Simvastatin plus capecitabine–cisplatin versus placebo plus capecitabine–cisplatin in patients with previously untreated advanced gastric cancer: A double-blind randomised phase 3 study

European Journal of Cancer (2014) 50, 2822– 2830

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Original Research

Simvastatin plus capecitabine–cisplatin versus placebo plus capecitabine–cisplatin in patients with previously untreated advanced gastric cancer: A double-blind randomised phase 3 study Seung Tae Kim a,1, Jung Hun Kang b,1, Jeeyun Lee a, Se Hoon Park a, Joon Oh Park a, Young Suk Park a, Ho Yeong Lim a, In Gyu Hwang c, Sang-Cheol Lee d, Keon-Woo Park e, Hyo Rak Lee f, Won Ki Kang a,⇑ a

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea b Division of Hematology-Oncology, Department of Medicine, College of Medicine, Gyeongsang National University, Jinju, South Korea c Division of Hematology-Oncology, Department of Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea d Division of Hematology-Oncology, Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea e Division of Hematology-Oncology, Department of Medicine, College of Medicine, Dankook University, Cheonan, South Korea f Division of Hematology-Oncology, Department of Medicine, Korea Cancer Center Hospital, Seoul, South Korea Received 21 March 2014; received in revised form 9 July 2014; accepted 6 August 2014 Available online 15 September 2014

KEYWORDS Synthetic 3-hydroxy-3methyglutaryl coenzyme A (HMG-CoA) Simvastatin Gastric cancer

Abstract Purpose: We aimed to the addition of synthetic 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to capecitabine–cisplatin (XP) in patients with previously untreated advanced gastric cancer (AGC). Methods: In this double-blind, placebo-controlled, phase III study, we enrolled patients aged 18 years or older with histological or cytological confirmed metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) at nine centres in Korea. Patients, stratified by disease measurability and participating site, were randomly assigned (1:1) to receive capecitabine 1000 mg/m2 twice daily for 14 days and cisplatin 80 mg/m2 on day 1 every 3 weeks plus either simvastatin 40 mg or placebo, once daily. Cisplatin was given for 8 cycles; capecitabine and simvastatin were administered until disease progression or unacceptable toxicities. This study is registered with ClinicalTrials.gov, number NCT01099085.

⇑ Corresponding author: Address: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, South Korea. Tel.: +82 2 3410 3451; fax: +82 2 3410 1754. E-mail address: [email protected] (W.K. Kang). 1 These two authors contributed equally.

http://dx.doi.org/10.1016/j.ejca.2014.08.005 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.

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Results: Between February 2009 and November 2012, 244 patients were enrolled and assigned to treatment groups (120 simvastatin, 124 placebo). Median progression free survival (PFS) for 120 patients allocated XP plus simvastatin was 5.2 months (95% confidence interval (CI) 4.3–6.1) compared with 4.63 months (95% CI 3.5–5.7) for 124 patients who were allocated to XP plus placebo (hazard ratio 0.930, 95% CI 0.684–1.264; p = 0.642). 63 (52.5%) of 120 patients in simvastatin group and 70 (56.4%) of 124 had grade 3 or higher adverse events. Conclusions: Addition of 40 mg simvastatin to XP does not increase PFS in our trial, although it does not increase toxicity. Low dose of simvastatin (40 mg) to chemotherapy is not recommended in untargeted population with AGC. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Gastric cancer (GC) is the second most common cause of cancer-related death world-wide and the most frequently occurring malignancy in Korea [1,2]. Although most patients with the early stage disease receive surgical resection with curative intent, more than 60% of these patients have a high rate of locoregional as well as distant recurrence [3–5]. For patients with unresectable, recurrent or advanced gastric cancer (AGC), systemic chemotherapy can improve survival and symptom control. Combination chemotherapy improves treatment outcomes compared with mono-chemotherapy or best supportive care (BSC) in patients with advanced gastric cancer [6]. Although there is no internationally accepted standard of first line chemotherapy regimen, either infusional or oral fluoropyrimidine plus platinum compound is now regarded as a standard regimen. However, more than half of patients with AGC who receive standard chemotherapy did not achieve response, and even in responders, the duration of response was as short as a few months [7]. Statins are synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors which are commonly used drugs for treatment of hypercholesterolemia. Statins inhibit the rate limiting step of the mevalonate pathway in which mevalonic acid is the precursor in the biosynthesis of isoprenoid molecules such as cholesterol, dolichol and ubiquinone. Mevalonatederived prenyl groups, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), facilitate essential intracellular functions of various proteins [8–10]. FFP and GGPP are essential substrates for posttranslational modifications of rat sarcoma viral oncogene homologue (RAS) and ras homologue gene family, member A (RHOA), which play an important role in cellular proliferation. Based on the effect of statin on posttranscriptional modifications of RAS and RHOA, the antitumour effect of statins has been suggested in various cancer cell lines [11–13]. However, most studies used high concentrations of statin which was not feasible for human use to demonstrate an antitumour effect [14–16]. Recently, we demonstrated antitumour effect of simvastatin using a dose level that is equivalent to cardiovascular therapeutic dose level

in humans [17,18]. In addition, other studies reported that low concentrations of statins induced apoptosis of microvascular endothelial cells and lowered vascular endothelial growth factor (VEGF) serum levels implicating a possible antiangiogenic role in cancer treatment [19,20]. Hence, our group conducted clinical trials for chemotherapy plus low-dose simvastatin in various cancer types and demonstrated that there were no additive side-effects [18,21]. In the placebo-controlled, double-blinded, simvastatin in combination with capecitabine–cisplatin (XP) in advanced gastric cancer study, we aimed to assess efficacy and safety of the addition of simvastatin to first line capecitabine–cisplatin (XP) chemotherapy in patients with unresectable advanced or metastatic gastric adenocarcinoma. 2. Patients and methods 2.1. Study design This study was a prospective, random-assignment, double-blinded, placebo-controlled phase III clinical trial. The protocol was approved at each participating site by an institutional review board. This study was registered with ClinicalTrials.gov, identifier: NCT01099085 and conducted according to the Declaration of Helsinki and all of its amendments. All patients provided written informed consent before study enrolment. Patients were assigned (1:1 ratio) to each treatment group by using randomisation with participating sites and disease measurability (measurable disease/ un-measurable disease) as stratification factors. 2.2. Eligibility criteria Patients were enrolled to this study based on the following eligibility criteria: histologically or cytologically confirmed adenocarcinoma of the stomach and gastroesophageal junction (GEJ); stage IV disease (based on American Joint Committee on Cancer 2002 staging system) not amenable to surgery, radiation or combined modality therapy with curative intent; measurable or evaluable disease based on Response Evaluation Criteria

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in Solid Tumours (RECIST) criteria, version 1.0; age 18 years or older; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2; adequate function of major organs (including cardiac, hepatic and renal function); and adequate bone marrow function (absolute neutrophil count [ANC] P 1.500/ul; platelet count P100,000/ul). Patients with active central nervous system (CNS) metastasis not controllable with radiotherapy or steroid or who had prior history of another malignancy within 5 years of study except for basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix, were excluded. Patients with lower density lipoprotein (LDL) level 6 lower limit normal level, or use of a statin as an anti-hyperlipidemia agent within 1 year of the study entry were also excluded in this study. 2.3. Treatment All patients received simvastatin 40 mg or placebo, administered orally once daily, which was continued until disease progression, unacceptable toxic effects or withdrawal of consent. All patients also received cisplatin 80 mg/m2 intravenously during 2 h on day 1 with hyperhydration plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 every 3 weeks. Cisplatin was given for eight cycles; capecitabine could be administered over more than 8 cycles with simvastatin until disease progression or unacceptable toxicity. Dose modifications for simvastatin, capecitabine and cisplatin were performed per the study protocol (see Supplementary Material). 2.4. Assessments Medical history, chest X-ray, EOCG performance status, physical examination and laboratory test (complete blood counts, chemistry, electrolyte, coagulation,

Creatinine phosphokinase, lipid profile and urinalysis) were assessed within one week before starting treatment. During treatment, physical examination, vital signs and laboratory test were repeated before every cycle. Tumour assessments (computed tomography scan of the chest, abdomen and pelvis) were allowed to be conducted within 28 days before starting the treatment and were performed every 2 cycles until the progression of disease. The same method and technique of tumour assessment were used to characterise each identified and reported lesion at the baseline and during the follow-up. The tumour response was classified on the basis of Response Evaluation Criteria in Solid Tumours (RECIST) criteria, version 1.0 guidelines with confirmation that response lasted longer than 4 weeks. Once disease progression had been documented, patients were followed for survival status every 2 months until death. Safety assessments were conducted until 21 days after the last dose of study treatment. Adverse effects were graded and monitored in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0). 2.5. Statistical analysis The intent to treat population included all recruited subjects who received any study medication. The safety population included all randomly assigned patients who received at least one dose of study treatment. Primary end-point of this study was progression free survival (PFS) which was defined as the time from date of first study treatment to date of first documented disease progression or death. Key secondary end-points were toxicity, response rate (RR) and overall survival (OS). To determine sample size, the following fixed design parameters were used: two-sided, 0.05 significance level,

Fig. 1. CONSORT diagram.

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patients) were required. The Kaplan–Meier method was used to estimate PFS curve, and Cox proportional hazards regression models were conducted with relevant covariates (sex, age ECOF performance status, primary site of cancer, measurability, liver metastasis, peritoneal metastasis, prior gastrectomy and prior [neo]adjuvant chemo[radio]therapy).

Table 1 Baseline characteristics (Intention-to-treat population). Variables

Capecitabine–cisplatin + Simvastatin (n = 120)

Placebo (n = 124)

No.

No.

%

85 39

68.5 31.5

%

Sex Male Female

91 29

Age, years Median Range

53.5 20–78

ECOG performance status 0–1 P2

119 1

99.2 0.8

120 4

96.7 3.3

Primary tumour site Stomach Gastroesophageal junction Unknown Measurable disease

94 6 20 76

78.3 5.0 16.6 63.3

99 6 19 80

79.8 4.8 15.3 64.5

Extent of disease Metastatic Liver metastasis Peritoneal metastasis

120 27 52

100.0 22.5 43.3

124 28 55

100.0 22.6 44.4

Previous treatment Neoadjuvant therapy Gastrectomy Adjuvant therapy

1 35 8

0.8 29.2 6.6

– 43 13

– 34.7 10.4

75.8 24.2

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3. Results

54.5 24–79

3.1. Patients Between February 2009 and November 2012, 244 patients were enrolled and assigned to treatment groups (120 simvastatin, 124 placebo) at nine centres in KOREA (Fig. 1). Patients’ characteristics were well balanced between treatment groups (Table 1). 3.2. Treatment

accrual of 55 patients per year, randomisation ratio of 1:1, approximately total accrual duration of 53 months and an additional 12 months of follow up and a 10% dropout rates. We hypothesised that PFS rate at 1 year in the placebo group was 20% from literature review. PFS rate at 1 year in the simvastatin group was 35% or more. Assuming an exponential PFS model, this comparison corresponds to a hazard ratio of 1.533 to provide 85% power. A total of 244 patients (218 eligible

Median treatment duration was 4.43 months in the simvastatin plus XP group and 4.50 months in the placebo plus XP group without significant difference. Median dose intensities (i.e. actual dose administered divided by planned dose) were 93.4% and 90.5% for capecitabine and 94.8% and 94.6% for cisplatin in simvastatin and placebo groups, respectively. Median dose intensity of simvastatin was 99.4%. 3.3. Efficacy 167 progression events occurred (82 in the simvastatin plus XP group and 85 in the placebo plus XP group). Median PFS, the primary objective in this study was 5.2 months (95% Confidence interval (CI), 4.3– 6.1 months) in the simvastatin group and 4.6 months (95% CI, 3.5–5.7) in the placebo group (hazard

Table 2 Unadjusted analysis of efficacy (intention to treat population). Variable

Capecitabine–cisplatin + Simvastatin (n = 120) No.

%

Overall survival Deaths Median overall survival, months 1-year survival

89 11.6 47.9

74.2

Progression-free survival Progression events Median progression free survival, months

82 5.2

68.3

Response Overall response rate Complete response Partial response Stable response

33 4 29 61

27.5 3.3 24.2 50.9

p-Value Placebo (n = 124)

95% confidence interval (CI)

No.

%

95 11.5 47.7

76.6

9.2–13.9 39.1–57.6

85 4.6

68.5

4.3–6.1

36 3 33 61

29.0 2.4 26.6 49.2

19.7–36.4

95% CI

9.9–13.1 39.3–57.5

0.818

3.5–5.7

0.642

21.2–37.8

0.936

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ratio[HR]; 0.930, 95% CI, 0.684–1.264, p = 0.664) (Table 2 and Fig. 2A). PFS rate at 1 year was 13.0% and 11.9% in the simvastatin and the placebo groups, respectively. OS was not significantly different between the two groups (HR; 0.966, 95% CI, 0.722–1.293, p = 0.818). Median OS was 11.6 months (95% CI, 9.2–13.9) in the simvastatin plus XP group and 11.5 months (95% CI, 9.9–13.1) in the placebo plus XP group (Table 2 and Fig. 2B). Overall response rate was not increased significantly with the addition of simvastatin (27.5% versus 29.0 in the placebo plus XP group, p = 0.936). 3.4. Adverse effects All patients enrolled were assessable for adverse effects. 63 (52.5%) of 120 patients in the simvastatin group and 70 (56.4%) of 124 had grade 3 or higher adverse events (Table 3). Most common grade 3 or higher adverse events were neutropenia (40.5%, simvastatin plus XP; 51% placebo plus XP), anaemia (13.3% versus 10.5%) and anorexia (7.5% versus 10.5%). The addition of simvastatin did not cause clinically significant increase in treatment related toxicities. Three patients experienced grade 3 or 4 increase of creatinine phosphokinase (CK) level which was considered to be related to the use of simvastatin. There were also patients with grade 3 or 4 elevated liver enzyme levels (2; alanine aminotransferase [ALT] and 3; aspartate aminotransferase [AST]) who had received simvastatin. However, abnormal elevations of CK, ALT and AST were eventually normalised with supportive management and there was no significant difference for simvastatin specific adverse events of grade 3 or 4 between two treatment groups.

Table 3 Most common grade 3 to 4 adverse events and adverse events of special interest to simvastatin. Capecitabine–cisplatin +

Any adverse events Neutropenia Anaemia Thrombocytopenia Febrile neutropenia Nausea Vomiting Anorexia Mucositis Diarrhoea Neuropathy Hand-Foot syndrome Pain Simvastatin special adverse events Alanine aminotransferase elevation Aspartate aminotransferase elevation Creatinine phosphokinase elevation

Simvastatin (n = 120)

Placebo (n = 124)

No.

%

No.

%

49 16 4 – 2 4 9 – 4 1 2 3

40.8 13.3 3.3 – 1.7 3.3 7.5 – 3.3 0.8 1.7 2.5

51 13 4 1 9 4 13 2 4 3 2 5

41.1 10.5 3.2 0.8 7.3 3.2 10.5 1.6 3.2 2.4 1.6 4.0

2 3 3

1.7 2.5 2.5

2 1 1

1.6 0.8 0.8

3.5. Subgroup analysis We analysed the difference of survival outcomes between subgroups according to baseline characteristics including sex, age, PS, primary tumour site, presence of measurable disease, liver metastasis, peritoneal metastasis, prior gastrectomy and prior (neo)adjuvant chemo(radio)therapy. We found few differences between treatment groups for either PFS or OS in analysis of subgroups (Tables 4 and 5). Any subgroups in which the 95% CI upper limits were less than 1 were not observed in our analysis.

Fig. 2. Kaplan–Meier estimates for progression free survival (PFS) (A) and overall survival (OS) (B) in randomly assigned patients.

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Table 4 Forest plots for progression free survival in a prespecified subgroup analysis. Parameter Sex Age ECOG Primary site Measurability Liver metastasis Peritoneal metastasis Prior Gastrectomy Prior (neo)adjuvant Chemo(radio)therapy

Male Female <65 years P65 years 0 P1 Stomach GEJ Measurable Non-measurable Yes No Yes No Yes No Yes No

N

Progression free survival (PFS) (SIMVA)

PFS (PLACEBO)

Hazard ratio (HR)

176 68 201 43 15 229 193 12 156 88 55 189 107 137 78 166 22 222

5.4 5.1 5.1 7.0 3.2 5.4 5.2 9.3 4.7 7.0 4.7 5.7 4.9 6.0 6.0 4.9 6.9 5.2

5.3 3.5 4.2 7.2 5.9 4.2 4.7 4.2 3.9 6.0 4.2 4.7 4.7 4.2 5.9 4.2 3.5 4.7

1.040 0.671 0.933 0.994 2.388 0.888 0.995 0.163 0.841 1.049 0.802 0.940 1.009 0.857 1.154 0.735 0.352 0.993

4. Discussion This study is the first phase III evaluation of HMGCoA reductase inhibitor, simvastatin, with chemotherapy in advanced gastric adenocarcinoma. We observed that the addition of simvastatin to capecitabine– cisplatin (XP) did not improve PFS compared with XP

(0.722–1.499) (0.375–1.201) (0.669–1.303) (0.436–2.265) (0.464–12.285) (0.646–1.219) (0.710–1.396) (0.017–1.597) (0.574–1.233) (0.619–1.776) (0.399–1.611) (0.666–1.327) (0.650–1.568) (0.558–1.316) (0.633–2.105) (0.508–1.064) (0.091–1.362)) (0.722–1.366)

alone. Therefore, the primary end-point was not met. PFS in the simvastatin plus XP (median 5.2 months) was not improved compared with results from previous randomised doublet or triplet chemotherapy regimens in first line setting of AGC (median 3.9–7.0 months). However, the addition of simvastatin using a dose level that is equivalent to cardiovascular therapeutic dose did not

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Table 5 Forest Plots for overall survival in a prespecified subgroup analysis. Parameter Sex Age ECOG Primary site Measurability Liver metastasis Peritoneal metastasis Prior Gastrectomy Prior (neo)adjuvant Chemo(radio)therapy

Male Female <65 years P65 years 0 P1 Stomach GEJ Measurable Non-measurable Yes No Yes No Yes No Yes No

N

Overall survival (OS) (SIMVA)

OS (PLACEBO)

Hazard ratio (HR)

176 68 201 43 15 229 193 12 156 88 55 189 107 137 78 166 22 222

11.9 11.6 11.6 17.3 13.2 11.6 11.1 20.3 11.1 17.2 11.1 11.9 11.6 11.6 18.0 10.3 13.7 11.6

11.8 11.0 11.9 10.8 10.8 11.5 11.0 8.7 11.4 12.2 10.8 12.2 11.9 11.9 16.1 10.8 10.9 11.8

0.947 1.047 0.965 0.893 1.801 0.942 1.009 0.647 1.013 0.822 1.083 0.987 1.082 0.924 0.901 0.976 0.966 0.972

significantly increase the adverse effect of XP chemotherapy alone. The potential role of statins as anti-cancer agents in various tumour types had been revealed successively [14–16,22,23]. Statins are synthetic HMG-CoA reductase inhibitors and are commonly used drugs for the treatment of hypercholesterolemia. Our group reported that

(0.673–1.334) (0.593–1.850) (0.701–1.329) (0.428–1.864) (0.347–9.342) (0.700–1.268) (0.737–1.381) (0.183–2.290) (0.703–1.458) (0.581–1.540) (0.537–2.181) (0.710–1.372) (0.728–1.609) (0.622–1.373) (0.520–1.562) (0.691–1.377) (0.333–2.801) (0.717–1.316)

the addition of 0.2 uM simvastatin (equivalent to the human cardiovascular dose) to cetuximab significantly enhanced anti-tumour activity in KRAS mutant colon cancer cells [17]. The concentration range of 0.1– 0.2 Um could be achieved by the dose of simvastatin, 0.5 mg kg 1 day 1 [12,24]. In addition, other studies reported that low concentrations of statins (equivalent

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to the human cardiovascular dose) induced apoptosis of microvascular endothelial cells and lowered VEGF serum levels implicating a possible anti-angiogenic role in cancer treatment [19,20,25]. Based on these findings, we decided the dose-level of simvastatin (40 mg) of this study and used this dose-level (simvastatin 40 mg) in other trials for statin [18,21]. However, the low dose of simvastatin may influence on outcomes of trials. Previously, we showed that simvastatin and lovastatin, at a concentration range of 0.1–0.2 uM, induced cell senescence or cytostatic effect of prostate cancer cells [12]. The cardiovascular therapeutic dose of 0.5 mg kg 1 day 1 of simvastatin and 1 mg kg 1 day 1 lovastatin could make the concentration range of 0.1–0.2 uM [12,24,26]. However, this low dose of statins may not be sufficient to control the growth of tumour cell lines [12]. To achieve more adequate control for tumour cells, a high concentration of statin was required [14,27–30]. Our group conducted a phase II study of high dose lovastatin, 35 mg/kg in GCs. Although high dose lovastatin monotherapy did not reveal the adequate anti-tumour activity, this dosage had relatively tolerable toxicities [14]. Other studies with the high dosage of statin also reported the tolerable toxicity-profiles [16]. Based on these findings, intermediate or high dosage of statin which can reach high concentrations must be considered to combine with the chemotherapy to improve the anti-tumour effect without the increased adverse effects. The research is needed to find the optimal dose of statin to inhibit more effectively the growth of tumour cells, on combining the chemotherapy. From the 120 patients randomly assigned to the simvastatin plus XP group, we obtained 42 tissue specimens (35%) with sufficient RNA for Nanostring-Based Multigene Assay of 519 human kinase genes. We evaluated the expression-nature of kinase genes by this the nCounterÒ assay (NanoString Technologies, Seattle, WA, USA) in 42 patients. Among expression nature of 519 kinase genes, overexpressed kinase genes related to the response for simvastatin plus XP were sorted while changing the weight of p-value. When the cut-off of p-value for the significance is 0.05, there is significant overexpression of 9 genes such as CDC7, PRKD1, PRKCG, RIPK2, PDK3, SPEG, MASTL, MYLK and MAP3K12 (Supplementary Material 2). It has been not known the relation between these kinase genes and mechanism of statin. Although we tried to do comprehensive genomic analysis for biomarkers to the activity of statin plus chemotherapy, sample size analysed was too small and validation and functional study for markers was not conducted. Although the difference in PFS, the primary endpoint in our study, did not reach statistical significance (5.2 v 4.6 months, HR, 930; p = 0.664), our results should not conclusively exclude the use of simvastatin for AGC. The low dose of simvastatin, 40 mg is too

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insufficient to achieve the concentration range with the repressive-effect on cancer cells. Given the emerging role of statins for anti-cancer effect, we believe that further studies are justified to investigate the intermediate or high dosage of simvastatin combined with synergistically interacted chemotherapy regimes in advanced GCs. Thus, currently, our group plans to conduct clinical trials for standard therapy plus simvastatin of the dose achieving the concentration range with the apoptotic effect in various advanced gastrointestinal cancers. Conflict of interest statement None declared. Acknowledgments We acknowledge the CJ Corp. who kindly donated simvastatin and placebo for the study. This work was supported by Grants from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102166). This study was supported by an Intramural grant from Samsung Medical Center (CRS109613). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.ejca.2014.08.005. References [1] Tanaka M, Ma E, Tanaka H, Ioka A, Nakahara T, Takahashi H. Trends of stomach cancer mortality in Eastern Asia in 1950– 2004: comparative study of Japan, Hong Kong and Singapore using age, period and cohort analysis. Int J Cancer 2012;130: 930–936. [2] Jung KW, Park S, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. Cancer Res Treat 2012;44:11–24. [3] Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000;87:236–42. [4] Landry J, Tepper JE, Wood WC, Moulton EO, Koerner F, Sullinger J. Patterns of failure following curative resection of gastric carcinoma. Int J Radiat Oncol Biol Phys 1990;19:1357–62. [5] Lim DH, Kim DY, Kang MK, et al. Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: a radiation oncologist’s view. Br J Cancer 2004;91:11–7. [6] Wagner AD, Unverzagt S, Grothe W. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3.1– 110). http://dx.doi.org/10.1002/14651858.CD004064.pub3 [Article No. CD004064]. [7] Van Cutsem E, Haller D, Ohtsu A. The role of chemotherapy in the current treatment of gastric cancer. Gastric Cancer 2002;5(Suppl. 1): 17–22.

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