774 Clinical report
S-1 combined with cisplatin versus cisplatin alone for the treatment of advanced gastric cancer: a pilot randomized-controlled trial Di Wua, Xin Lib, Jinxue Tonga, Lingyu Suna, Hongqun Zhenga, Changlu Gaoa, Dongdong Yanga, Dongzhe Liua and Qifan Zhanga We aimed to assess the efficacy and safety of S-1 combined with cisplatin (SC) over cisplatin alone (C) for the treatment of advanced gastric cancer in China. Between July 2009 and June 2011, 72 eligible patients with advanced gastric cancer were selected and divided randomly into two groups. Thirty-six patients received SC, with S-1 on days 1 through 14 of a 21-day cycle and cisplatin (60 mg/m2 on day 1) every 4 weeks for two cycles. The other 36 patients were administered only cisplatin (in the same manner as SC). The primary outcome was overall survival. The secondary outcomes were progression-free survival and adverse events. The 2-year overall response rate was 51.5 and 42.3% for the SC and C groups, respectively, and the difference was statistically significant, whereas the median overall survival was 9.4 months (range, 1.9–24.4 months) and 7.6 months (range, 1.7–21.4 months), respectively (P = 0.039). The median progression-free survival was 7.7 months for SC (range, 1.8–19.4 months), whereas it was
6.5 months (range, 1.5–16.4 months) for C (P = 0.047). The toxicity profile was similar in both groups. In summary, we have shown that S-1 combined with cisplatin is more effective, with acceptable toxicity in comparison with cisplatin alone in Chinese patients with advanced gastric cancer. Chinese Clinical Trials Register: ChiCTRTRC-13003993. Anti-Cancer Drugs 26:774–778 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
assess the efficacy and safety of S-1 combined with cisplatin (SC) versus cisplatin alone (C) for the treatment of AGC in China. Therefore, we conducted a pilot randomized-controlled study to evaluate the efficacy and safety of SC for the treatment of AGC in China.
Gastric cancer is the second most common cause of cancer death worldwide, and it remains difficult to cure [1,2]. Although the prognosis of early gastric cancer is satisfactory [3,4], that of advanced gastric cancer (AGC) remains poor [5,6]. A potential curative treatment for patients with gastric cancer is surgical resection [7,8], but most patients show regional and distant recurrence after surgery [9–11]. Thus, alternative therapies such as chemotherapy are needed. Chemoradiotherapy is reportedly an effective intensive locoregional treatment for gastric cancer [12–15]. The most common combination chemotherapeutic regimens for AGC are based on fluorouracil (5-FU) and/or cisplatin, and these regimens are often considered reference treatments [16,17]. However, the 5-year survival rates reported in previous studies remain less than 40%; therefore, it is important to find a highly effective chemotherapeutic regimen for patients with AGC. S-1 is a new oral fluoropyrimidine agent designed to enhance anticancer activity and reduce gastrointestinal toxicity [18]. It has become the most widely used drug for treating AGC in Japan [19,20]. However, it has seldom been used in China for treating AGC. In addition, there have been no reported randomized-controlled trials to 0959-4973 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Anti-Cancer Drugs 2015, 26:774–778 Keywords: advanced gastric cancer, cisplatin, S-1 Departments of aSurgical Oncology and bInternal Medicine-Cardiovascular Department, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China Correspondence to Qifan Zhang, MD, PhD, Department of Surgical Oncology, Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, Heilongjiang Province 150001, China Tel/fax: + 86 0451 8219 3658; e-mail: [email protected] Received 9 March 2015 Revised form accepted 29 March 2015
Patients and methods Patient selection
The patient eligibility criterion for enrollment into this study was histologically proven, unresectable advanced or recurrent gastric cancer with measurable lesions diagnosed between July 2009 and June 2011. Other eligibility criteria included age between 20 and 75 years, Eastern Cooperative Oncology Group performance status of 2 or less, no previous chemotherapy or radiotherapy, ability to orally intake food and liquids, life expectancy longer than 3 months, and adequate hematological, hepatic, and renal function. Patients also had to have the following standard laboratory test results: a leukocyte count of 4000–12 000/μl, neutrophil count of 2000/μl or more, a platelet count of 100 000/μl or more, a hemoglobin level of 8 g/dl or more, a serum bilirubin level of 1.5 mg/dl or more, and serum aspartate transaminase and alanine transaminase levels of 100 IU/ml or less. Patients were excluded if they were pregnant or had more than one type of cancer, malignant pleural or DOI: 10.1097/CAD.0000000000000242
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Chemotherapy for advanced gastric cancer Wu et al. 775
abdominal effusion, or serious comorbidities such as cardiac failure, renal or liver dysfunction, active infection, neurologic or psychiatric disorders, or a history of chemotherapy or radiotherapy for the treatment of AGC. The study was approved by the institutional ethics committee. Patients were stratified using the block randomization method of the SAS package (version 8.2; SAS Institute Inc., Cary, North Carolina, USA) by a statistician with no clinical involvement in this study. After qualifying, patients were assigned to either the SC or the C group. The allocation was concealed in sequentially numbered, opaque, sealed envelopes containing the randomization assignments. Treatment schedule
Patients in the C group received cisplatin 75 mg/m2 intravenously over 1–3 h on day 1 and then at 4-week intervals. In addition to receiving the same intervention as the C group, patients in the SC group were also administered S-1 on days 1–14 of a 21-day cycle. The daily dose of S-1 was assigned according to the body surface area as follows: less than 1.25 m2, 40 mg two times daily; more than or equal to 1.25 m2 and less than 1.5 m2, 50 mg two times daily; and more than or equal to 1.5 m2, 60 mg two times daily. Toxicity evaluation
The toxicity profile of all eligible patients who received any treatment was evaluated and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 3.0 [21]. Statistical analysis
An intention-to-treat analysis was carried out. The primary outcome, overall survival (OS), was defined as the interval between enrollment and death from any cause. The secondary outcome, progression-free survival (PFS), was defined as the time from the starting date of enrollment until disease progression or death. Patients whose disease had not progressed at the time of study treatment discontinuation continued to be assessed until progression was documented. Sample size was calculated on the basis of an expected 15% difference between the two groups, with 80% power and a two-sided α value of 0.05. OS and PFS rates were calculated using the Kaplan–Meier method, and P value less than 0.05 was considered statistically significant. All P values were obtained by carrying out a two-tailed t-test.
Results In this study, 158 participants were initially screened, of whom 86 were excluded. Of these 86 patients, 73 did not fulfill the study criteria and 13 declined to participate. The remaining 72 patients (36 treated with SC and 36 treated with C) were entered into the study. All
participants could undergo evaluations for efficacy and safety. Eleven patients were withdrawn from the study and five were withdrawn because of adverse events (AEs) (Fig. 1). The baseline characteristics of the patients were similar in the two treatment groups (Table 1). The mean age of the patients was 64.1 years in the SC group and 62.7 years in the C group. The performance status was 0 for 41.7% of patients treated with SC and 44.4% of patients treated with C and it was 1 for 58.3% of patients treated with SC and 44.4% of patients treated with C. The primary lesion was 55.6% in the SC group and 50.0% in the C group. Histological types were intestinal (58.3% in the SC group and 61.1% in the C group), diffuse (36.1% in the SC group and 30.6% in the C group), and others (5.6% in the SC group and 8.3% in the C group). The diagnosis was AGC (86.1% in the SC group and 83.3% in the C group) and relapse gastric cancer (13.9% in the SC group and 16.7% in the C group). Adjuvant chemotherapy was used in 8.3% of patients in the SC group and 11.1% of patients in the C group. The overall response rate as determined by the RECIST criteria was 51.5% for SC and 42.3% for C; the difference was statistically significant (P < 0.05). The median OS was 9.4 months (range, 1.9–24.4 months) and 7.6 months (range, 1.7–21.4 months) for the SC and C groups, respectively (P = 0.039; Fig. 2). In addition, the median PFS was 7.7 and 6.5 months for the SC (range, 1.8–19.4 months) and C groups (range, 1.5–16.4 months), respectively (P = 0.047; Fig. 3). All of the AEs that occurred in each group are listed in Table 2. The major hematological toxicities were neutropenia (30.6% in the SC group and 25.0% in the C group), leukopenia (19.4% in both SC and C groups), and hemoglobin (13.9% in the SC group and 8.3% in the C group). The most common grades 3 or 4 nonhematological toxicities were anorexia (19.4% in the SC group and 16.7% in the C group), nausea (11.1% in the SC group and 8.3% in the C group), and creatinine (13.9% in the SC group and 11.1% in the C group). There were no treatment-related deaths in either group.
Discussion This study showed that a combination of cisplatin and S-1 was highly active in treating AGC in terms of our primary endpoint, OS, and had an acceptable and manageable toxicity profile. Furthermore, patients in the SC group had a better outcome than those in the C group in terms of our secondary endpoint, PFS. These results suggest that SC is a potential new treatment option for patients with AGC in China. Preclinical studies have shown that SC resulted in high response and survival rates in patients with AGC. Two phase II studies by Sakata and colleagues [22,23] in patients with AGC showed response rates exceeding
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776 Anti-Cancer Drugs 2015, Vol 26 No 7
Fig. 1
Participants assessed for eligibility (n = 158) Excluded (n = 86) - Not meeting inclusion criteria (n = 73) - Declined to participate (n = 13) Randomized (n = 72)
Group SC Allocated to S-1 plus cisplatin (n = 36)
Group C Allocated to cisplatin (n = 36)
Withdrawal due to - Adverse event (n = 3) - Consent withdrawn (n = 1) - Lost to follow-up (n = 2) - Other (n = 0)
Withdrawal due to - Adverse event (n = 2) - Consent withdrawn (n = 1) - Lost to follow-up (n = 1) - Other (n = 1)
Completed treatment with S-1 plus cisplatin (n = 30)
Completed treatment with cisplatin (n = 31)
Flow of participants through the trial. C, cisplatin; SC, S-1 plus cisplatin.
Baseline characteristics of participants at trial entry Variable
Age [mean (SD)] (years) Race Sex
Fig. 2
SC (n = 36) [n (%)]
C (n = 36) [n (%)]
P value
64.1 (20.5)
62.7 (18.9)
0.69
Asian (Chinese)
36 (100.0)
36 (100.0)
1.00
Male Female
25 (69.4) 11 (30.6)
23 (63.9) 13 (36.1)
0.62 0.62
0 1
15 (41.7) 21 (58.3)
16 (44.4) 20 (55.6)
0.81 0.81
Yes No
20 (55.6) 16 (44.4)
18 (50.0) 18 (50.0)
0.64 0.64
Intestinal Diffuse Others
21 (58.3) 13 (36.1) 2 (5.6)
22 (61.1) 11 (30.6) 3 (8.3)
0.81 0.62 0.65
31 (86.1) 5 (13.9)
30 (83.3) 6 (16.7)
0.74 0.74
3 (8.3) 33 (91.7)
4 (11.1) 32 (88.9)
0.69 0.69
Performance status
Primary lesion
Histology
Diagnosis
1.0
Survival function SC C SC-censored C-censored
0.8
Cumulative survival
Table 1
0.6
0.4
0.2
0.0
Advanced Relapse Adjuvant chemotherapy Yes No
0
6
12 Time (months)
18
24
Overall survival. C, cisplatin; SC, S-1 plus cisplatin.
C, cisplatin; SC, S-1 plus cisplatin.
40%. Phase III trials reported that SC can be used as a standard first-line regimen for AGC in Japan [14,20]. In addition, another phase III trial comparing the standard 5-week cycle of SC with a 3-week cycle of SC was conducted in patients with AGC. This trial showed that the median PFS times in the 3- and 5-week cycle groups were 5.5 and 4.9 months, respectively, and it concluded
that a 3-week cycle of SC was superior to a 5-week cycle of SC in terms of PFS [24]. SC also had a favorable safety profile in this study. The overall frequency of AEs was similar in both groups and most side effects were not severe. The frequencies of both drug-related AEs and severe AEs were higher in the SC group than in the C group.
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Chemotherapy for advanced gastric cancer Wu et al. 777
Acknowledgements
Fig. 3
1.0
0.8 Cumulative survival
Di Wu and Qifan Zhang conceived the study, and participated in its coordination and design; Xin Li carried out the statistical analysis and wrote the paper; and Jinxue Tong, Lingyu Sun, Hongqun Zheng, Changlu Gao, Dongdong Yang, and Dongzhe Liu carried out the clinical assessment and participated in most of the study. All authors read and approved the final manuscript.
Survival function SC C SC-censored C-censored
0.6
Conflicts of interest
0.4
There are no conflicts of interest.
0.2
References 1 2
0.0 0
6
12 Time (months)
18
24
Progression-free survival. C, cisplatin; SC, S-1 plus cisplatin.
3
4
5 Table 2
Summary of adverse events
Adverse events Hematologic Leukopenia Platelets Hemoglobin Neutropenia Febrile neutropenia Nonhematologic Anorexia Nausea Vomiting Diarrhea Fatigue Stomatitis Creatinine Bilirubin AST ALT
SC (n = 36) G3/4 (≥ G3) [n (%)]
C (n =36) G3/4 ( ≥ G3) [n (%)]
6/1 1/0 4/1 9/2 1/0
(19.) (2.8) (13.9) (30.6) (2.8)
7/0 0/0 3/0 8/1 0/0
(19.4) (0) (8.3) (25.0) (0)
6/1 4/0 3/0 2/0 2/0 1/0 5/0 1/0 3/0 1/1
(19.4) (11.1) (8.3) (5.6) (5.6) (2.8) (13.9) (2.8) (8.3) (2.8)
6/0 3/0 2/0 1/0 2/0 1/0 4/0 1/0 2/0 2/0
(16.7) (8.3) (5.6) (2.8) (5.6) (2.8) (11.1) (2.8) (5.6) (5.6)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, cisplatin; SC, S-1 plus cisplatin.
6
7
8
9
10 11 12
This study has several strengths. First, the trial was randomized, thereby reducing selection bias. Second, the dose used in this study followed that used in the previous studies. It reflected the positive effects for AGC. Further studies with a larger sample size and a longer duration of SC treatment are needed to further confirm the results of this study in China.
13
14 15
16
Conclusion
The results of this study show promising efficacy and a very acceptable toxicity profile for SC in patients with AGC. Further evaluation of this regimen in a randomized trial is expected.
17
Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol 2009; 472:467–477. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60:277–300. Kunisaki C, Makino H, Kimura J, Takagawa R, Kosaka T, Ono HA, et al. Impact of lymphovascular invasion in patients with stage I gastric cancer. Surgery 2010; 147:204–211. Kunisaki C, Akiyama H, Nomura M, Matsuda G, Otsuka Y, Ono HA, et al. Lymph node status in patients with submucosal gastric cancer. Ann Surg Oncol 2006; 13:1364–1371. Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, et al. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 2000; 18:2648–2657. Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 2003; 21:54–59. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010; 11:439–449. Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol 2006; 7:309–315. Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011; 29:4387–4393. Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000; 87:236–242. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011; 14:101–112. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345:725–730. Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 2012; 30:2327–2333. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011; 14:113–123. Kassam Z, Mackay H, Buckley CA, Fung S, Pintile M, Oza A, et al. Adjuvant chemoradiation for gastric cancer with infusional 5-fluorouracil and cisplatin: a phase I study. Curr Oncol 2010; 17:34–41. Sumpter K, Harper-Wynne C, Cunningham D, Rao S, Tebbutt N, Norman AR, et al. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer 2005; 92:1976–1983. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 2010; 28:1547–1553.
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Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996; 7:548–557. Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, et al. Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group: fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol 2009; 10:1063–1069. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008; 9:215–221.
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Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v30. Washington, DC: Cancer Therapy Evaluation Program; 2006. Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T. Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur–0.4 M gimestat–1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 1998; 34:1715–1720. Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000; 58:191–197. Ryu MH, Baba E, Lee KH, Boku N, Park YI, Hyodo I, et al. Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study [abstract]. J Clin Oncol (suppl) 2013; 31:LBA4024.
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S-1 combined with cisplatin versus cisplatin alone for the treatment of advanced gastric cancer: a pilot randomized-controlled trial Di Wua, Xin Lib, Jinxue Tonga, Lingyu Suna, Hongqun Zhenga, Changlu Gaoa, Dongdong Yanga, Dongzhe Liua and Qifan Zhanga We aimed to assess the efficacy and safety of S-1 combined with cisplatin (SC) over cisplatin alone (C) for the treatment of advanced gastric cancer in China. Between July 2009 and June 2011, 72 eligible patients with advanced gastric cancer were selected and divided randomly into two groups. Thirty-six patients received SC, with S-1 on days 1 through 14 of a 21-day cycle and cisplatin (60 mg/m2 on day 1) every 4 weeks for two cycles. The other 36 patients were administered only cisplatin (in the same manner as SC). The primary outcome was overall survival. The secondary outcomes were progression-free survival and adverse events. The 2-year overall response rate was 51.5 and 42.3% for the SC and C groups, respectively, and the difference was statistically significant, whereas the median overall survival was 9.4 months (range, 1.9–24.4 months) and 7.6 months (range, 1.7–21.4 months), respectively (P = 0.039). The median progression-free survival was 7.7 months for SC (range, 1.8–19.4 months), whereas it was
6.5 months (range, 1.5–16.4 months) for C (P = 0.047). The toxicity profile was similar in both groups. In summary, we have shown that S-1 combined with cisplatin is more effective, with acceptable toxicity in comparison with cisplatin alone in Chinese patients with advanced gastric cancer. Chinese Clinical Trials Register: ChiCTRTRC-13003993. Anti-Cancer Drugs 26:774–778 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
assess the efficacy and safety of S-1 combined with cisplatin (SC) versus cisplatin alone (C) for the treatment of AGC in China. Therefore, we conducted a pilot randomized-controlled study to evaluate the efficacy and safety of SC for the treatment of AGC in China.
Gastric cancer is the second most common cause of cancer death worldwide, and it remains difficult to cure [1,2]. Although the prognosis of early gastric cancer is satisfactory [3,4], that of advanced gastric cancer (AGC) remains poor [5,6]. A potential curative treatment for patients with gastric cancer is surgical resection [7,8], but most patients show regional and distant recurrence after surgery [9–11]. Thus, alternative therapies such as chemotherapy are needed. Chemoradiotherapy is reportedly an effective intensive locoregional treatment for gastric cancer [12–15]. The most common combination chemotherapeutic regimens for AGC are based on fluorouracil (5-FU) and/or cisplatin, and these regimens are often considered reference treatments [16,17]. However, the 5-year survival rates reported in previous studies remain less than 40%; therefore, it is important to find a highly effective chemotherapeutic regimen for patients with AGC. S-1 is a new oral fluoropyrimidine agent designed to enhance anticancer activity and reduce gastrointestinal toxicity [18]. It has become the most widely used drug for treating AGC in Japan [19,20]. However, it has seldom been used in China for treating AGC. In addition, there have been no reported randomized-controlled trials to 0959-4973 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Anti-Cancer Drugs 2015, 26:774–778 Keywords: advanced gastric cancer, cisplatin, S-1 Departments of aSurgical Oncology and bInternal Medicine-Cardiovascular Department, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China Correspondence to Qifan Zhang, MD, PhD, Department of Surgical Oncology, Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin, Heilongjiang Province 150001, China Tel/fax: + 86 0451 8219 3658; e-mail: [email protected] Received 9 March 2015 Revised form accepted 29 March 2015
Patients and methods Patient selection
The patient eligibility criterion for enrollment into this study was histologically proven, unresectable advanced or recurrent gastric cancer with measurable lesions diagnosed between July 2009 and June 2011. Other eligibility criteria included age between 20 and 75 years, Eastern Cooperative Oncology Group performance status of 2 or less, no previous chemotherapy or radiotherapy, ability to orally intake food and liquids, life expectancy longer than 3 months, and adequate hematological, hepatic, and renal function. Patients also had to have the following standard laboratory test results: a leukocyte count of 4000–12 000/μl, neutrophil count of 2000/μl or more, a platelet count of 100 000/μl or more, a hemoglobin level of 8 g/dl or more, a serum bilirubin level of 1.5 mg/dl or more, and serum aspartate transaminase and alanine transaminase levels of 100 IU/ml or less. Patients were excluded if they were pregnant or had more than one type of cancer, malignant pleural or DOI: 10.1097/CAD.0000000000000242
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Chemotherapy for advanced gastric cancer Wu et al. 775
abdominal effusion, or serious comorbidities such as cardiac failure, renal or liver dysfunction, active infection, neurologic or psychiatric disorders, or a history of chemotherapy or radiotherapy for the treatment of AGC. The study was approved by the institutional ethics committee. Patients were stratified using the block randomization method of the SAS package (version 8.2; SAS Institute Inc., Cary, North Carolina, USA) by a statistician with no clinical involvement in this study. After qualifying, patients were assigned to either the SC or the C group. The allocation was concealed in sequentially numbered, opaque, sealed envelopes containing the randomization assignments. Treatment schedule
Patients in the C group received cisplatin 75 mg/m2 intravenously over 1–3 h on day 1 and then at 4-week intervals. In addition to receiving the same intervention as the C group, patients in the SC group were also administered S-1 on days 1–14 of a 21-day cycle. The daily dose of S-1 was assigned according to the body surface area as follows: less than 1.25 m2, 40 mg two times daily; more than or equal to 1.25 m2 and less than 1.5 m2, 50 mg two times daily; and more than or equal to 1.5 m2, 60 mg two times daily. Toxicity evaluation
The toxicity profile of all eligible patients who received any treatment was evaluated and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 3.0 [21]. Statistical analysis
An intention-to-treat analysis was carried out. The primary outcome, overall survival (OS), was defined as the interval between enrollment and death from any cause. The secondary outcome, progression-free survival (PFS), was defined as the time from the starting date of enrollment until disease progression or death. Patients whose disease had not progressed at the time of study treatment discontinuation continued to be assessed until progression was documented. Sample size was calculated on the basis of an expected 15% difference between the two groups, with 80% power and a two-sided α value of 0.05. OS and PFS rates were calculated using the Kaplan–Meier method, and P value less than 0.05 was considered statistically significant. All P values were obtained by carrying out a two-tailed t-test.
Results In this study, 158 participants were initially screened, of whom 86 were excluded. Of these 86 patients, 73 did not fulfill the study criteria and 13 declined to participate. The remaining 72 patients (36 treated with SC and 36 treated with C) were entered into the study. All
participants could undergo evaluations for efficacy and safety. Eleven patients were withdrawn from the study and five were withdrawn because of adverse events (AEs) (Fig. 1). The baseline characteristics of the patients were similar in the two treatment groups (Table 1). The mean age of the patients was 64.1 years in the SC group and 62.7 years in the C group. The performance status was 0 for 41.7% of patients treated with SC and 44.4% of patients treated with C and it was 1 for 58.3% of patients treated with SC and 44.4% of patients treated with C. The primary lesion was 55.6% in the SC group and 50.0% in the C group. Histological types were intestinal (58.3% in the SC group and 61.1% in the C group), diffuse (36.1% in the SC group and 30.6% in the C group), and others (5.6% in the SC group and 8.3% in the C group). The diagnosis was AGC (86.1% in the SC group and 83.3% in the C group) and relapse gastric cancer (13.9% in the SC group and 16.7% in the C group). Adjuvant chemotherapy was used in 8.3% of patients in the SC group and 11.1% of patients in the C group. The overall response rate as determined by the RECIST criteria was 51.5% for SC and 42.3% for C; the difference was statistically significant (P < 0.05). The median OS was 9.4 months (range, 1.9–24.4 months) and 7.6 months (range, 1.7–21.4 months) for the SC and C groups, respectively (P = 0.039; Fig. 2). In addition, the median PFS was 7.7 and 6.5 months for the SC (range, 1.8–19.4 months) and C groups (range, 1.5–16.4 months), respectively (P = 0.047; Fig. 3). All of the AEs that occurred in each group are listed in Table 2. The major hematological toxicities were neutropenia (30.6% in the SC group and 25.0% in the C group), leukopenia (19.4% in both SC and C groups), and hemoglobin (13.9% in the SC group and 8.3% in the C group). The most common grades 3 or 4 nonhematological toxicities were anorexia (19.4% in the SC group and 16.7% in the C group), nausea (11.1% in the SC group and 8.3% in the C group), and creatinine (13.9% in the SC group and 11.1% in the C group). There were no treatment-related deaths in either group.
Discussion This study showed that a combination of cisplatin and S-1 was highly active in treating AGC in terms of our primary endpoint, OS, and had an acceptable and manageable toxicity profile. Furthermore, patients in the SC group had a better outcome than those in the C group in terms of our secondary endpoint, PFS. These results suggest that SC is a potential new treatment option for patients with AGC in China. Preclinical studies have shown that SC resulted in high response and survival rates in patients with AGC. Two phase II studies by Sakata and colleagues [22,23] in patients with AGC showed response rates exceeding
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776 Anti-Cancer Drugs 2015, Vol 26 No 7
Fig. 1
Participants assessed for eligibility (n = 158) Excluded (n = 86) - Not meeting inclusion criteria (n = 73) - Declined to participate (n = 13) Randomized (n = 72)
Group SC Allocated to S-1 plus cisplatin (n = 36)
Group C Allocated to cisplatin (n = 36)
Withdrawal due to - Adverse event (n = 3) - Consent withdrawn (n = 1) - Lost to follow-up (n = 2) - Other (n = 0)
Withdrawal due to - Adverse event (n = 2) - Consent withdrawn (n = 1) - Lost to follow-up (n = 1) - Other (n = 1)
Completed treatment with S-1 plus cisplatin (n = 30)
Completed treatment with cisplatin (n = 31)
Flow of participants through the trial. C, cisplatin; SC, S-1 plus cisplatin.
Baseline characteristics of participants at trial entry Variable
Age [mean (SD)] (years) Race Sex
Fig. 2
SC (n = 36) [n (%)]
C (n = 36) [n (%)]
P value
64.1 (20.5)
62.7 (18.9)
0.69
Asian (Chinese)
36 (100.0)
36 (100.0)
1.00
Male Female
25 (69.4) 11 (30.6)
23 (63.9) 13 (36.1)
0.62 0.62
0 1
15 (41.7) 21 (58.3)
16 (44.4) 20 (55.6)
0.81 0.81
Yes No
20 (55.6) 16 (44.4)
18 (50.0) 18 (50.0)
0.64 0.64
Intestinal Diffuse Others
21 (58.3) 13 (36.1) 2 (5.6)
22 (61.1) 11 (30.6) 3 (8.3)
0.81 0.62 0.65
31 (86.1) 5 (13.9)
30 (83.3) 6 (16.7)
0.74 0.74
3 (8.3) 33 (91.7)
4 (11.1) 32 (88.9)
0.69 0.69
Performance status
Primary lesion
Histology
Diagnosis
1.0
Survival function SC C SC-censored C-censored
0.8
Cumulative survival
Table 1
0.6
0.4
0.2
0.0
Advanced Relapse Adjuvant chemotherapy Yes No
0
6
12 Time (months)
18
24
Overall survival. C, cisplatin; SC, S-1 plus cisplatin.
C, cisplatin; SC, S-1 plus cisplatin.
40%. Phase III trials reported that SC can be used as a standard first-line regimen for AGC in Japan [14,20]. In addition, another phase III trial comparing the standard 5-week cycle of SC with a 3-week cycle of SC was conducted in patients with AGC. This trial showed that the median PFS times in the 3- and 5-week cycle groups were 5.5 and 4.9 months, respectively, and it concluded
that a 3-week cycle of SC was superior to a 5-week cycle of SC in terms of PFS [24]. SC also had a favorable safety profile in this study. The overall frequency of AEs was similar in both groups and most side effects were not severe. The frequencies of both drug-related AEs and severe AEs were higher in the SC group than in the C group.
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Chemotherapy for advanced gastric cancer Wu et al. 777
Acknowledgements
Fig. 3
1.0
0.8 Cumulative survival
Di Wu and Qifan Zhang conceived the study, and participated in its coordination and design; Xin Li carried out the statistical analysis and wrote the paper; and Jinxue Tong, Lingyu Sun, Hongqun Zheng, Changlu Gao, Dongdong Yang, and Dongzhe Liu carried out the clinical assessment and participated in most of the study. All authors read and approved the final manuscript.
Survival function SC C SC-censored C-censored
0.6
Conflicts of interest
0.4
There are no conflicts of interest.
0.2
References 1 2
0.0 0
6
12 Time (months)
18
24
Progression-free survival. C, cisplatin; SC, S-1 plus cisplatin.
3
4
5 Table 2
Summary of adverse events
Adverse events Hematologic Leukopenia Platelets Hemoglobin Neutropenia Febrile neutropenia Nonhematologic Anorexia Nausea Vomiting Diarrhea Fatigue Stomatitis Creatinine Bilirubin AST ALT
SC (n = 36) G3/4 (≥ G3) [n (%)]
C (n =36) G3/4 ( ≥ G3) [n (%)]
6/1 1/0 4/1 9/2 1/0
(19.) (2.8) (13.9) (30.6) (2.8)
7/0 0/0 3/0 8/1 0/0
(19.4) (0) (8.3) (25.0) (0)
6/1 4/0 3/0 2/0 2/0 1/0 5/0 1/0 3/0 1/1
(19.4) (11.1) (8.3) (5.6) (5.6) (2.8) (13.9) (2.8) (8.3) (2.8)
6/0 3/0 2/0 1/0 2/0 1/0 4/0 1/0 2/0 2/0
(16.7) (8.3) (5.6) (2.8) (5.6) (2.8) (11.1) (2.8) (5.6) (5.6)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, cisplatin; SC, S-1 plus cisplatin.
6
7
8
9
10 11 12
This study has several strengths. First, the trial was randomized, thereby reducing selection bias. Second, the dose used in this study followed that used in the previous studies. It reflected the positive effects for AGC. Further studies with a larger sample size and a longer duration of SC treatment are needed to further confirm the results of this study in China.
13
14 15
16
Conclusion
The results of this study show promising efficacy and a very acceptable toxicity profile for SC in patients with AGC. Further evaluation of this regimen in a randomized trial is expected.
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