Yen et al. World Journal of Surgical Oncology (2021) 19:124 https://doi.org/10.1186/s12957-021-02233-2 RESEARCH Open Access Adjuvant tegafur-uracil (UFT) or S-1 monotherapy for advanced gastric cancer: a single center experience Hung-Hsuan Yen1,2, Chiung-Nien Chen2, Chi-Chuan Yeh2,3 and I-Rue Lai2,4* Abstract Background: Adjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur- uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable. The real-world data of adjuvant UFT has less been investigated. Methods: Patients with pathological stage II-IIIB (except T1) gastric cancer receiving adjuvant UFT or S-1 monotherapy after D2 gastrectomy were included. Usage of UFT or S-1 was based on reimbursement policy of the Taiwanese healthcare system. The characteristics, chemotherapy completion rates, and 5-year recurrence-free survival (RFS) and overall survival (OS), were compared between these two groups. Results: From 2005 to 2016, 86 eligible patients were included. Most tumor characteristics were similar between the UFT group (n = 37; age 59.1 ± 13.9 years) and S-1 group (n = 49; age 56.3 ± 10.7 years), except there were significantly more Borrmann type III/IV (86.5% versus 67.3%; p = 0.047) and T4 (56.8% versus 10.2%; p < 0.001) lesions in the UFT group than in the S-1 group. The chemotherapy complete rates were similar in the two groups. The 5-year RFS was 56.1% in the UFT group and 59.6% in the S-1 group (p = 0.71), and the 5-year OS was 78.3% in the UFT group and 73.1% in the S-1 group (p = 0.48). The hazard ratio of adjuvant chemotherapy (S-1 versus UFT) on RFS was 1.25 (95% confidence interval = 0.53-2.94) when Borrmann type and T and N stages were adjusted. Conclusions: This small cohort study showed adjuvant UFT, and S-1 monotherapy had a comparable long-term outcome for pathological stage II-IIIB gastric cancer following D2 gastrectomy. Keywords: Adjuvant chemotherapy, Gastric cancer, S-1, Tegafur, UFT * Correspondence: [email protected] 2Department of Surgery, National Taiwan University Hospital, No. 7 Chung-Shan South Rd, Zhongzheng District, Taipei 10002, Taiwan 4Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yen et al. World Journal of Surgical Oncology (2021) 19:124 Page 2 of 9 Background by two senior surgeons (I.-R. L. and C.-N. C) in a tertiary Gastric cancer has been the 3rd most deadly cancer referral medical center from 2005 to 2016. Patients with worldwide [1]. Radical gastrectomy with lymph node pathological stage II-IIIB gastric adenocarcinoma (ex- dissection is the treatment of choice for resectable cluding T1 cases), based on the American Joint Commit- gastric cancer [2], and adjuvant chemotherapy is recom- tee on Cancer (AJCC) 8th staging system, were included mended for pathological stage II-IIIB gastric cancer based in the study. The surgical procedure followed the princi- on several randomized controlled trials (RCTs), Japanese ples provided by Japanese Gastric Cancer Association gastric cancer treatment guidelines, and Korean practice [11, 16, 17]. The patients, who, declined adjuvant guideline for gastric cancer [3–12]. chemotherapy, had a positive margin on final pathology Dihydropyrimidine dehydrogenase (DPD) inhibitory report, were treated with neoadjuvant chemotherapy, fluoropyrimidine (DIF), the oral form prodrug of 5- had concomitant malignancy, were lost to follow-up flurouracil (5-FU), has been developed since 1980 [10], (no-show since the first postoperative outpatient follow- and is currently the most important chemotherapeutic up), had operative mortality (death occurring < 1 month agent used in adjuvant chemotherapy for advanced gas- of the index gastrectomy), or received adjuvant chemo- tric cancer. Tegafur-uracil (UFT) is the first generation therapy other than UFT or S-1, were excluded from the of oral DPD DIF, followed by tegafur-gimeracil-oteracil analysis. For patients who were lost to follow-up or had (S-1), the next generation of oral DPD DIF. S-1 contains operative mortality, discussion and decision of the oteracil that inhibits phosphorylation of 5-FU within the adjuvant chemotherapy were not made. A total of 262 gastrointestinal mucosal cells and thus theoretically re- patients had been screened initially and 86 patients who duces the gastrointestinal toxicity [13]. met the criteria were included (Fig. 1). The study was UFT was firstly used as an adjuvant monotherapy for approved by the Institutional Review Board of National pathological T2N1-2 gastric cancer in 1997 [9], but the Taiwan University Hospital. introduction of S-1 has replaced UFT gradually since 2001. In addition, S1 monotherapy has further become Treatment and follow-up the standard adjuvant therapy for advanced gastric can- All the included patients were evaluated for and began cer in 2007 since the results of Adjuvant Chemotherapy adjuvant chemotherapy within 6 weeks after surgery. Trial of TS-1 for Gastric Cancer (ACTS-GC) was pub- The eligible patients were classified into two groups, the lished [7, 8, 14]. In Taiwan, UFT was approved for ad- UFT and S-1 groups, based on the type of adjuvant vanced gastric cancer and reimbursed by the Taiwanese chemotherapy. During the period between 2005 and healthcare system in October 2000; on the other hand, 2010, UFT was the only available oral fluoropyrimidine S-1 was approved for advanced gastric cancer based on for advanced gastric cancer as adjuvant chemotherapy. the same inclusion criteria in the ACTS-GC in April Then S-1, the next generation of oral fluoropyrimidine, 2010 but was not reimbursed until December 2016. was introduced to our hospital since 2010. The UFT Although both UFT and S-1 are indicated for advanced group was given oral UFT 267 mg/m2 in two or three gastric cancer as adjuvant monotherapy in Taiwan, real- doses per day for 28 days a course for 24 course (96 world experiences and comparisons of efficacy and toler- weeks) [15], and the S-1 group was given oral S-1 80 ance between these two oral DPD DIFs remain suboptimal mg/m2 in two doses per day for 28 days followed by 14 and are only limited to sub-group analysis in one clinical days rest for 8 courses (48 weeks) [7, 8]. The dosage of trial, the Stomach cancer Adjuvant Multi-Institutional UFT or S-1 was reduced if any intolerable adverse event group Trial (SAMIT) [15]. or ≥ grade 3 adverse event occurred. Although we used In the era of coronavirus disease (COVID-19) pandemic, the same ACTS-GC protocol in the S-1 group, we al- the supply chain of chemotherapeutic agents could be no ways extended the total number of chemotherapy course longer guaranteed. Re-evaluation of the existing alterna- from 8 courses (48 weeks) to 12 courses (72 weeks) if tive in the adjuvant treatment may be necessary. In this dose de-escalation was required [18, 19]. The general study, we shared our experiences of using UFT or S-1 principles for discontinuing UFT or S-1 in our routine monotherapy as adjuvant treatment for pathological stage practice included the following: (1) recurrence or death; II-IIIB gastric cancer after D2 gastrectomy, based on the (2) adverse events, more than 29 days of unresolved unique historical cohorts formed by the different timings events that prevented starting or continuing a course; when UFT and S-1 were available in Taiwan. and (3) patients’ preference. Completion of the adjuvant chemotherapy was defined as patients who had finished Methods 24 courses for UFT or 8 courses for S-1 regardless of Study design and identification of the study cohort any dose reduction or schedule modification. This is a retrospective cohort study for patients receiving All patients received outpatient follow-up every 3 adjuvant UFT or S-1 monotherapy after D2 gastrectomy months during the first 2 years and then every 6 months Yen et al. World Journal of Surgical Oncology (2021) 19:124 Page 3 of 9 Fig. 1 Flow diagram of the subjects for the study. AJCC, American Joint Cancer Committee; RFS, recurrence-free survival; OS, overall survival; UFT, tegafur-uracil; S-1, tegafur-gimeracil-oteracil from the third to fifth year postoperatively. Weight and staging [16], and follow-up duration, were recorded recording, symptom inquiry, and physical examination, and compared between the UFT and S-1 groups. The adju- were conducted at every outpatient follow-up. Blood vant chemotherapy completion rates, sites of the first recur- sample for routine complete blood count, basic chemis- rence, and adverse events were also compared between try panel (liver and renal functions), and tumor marker these two groups.