|Year : 2015 | Volume
| Issue : 2 | Page : 331-335
Clinical study of tegafur-gimeracil-oteracil potassium capsule (s-1) and oxaliplatin combination chemotherapy in advanced colorectal cancer
Huaqun Liu1, Yigang Wang2, Guozhong Li1, Wenguang Song1, Ruilin Wang1
1 Department of Chemoradiotherapy, Workers' Hospital of Tangshan City, Tangshan, Hebei Province, China
2 Department of Anus intestines, Workers' Hospital of Tangshan City, Tangshan, Hebei Province, China
|Date of Web Publication||7-Jul-2015|
Anus intestines Department, Workers' Hospital of Tangshan City, No. 27 Wenhua Road, Lubei district, Tangshan - 063000, Hebei Province
Source of Support: None, Conflict of Interest: None
Objective: The aim of this study was to evaluate the therapeutic efficacy and toxicity of a combination of tegafur-gimeracil-oteracil potassium capsules (S-1) with oxaliplatin for treatment of advanced or recurrent colorectal cancer.
Subjects and Methods: Between October 2009 and October 2011, 70 patients at our hospital with advanced or recurrent colorectal cancer were enrolled into our study and divided randomly into two groups: A treatment group (S-1 combined with oxaliplatin) and a control group (Xeloda combined with oxaliplatin). All patients received 130 mg/m 2 oxaliplatin by intravenous infusion on day 1, every three weeks. Patients in the treatment group were treated with oral administration of 30-40 mg/m 2 S-1 twice daily for 14 days. Patients in the control group were treated with oral administration of 1000 mg/m 2 Xeloda twice daily for 14 days. The efficacy and toxicity of the combination therapy were evaluated after two cycles of treatment.
Results: The response rates in the treatment and control groups were 54.3% and 42.9%, respectively. The disease control rates of the two groups were 80.0% and 74.3%, respectively. The 1-year and 2-year survival rates were 73.6% and 39.1% in the treatment group, respectively, compared to 73.8% and 37.8% in the control group. No statistical difference between the two groups for any of the parameters, including toxicity, was observed (P > 0.05).
Conclusion: The efficacy of the S-1 and oxaliplatin combination regimen in advanced or recurrent colorectal cancer treatment is not inferior to the combination of Xeloda and oxaliplatin and does not result in additional toxicity. Therefore, S-1 could be used to substitute Xeloda in combined chemotherapy with oxaliplatin for the treatment of advanced or recurrent colorectal cancer.
Keywords: Advanced or recurrent colorectal cancer, gimeracil and oteracil potassium capsules, oxaliplatin, tegafur, xeloda
|How to cite this article:|
Liu H, Wang Y, Li G, Song W, Wang R. Clinical study of tegafur-gimeracil-oteracil potassium capsule (s-1) and oxaliplatin combination chemotherapy in advanced colorectal cancer. J Can Res Ther 2015;11:331-5
|How to cite this URL:|
Liu H, Wang Y, Li G, Song W, Wang R. Clinical study of tegafur-gimeracil-oteracil potassium capsule (s-1) and oxaliplatin combination chemotherapy in advanced colorectal cancer. J Can Res Ther [serial online] 2015 [cited 2020 Apr 8];11:331-5. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/331/157339
| > Introduction|| |
Colorectal cancer is one of the most common cancers worldwide, especially in industrialized countries.  Currently, the gold standard for the treatment of early stage colorectal cancer is surgical resection. Occasionally, postoperative adjuvant chemotherapy may be applied, depending on the patient's condition. However, for patients with advanced colorectal cancer, chemotherapy is the main course of treatment and is sometimes combined with targeted molecular therapy, which may significantly improve the therapeutic effect. 5-Fluorouracil/leucovorin (5-FU/LV)-based chemotherapy combined with oxaliplatin or irinotecan is the preferred standard treatment for patients with advanced or recurrent colorectal cancer.  However, there are few alternatives available if the patient fails to respond to chemotherapy or experiences toxicity. The combination drug tegafur-gimeracil-oteracil capsule (S-1) is a recently developed anticancer drug effective against tumors in the gastrointestinal tract. The response rate to S-1 monotherapy in advanced colorectal cancer is 19-39%. ,, To explore more effective treatments for advanced colorectal cancer, we performed a study on the efficacy of S-1 and oxaliplatin combination chemotherapy in advanced or recurrent colorectal cancer. The results of the study, performed between October 2009 and October 2011, were satisfactory and are presented here.
| > Subjects and methods|| |
Seventy patients with confirmed advanced or recurrent colorectal cancer were divided into two groups, a treatment group (S-1 combined with oxaliplatin, n = 35) and a control group (Xeloda combined with oxaliplatin, n = 35). Enrollment criteria were a clear pathological diagnosis, prior treatment with at least one cycle of 5-FU/LV-based combination chemotherapy, presence of at least one lesion assessable by imaging; Karnofsky Performance Scale score ≥70, no serious heart or lung disease, and an ability to tolerate at least two cycles of chemotherapy. No statistical differences in the general data were found between the two groups [P > 0.05, [Table 1]]. This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Workers' Hospital of Tangshan City. Written informed consent was obtained from all participants.
Patients in the treatment group were treated with the S-1 and oxaliplatin regimen. These patients received 30-40 mg/m 2 S-1 (Lunan Pharmaceutical, Shandong, China) by oral administration twice daily for 14 days combined with intravenous infusion of 130 mg/m 2 oxaliplatin (Jiangsu Hengrui Pharmaceuticals Co., Ltd., Jiangsu, China) for 3 hours on day 1. During the regimen, tropisetron was used as an antiemetic. Patients in the control group were treated with the XELOX regimen. These patients received 1000 mg/m 2 ×eloda (Roche Pharmaceuticals Ltd., Switzerland) by oral administration twice daily for 14 days combined with oxaliplatin in the same dosage and length of time as the treatment group. The treatment cycle was repeated every three weeks for both groups. The total treatment periods of the two groups were 4 to 6 cycles.
Evaluation of therapeutic effect
Therapeutic efficacy and toxicity in the two groups were evaluated after two cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumors established by the World Health Organization (WHO), target lesion responses can be classified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). CR requires the disappearance of all target lesions and the maintenance of a target lesion-free state for more than 4 weeks. PR is defined by a reduction by at least 50% in the sum of diameters of target lesions compared the sum of the baseline diameters. PD is represented by an increase by at least 20% in the sum of the long diameters of target lesions, compared to the smallest sum of the long diameters observed in the patient during the study or the appearance of one or more new lesions. SD is assigned when there is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, compared to the smallest sum of the long diameters while in the study. Toxic responses were assigned grades from 0 to 4 according to the WHO classification criteria. The response rate was calculated as (CR + PR)/total cases, and the disease control rate was calculated as (CR + PR + SD)/total cases.
Data processing was performed using the Statistical Package for the Social Sciences (SPSS) software package v16.0 (Chicago, IL, USA). Median overall survival (OS), and 1-year and 2-year survival rates were calculated using a Kaplan-Meier curve. Long-term survival rates of the two groups were compared using a log-rank test. Comparison of the response rate between the two groups was performed using a Chi-squared test. Significance was defined as P < 0.05.
| > Results|| |
All patients were able to tolerate more than two cycles of chemotherapy. There was no significant difference in the short-term therapeutic efficacy between the two groups [P > 0.05, [Table 2]]. Using Kaplan-Meier curves to predict long-term survival, the 1-year and 2-year survival rates were calculated as 73.6% and 39.1% in the treatment group and 73.8% and 37.8% in the control group, respectively. There was no statistical difference between the two groups [P > 0.05, [Figure 1]].
|Figure 1: The overall survival (OS) curves of the two groups: The solid line represented the treatment group, median OS were 18.8 m, the 1-year and 2-year survival rates were 73.6% and 39.1%; the dashed line represented the control group, median OS 19.2 m, 1-year and 2-year survival rates were 73.8% and 37.8%|
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The toxicity, including myelosuppression, gastrointestinal effects, and neurotoxicity, of the two regimens was also compared. Observed thrombocytopenia in the treatment group was higher than in the control group. In particular, one patient in the treatment group developed grade 3 thrombocytopenia. However, there was no statistical difference in myelosuppression between the two groups (P > 0.05). While hand-foot syndrome was more common in the control group (9/35), no statistical difference was observed for any of the parameters between the two groups [Table 3].
| > Discussion|| |
Significant advances in metastatic colorectal cancer treatment have been made recently and have prolonged the median survival from 6 months to 2 years. Currently, there are a number of chemotherapy drugs effective against metastatic colorectal cancer, including 5-FU (fluorouracil derivatives such as Xeloda and tegafur), oxaliplatin (L-OHP), and irinotecan (CPT-11). There are also several targeted drugs used in combination with chemotherapy, including bevacizumab, cetuximab, and panitumumab. For first- and second-line treatment against metastatic colorectal cancer, National Comprehensive Cancer Network guidelines recommend diverse combinations of the aforementioned drugs, especially the first three drugs. However, many patients fail to respond to 5-FU-based chemotherapy and are faced with a shortage of effective and well-tolerated alternatives, creating an urgent clinical problem.
Tegafur, gimeracil, and oteracil potassium capsules, also known as S-1, are developed by Taiho Pharmaceuticals Company (Japan) and were approved for clinical use in 2003. S-1 is a new class of oral fluorouracil anti-cancer drugs comprising tegafur, gimeracil, and oteracil potassium in a ratio of 1:0.4:1.  Tegafur is a precursor of 5-FU with good oral absorption and excellent bioavailability. Anti-tumor activity is achieved by conversion into 5-FU in vivo. In tumors, high concentrations of tegafur accumulate, increasing its chemotherapeutic index to two-fold that of 5-FU with only one-seventh to one-fourth of the toxicity. Gimeracil selectively inhibits hepatic dihydropyrimidine dehydrogenase and prevents catabolism of 5-FU. This allows high concentrations of 5-FU to be maintained over a long period of time in tumor cells, mimicking continuous infusion of 5-FU. , Oteracil potassium selectively antagonizes orotate phosphoribosyl transferase distributed within the digestive tract. Oral administration of oteracil potassium can result in high concentrations of the drug in the gastrointestinal tract tissue, reducing the amount of active products of 5-FU within gastrointestinal tract tissue and thereby mitigating gastrointestinal side effects. , Van den Brande et al. treated 34 patients with advanced colorectal cancer with S-1 monotherapy with a total responserate of 24%, disease control rate of 70%, and toxicity incidence rate of about 35% (mainly grade 3-4 diarrhea). Their results showed that S-1 can be used in specific treatment of advanced colorectal cancer with tolerable toxicity. Kuriaki Shirao et al.,  also used S-1 monotherapy to treat metastatic colorectal cancer and achieved a response rate of 39.5%, a disease control rate of 89.5% and a 1-year survival rate of 47.4%. The patients in their study also experienced toxicity, mainly grade 1-2 toxicity, including myelosuppression and gastrointestinal toxicity. These studies showed that S-1 monotherapy for the treatment of metastatic colorectal cancer is effective and may be an option for clinical application. Two-drug combination chemotherapy using S-1 and oxaliplatin could not only reduce the toxicity of continuous infusion of 5-FU, but also increase the body's tolerance to chemotherapy. S-1 has a synergistic effect with oxaliplatin and the combination maintains the intensity of chemotherapy and enhances the therapeutic effect without an increase in side effects. For patients sensitive and stable under chemotherapy, S-1monotherapy can be applied. A combination of S-1 and oxaliplatin was also used to treat 52 patients with recurrent colorectal cancer by Hong.  The total response rate was 47.1% and the median progression-free survival was 6.4months. At the end of a follow-up period of 17 months, the median overall survival was not reached. The incidence rate of grade more than three adverse reactions was below 10%, suggesting that S-1 combined with oxaliplatin for treatment of advanced colorectal cancer is simple and clinically effective.
Xeloda, a derivative of fluorouracil, is effective in the treatment of gastrointestinal tumors and commonly used in colorectal cancer therapy. The use of Xeloda monotherapy in first-line treatment of advancedo r recurrent colorectal cancer in 603 patients was reported.  A total response rate of 25.7%, disease control rate of 48.3%, median survival time of 12.9 months, 1-year survival rate of 52.5%, and 2-year survival rate of 22.4% were observed. The main toxic side effect of Xeloda monotherapy was hand-foot syndrome, with an incidence rate of less than 20%, indicating that the therapy is well-tolerated. Combination therapy could further improve the efficacy of chemotherapy and prolong survival. A XELOX regimen combining Xeloda with oxaliplatin is the standard first-line chemotherapy against recurrent or metastatic colorectal cancer. With an overall response rate of 37-55%, median survival is 17-20 months and major toxic side effects are peripheral neurotoxicity, hand-foot syndrome, diarrhea, and hematologic toxicity, all of which can be tolerated. ,,,,
S-1 or Xeloda in combination with oxaliplatin are both effective in the treatment of colorectal cancer. However, there are few direct comparisons of the two in combination chemotherapy. In this study, we compared S-1 (treatment group) and Xeloda (control group), both in combination with oxaliplatin, for the treatment of advanced or recurrent colorectal cancer in 70 patients. The response rates of the two groups were 54.3% and 42.9%, and the disease control rates were 80.0% and 74.3%, respectively. Though not statistically significant due to small sample sizes, a trend in some short-term effects was initially observed. As the study continues to enroll more patients, these trends may become significant. There was no statistically significant difference in long-term efficacy, median survival time, and the 1- and 2-year survival rates between the two groups. Our results indicate that, for the treatment of advanced colorectal cancer, the efficacy of a combination of S-1 and oxaliplatin is comparable to one with Xeloda and oxaliplatin. Toxicity in the treatment group was mainly hematologic, while hand-foot syndrome was more common in the control group. Nevertheless, there was no statistically significant difference between the two groups. Our results are consistent with previous studies , showing that there is no significant difference in therapeutic effect between the two combination chemotherapies. Therefore, these two combination chemotherapy regimens could replace each other clinically.
In conclusion, our results suggest that combination chemotherapy of S-1 and oxaliplatin in advanced or recurrent colorectal cancer is effective and has no additional associated toxicity compared to the XELOX regimen. Therefore, we conclude that S-1 may be used in place of Xeloda in the treatment of advanced or recurrent colorectal cancer.
| > References|| |
Ladabaum U, Allen J, Wandell M, Ramsey S. Colorectal Cancer Screening with blood-based biomarkers: Cost-effectiveness of methylated septin 9 DNA versus current strategies. Cancer Epidemiol Biomarkers Prev 2013;22:1567-76.
Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, et al.
ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:2479-516.
Shin SJ, Jeong JH, Park YS, Lee KH, Shim BY, Kim TW, et al.
Phase II trial of S-1 monotherapy in elderly or frail patients with metastatic colorectal cancer. Invest New Drugs 2011;29:1073-80.
Shirao K, Ohtsu A, Takada H, Mitachi Y, Hirakawa K, Horikoshi N, et al.
Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 2004;100:2355-61.
Van den Brande J, Schöffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Köhler K, et al.
EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer. Br J Cancer 2003;88:648-53.
Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, et al.
Antitumor activity of 1 M tegafur0.4M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996;56:2602-6.
Takechi T, Nakano K, Uchida J, Mita A, Toko K, Takeda S, et al.
Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 1997;39:205-11.
Horio T, Tsujimoto H, Akase T, Sakamoto N, Yaguchi Y, Hiraki S, et al.
Syndrome of inappropriate antidiuretic Hormone secretion following dajuvant CDDP and 5-FU administration in a patient with esophageal carcinoma. Gan To Kagaku Ryoho 2010;37:1945-8.
Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 1993;53:4004-9.
Takechi T, Fujioka A, Matsushima E, Fukushima M. Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2, 4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer 2002;38:1271-7.
Hong J, Han SW, Ham HS, Kim TY, Choi IS, Kim BS, et al.
Phase II study of biweekly S-1 and oxaliptin combination chemotherapy in metastatic colorectal cancer and pharmacogenetic analysis. Cancer Chemother Pharmacol 2011;67:1323-31.
Van Cutsem E,
Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, et al
. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 2004;90:1190-7.
Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al
. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 2001;19:2282-92.
Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, et al
. XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004;22:2084-91.
Zeuli M, Nardoni C, Pino MS, Gamucci T, Gabriele A, Ferraresi V, et al
. Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer. Ann Oncol 2003;14:1378-82.
Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al
. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-12.
Shields AF, Zalupski MM, Marshall JL, Meropol NJ. Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: A phase II trial. Cancer 2004;100:531-7.
Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, et al
. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: A randomised, non-inferiority phase 3 trial. Lancet Oncol 2012;13:1125-32.
Watanabe K, Kawahara H, Enomoto H, Toyama Y, Akiba T, Yanaga K. Feasibility study of oxaliplatin with oral S-1 or capecitabine as first-line therapy for patients with metastases from colorectal cancer. Anticancer Res 2013;33:4029-32.
[Table 1], [Table 2], [Table 3]