup analyses for OS and RFS exhibited the benefits of S-1 in patients aged <75 years and in patients with primary sites of extrahepatic and perineural invasion and curability of R0. DISCUSSION: S-1 adjuvant therapy is promising for improving the postoperative survival of patients with resected advanced BTC, positive nerve invasion, and R0 resection.

Biweekly oxaliplatin plus S1 for Chinese elderly patients with advanced gastric or gastroesophageal junction cancer as the first-line therapy: a single-arm, phase 2 study.

BACKGROUND: SOX (oxaliplatin and S1, every 3 weeks) is one of the most common first-line chemotherapy for advanced or metastatic G/GEJ (gastric or gastroesophageal junction) cancer in Asia, but it has noticeable hematological and neurological toxicity. In China, the majority of gastric cancer patients are middle-aged and elderly with poor tolerance to 3-weekly chemotherapy. Therefore, we aimed to assess efficacy and safety of biweekly SOX for Chinese advanced G/GEJ cancer patients aged ≥ 60 years as the first-line treatment in a single arm phase 2 study. METHODS: Oxaliplatin was administered intravenously on day 1 at 85 mg/m2. S-1 was given at 80, 100 or 120 mg/day, depending on the body surface area (< 1.25 m2, 1.25 to < 1.5 m2, or ≥ 1.5 m2), twice daily, on day 1-10, every 2 weeks. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. RESULTS: Between May 2016 and Sep 2018, 42 patients were enrolled. The median follow-up was 43.6 months. The ORR and DCR were 52.4% and 85.7%, respectively. The median PFS was 4.6 months (95%CI 2.486-6.714), and the median OS was 11.1 months (95%CI 8.001-14.199). The most common treatment-related adverse events (TRAEs) of any grade included thrombocytopenia (59.5%), neutropenia (57.1%), appetite loss (57.1%) and nausea (54.8%). Only two patients suffered from grade 3 TRAEs (4.8%), including neutropenia (1 patient, [2.4%]) and diarrhea (1 patient, [2.4%]). No ≥ grade 4 TRAEs occurred. CONCLUSIONS: Biweekly SOX seemed to have favorable tolerance without compromising the efficacy as the first-line therapy in Chinese elderly patients aged ≥ 60 years with advanced G/GEJ cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04694404 (5/1/2021). This study was approved by the Ethical Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, (17-048/1303).

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.

Pathological complete response at the para-aortic nodes as a possible surrogate endpoint in gastric cancer surgery with para-aortic node dissection after neoadjuvant chemotherapy.

PURPOSE: Gastric cancer with para-aortic node (PAN) metastasis has a chance to be cured with multidisciplinary treatment of D2 and PAN dissection (PAND) following neoadjuvant chemotherapy (NAC), but its prognosis remains unsatisfactory. To establish a better multidisciplinary treatment, a better surrogate endpoint is needed. The present study focused on a pathological complete response at the PANs alone as a new surrogate endpoint and evaluated its prognostic value. METHODS: The study examined patients who received radical gastrectomy with D2 and PAND after NAC for gastric cancer with PAN metastasis from 2004 to 2015. The study compared five methods of evaluating the response to NAC: RECIST, clinical disappearance of PANs (cPAN), histological response of the primary tumor defined by Japanese Classification of Gastric Carcinoma (JCGC histological criteria) and Becker's criteria, and pathological disappearance of PANs (pPAN). The efficacy of these methods was compared using the hazard ratio (HR) for death between responders and non-responders. RESULTS: Thirty-two patients were analyzed. The respective HR and 5-year overall survival rates of responders and non-responders were 1.316 and 49.1% vs. 60.0% by RECIST, 1.106 and 52.9% vs. 52.5% by cPAN, 0.246 and 71.3% vs. 28.6% by JCGC histological criteria, 0.239 and 76.2% vs. 36.8% by Becker's criteria, and 0.074 and 81.0% vs. 0.0% by pPAN. CONCLUSIONS: A pathological complete response at the PANs had the lowest HR and clearly differentiated the survival, suggesting it might be a good surrogate endpoint for identifying future candidates for NAC in multidisciplinary treatment for gastric cancer with PAN metastasis.

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.

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.

A phase II study of gemcitabine/nab-paclitaxel/S-1 combination neoadjuvant chemotherapy for patients with borderline resectable pancreatic cancer with arterial contact.

BACKGROUND: The prognosis of patients with borderline resectable pancreatic cancer with arterial contact (BRPC-A) is extremely poor, and effective preoperative treatment is indispensable. We evaluated the clinical efficacy and safety of neoadjuvant chemotherapy, including gemcitabine, nab-paclitaxel and S-1 (GAS), for patients with BRPC-A. MATERIAL AND METHODS: A multicentre, single-arm, phase II study was performed. Patients were administered 1000 mg/m2 gemcitabine on day 1, 125 mg/m2 nab-paclitaxel on day 1 and 60-100 mg/day S-1 on days 1-7 during a 14-day cycle. Patients were then assessed for resectability and response to treatment after six cycles. The primary end-points were 2-year overall survival (OS) rate and median OS time (trial registration: jRCTs061180045, UMIN000016630). RESULTS: Forty-seven patients with BRPC-A were eligible for the present study. Six courses of neoadjuvant GAS regimen were completed in all eligible patients. The rate of grade III/IV toxicities occurred in 14 (30%) patients during the neoadjuvant GAS regimen. The response and disease control rates were 43% and 96%, respectively. Forty-five (96%) patients received potentially curative pancreatectomy, whereas two did not owing to disease progression. R0 resection was performed in 40 (86%) of 47 eligible patients. Eleven (24%) patients experienced postoperative major complications (>grade III), including one mortality. The 2-year OS rate and median OS time among 47 eligible patients were 70.1% and 41.0 months, respectively. CONCLUSIONS: The neoadjuvant GAS chemotherapy regimen for BRPC-A showed good efficacy with mild toxicity, resulting in a high R0 resection rate and prolonged survival in patients with BRPC-A.

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.

Eggshell Membrane Ameliorates Hyperuricemia by Increasing Urate Excretion in Potassium Oxonate-Injected Rats.

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1ß levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.

Efficacy of paclitaxel and S-1 combined with apatinib in the conversion therapy for unresectable advanced gastric cancer.

PURPOSE: To explore the safety and effectiveness of paclitaxel and tegafur, gimeracil and oteracil potassium (S-1) combined with apatinib in the conversion therapy for unresectable advanced gastric cancer. METHODS: A total of 66 patients with advanced gastric cancer received treatment with paclitaxel + S-1 + apatinib. Patients evaluated as resectable advanced gastric cancer by the multiple disciplinary team (MDT) underwent the surgery. The clinical efficacy and adverse reactions of the patients receiving conversion therapy and the related indicators of those undergoing operation were recorded. Later, the survival of the patients was compared between successful conversion therapy (surgery) group and unsuccessful conversion therapy (non-surgery) group. RESULTS: All the 66 patients completed 3-7 cycles of chemotherapy, with a median of 5 cycles, and the objective response rate (ORR) after conversion therapy was 71.2% (47/66). Among them, 48 patients received operation for (225.2±37.3) min on average, with the intraoperative blood loss of (168.2±40.9) mL and (50.9±12.3) intraoperative dissected lymph nodes, including 34 (70.8%) cases of R0 resection. According to the postoperative pathological tumor regression grading (TRG), there were 2 (4.2%) TRG 0 cases, 10 (20.8%) TRG 1 cases, 28 (58.3%) TRG 2 cases and 8 (16.7%) TRG 3 cases. The follow-up results revealed that the one-year overall survival (OS) of the patients was 93.8% (45/48) in successful conversion therapy (surgery) group and 61.1% (11/18) in unsuccessful conversion therapy (non-surgery) group. CONCLUSION: Paclitaxel and S-1 combined with apatinib can achieve a higher R0 resection rate, and improve the survival rate of patients with successful conversion therapy, showing high safety and efficacy.

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

Randomized phase II study of SOX+B-mab versus SOX+C-mab in patients with previously untreated recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study).

BACKGROUND: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. METHODS: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. RESULTS: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). CONCLUSIONS: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. TRIAL REGISTRATION: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920.

HER2-Directed Therapy in Advanced Gastric and Gastroesophageal Adenocarcinoma: Triumphs and Troubles.

OPINION STATEMENT: Gastric and gastroesophageal junction (GEJ) cancers represent the third leading cause of malignancy-associated death worldwide. Approximately 15-20% of these adenocarcinomas overexpress the human epidermal growth factor receptor 2 (HER2), a pro-proliferative receptor tyrosine kinase that has been therapeutically exploited in other disease contexts. The landmark ToGA trial demonstrated that trastuzumab, an anti-HER2 antibody, could improve overall survival for patients with HER2 overexpressing advanced gastric and GEJ adenocarcinomas. In the ensuing decade, great effort has been made to refine and expand this therapeutic strategy through a variety of avenues including optimization of chemotherapy backbones, identifying potential synergy with immune checkpoint inhibition, deployment of alternative HER2-targeted antibodies, use of small molecule inhibitors, and development of HER2-directed antibody drug conjugates. While the results of these efforts have had variable success, they have led to a greater understanding of the mechanisms of both primary and acquired resistance to HER2-directed therapies, laying the groundwork for future investigations. Recently, KEYNOTE-811 and DESTINY-Gastric01 have led to the FDA approvals of pembrolizumab in combination with trastuzumab and chemotherapy in the 1st-line advanced setting and trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki) in the 2nd-line setting, respectively. Herein, we review these significant works as well as discuss the ongoing investigations they have inspired, which aim to find and utilize additional means for targeting HER2 in gastric and GEJ cancers.

Neoadjuvant Intraperitoneal and Systemic Chemotherapy Versus Neoadjuvant Systemic Chemotherapy With Docetaxel, Oxaliplatin, and S-1 for Gastric Cancer With Peritoneal Metastasis: A Propensity Score Matched Analysis.

BACKGROUND: The optimal treatment for gastric cancer with peritoneal metastasis (GCPM) remains debatable. This study aimed to compare the efficacy and safety of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) versus neoadjuvant systemic chemotherapy (NSC) for GCPM. METHODS: Patients of GCPM received neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 between January 2011 and June 2019 were retrospectively evaluated. Propensity score matched (PSM) analysis was carried out to reduce the selection bias. Multivariate Cox regression model was applied to screen the prognostic factors. RESULTS: After PSM processing, 71 patients in each group were matched among the 186 GCPM patients included. NIPS yielded a better ascites and cytology response to chemotherapy, higher conversion resection rate and R0 resection rate than NSC. The overall survival (OS) rate in NIPS group was better than that in NSC group. Multivariate analysis revealed that the P stage, ascites response, conversion surgery rate and R0 resection rate were independent prognostic factors. Subgroup analysis indicated that NIPS showed a survival benefit over NSC only in patients with cT3-4a, P1-2, whose cytology turned negative, and who received conversion surgery; while not in patients with cT4b, P0 or P3, whose cytology did not turn negative, or who did not receive conversion surgery. CONCLUSIONS: NIPS is a safe and feasible treatment for GCPM, which showed more benefit than NSC.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Efficacy of apatinib combined with tegafur gimeracil and oteracil potassium in the second-line treatment of advanced gastric cancer.

PURPOSE: To investigate the clinical efficacy and safety of apatinib combined with tegafur-gimeracil-oteracil potassium (S-1) in the second-line treatment of advanced gastric cancer. METHODS: A total of 126 patients with advanced gastric cancer admitted to our hospital from January 2017 to September 2018 were enrolled as the research objects, none of whom underwent surgery. For these patients, second-line treatment was recommended due to the failure of first-line treatment. According to the different therapeutic options, patients were categorized into S-1 group (n=63) and Apatinib group (S-1 combined with apatinib, n=63), and drugs were administered orally. The clinical efficacy, serological indicators, adverse reactions and immune function were compared between the two groups. Besides, the survival status of patients was recorded through follow-up. RESULTS: In S-1 group and Apatinib group, the objective response rate (ORR) was 30.2% (19/63) vs. 50.8% (32/63) and the disease control rate (DCR) was 54.0% (34/63) vs. 74.6% (47/63), respectively. The results indicated that Apatinib group was superior to S-1 group in terms of ORR and DCR, suggesting statistically significant differences (p=0.018, p=0.016). Compared with those before treatment, the serum levels of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and tumor supplied group of factors (TSGF) in the two groups of patients were prominently reduced after treatment (p<0.05). After treatment, CA19-9 and TSGF levels were remarkably lower in Apatinib group than those in S-1 group (p=0.008, p=0.023), and there was no statistically significant difference in the CEA level between the two groups (p=0.057). After treatment, the quality of life of patients was improved notably in Apatinib group compared with that in S-1 group (p=0.002). Adverse reactions mainly involved hematological toxicity, nausea and vomiting, abnormal renal function, impairment of hepatic function, neurotoxicity, hypertension and hand-foot syndrome, most of which were in grade I-II and relieved after symptomatic treatment and could be tolerated for continued treatment. Serious adverse reactions in grade III-IV occurred rarely. No statistically significant difference was found in the incidence rate of adverse reactions between the two groups of patients (p>0.05). Besides, according to the follow-up results, median overall survival (OS) was 8.1 months vs. 10.7 months and median progression-free survival (PFS) was 4.2 months vs. 5.3 months, respectively, in S-1 group and Apatinib group. The results of log-rank test demonstrated that Apatinib group was superior to S-1 group with respect to OS, showing a statistically significant difference (p=0.028), and no statistically significant difference was found in PFS between the two groups of patients (p=0.159). CONCLUSION: In the second-line treatment of advanced gastric cancer, apatinib combined with S-1 is superior to S-1 alone in term of clinical efficacy, and its adverse reactions can be tolerated. Apatinib combined with S-1 can prominently improve the quality of life, reduce the serum tumor marker levels and prolong the OS of patients, but it cannot extend the PFS.

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.