今日の臨床サポート 今日の臨床サポート

著者: 井ノ口幹人 武蔵野赤十字病院 外科

監修: 杉原健一 東京医科歯科大学大学院

著者校正/監修レビュー済:2024/06/26
参考ガイドライン:
  1. 日本胃癌学会:胃癌治療ガイドライン 医師用 2021年7月改訂 第6版
患者向け説明資料

改訂のポイント:
  1. 切除不能進行・再発胃癌に対する一次治療についてのガイドライン速報(2021年12月)の内容に基づき、以下について追記した。
  1. 切除不能進行・再発胃癌の場合には化学療法の適応となる。分子標的薬や免疫チェックポイント阻害薬の選択のために、腫瘍の生検や切除材料を用いてHER2蛋白質、PD-L1蛋白質の免疫染色を行う。またミスマッチ修復蛋白質の免疫染色も行いマイクロサテライト不安定性を調べておく。
  1. HER2陰性の切除不能進行・再発胃癌に対して推奨される一次治療は、フッ化ピリミジン製剤(S-1、カペシタビン、5-FU)とプラチナ製剤(オキサリプラチン、シスプラチン)の化学療法とニボルマブの併用療法である。
  1. 近年、免疫チェックポイント阻害薬のニボルマブと化学療法の有用性を示す2つのランダム化試験が発表された。1つ目が日本を含む全世界で施行された第Ⅲ相のCheckMate649試験である(Janjigian YY, et al. Lancet. 2021 Jul 3;398(10294):27-40.)。CPS (combined positive score:腫瘍組織における PD-L1 を発現した腫瘍細胞及び免疫細胞数の総腫瘍細胞数に対する%)が5以上のサブセットにおける無増悪生存期間は化学療法+ニボルマブ群で有意に延長し、奏効割合は化学療法+ニボルマブ群で高かった。中間解析において全生存期間も有意に化学療法+ニボルマブ群で延長していた。全登録例でも全生存期間は有意に延長した。
  1. 2つ目はアジア(日本・韓国・台湾)にて実施された第II/III相のATTRACTION-4 試験である(Kang YK, et al. Lancet Oncol. 2022 Feb;23(2):234-247.)。HER2 陰性の未治療胃癌患者に対する標準治療(S-1 とオキサリプラチンの併用療法もしくはカペシタビンとオキサリプラチンの併用療法)に対するニボルマブの優越性が検討され、ニボルマブ併用群で無増悪生存期間は有意に延長した。しかし全生存期間は有意差を認めなかった。本試験ではCPSを用いた解析は行われていない。

概要・推奨   

  1. 内視鏡的粘膜下層剥離術の絶対適応は、臨床的StageⅠの粘膜内癌のうち、①分化型、UL0(潰瘍瘢痕なし)、②分化型、UL1(潰瘍瘢痕あり)、大きさが3 ㎝以下、③未分化型、UL0、大きさが2 ㎝以下である(推奨度1 RJ)
  1. 臨床的StageⅠに対する腹腔鏡下幽門側胃切除術は標準治療のひとつとして強く推奨する(推奨度1 RsJ)。腹腔鏡下胃全摘術と腹腔鏡下噴門側胃切除術は明確なデータはなく弱く推奨する(推奨度2 OJ)
  1. ロボット支援下手術は臨床的StageⅠに対して行うことを弱く推奨する(推奨度2 OJ)
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病態・疫学・診察 

疾患情報(疫学・病態)  
  1. わが国を含む東アジアでは胃癌罹患の主な原因はヘリコバクター・ピロリ菌である。ピロリ菌の有する東アジア型CagAが胃癌の発症に深く関与していると考えられている[1]。しかし、わが国ではピロリ菌感染率の低下に伴い、罹患率が低下している。西欧や米国ではヘリコバクター・ピロリ菌感染率が低く、さらに欧米型CagAを有するため、胃癌の罹患率が低いと考えられる。一方で食道胃接合部癌は増加傾向であり、食道胃逆流症がリスク因子のひとつである[2]
  1. 他の胃癌のリスク因子としてアルコール摂取、喫煙、肥満、βカロテンの摂取不足、塩分・野菜の漬物・発酵大豆食品・加工肉の摂取が挙げられる[3]
  1. 男女比は2:1程度である。
  1. 2018年のInternational Agency for Research on Cancer (IARC) の報告(GLOBOCAN2018)では世界での胃癌の罹患数は約103万人(全癌罹患数の5.7%)であり、肺癌、乳癌、大腸癌、前立腺癌に次いで第5位であった。死亡数は約78万人(全癌死亡数の8.2%)であり、肺癌、大腸癌に次いで第3位であった[4]
  1. わが国の2016年の胃癌の罹患数は約13万5千人であった。全体で大腸癌に次いで2位であり、男性では1位、女性では乳癌、大腸癌に次いで3位であった[5]
  1. わが国の2018年の胃癌の死亡数は約4万4千人であった。全体で肺癌、大腸癌に次いで3位であり、男性では肺癌に次いで2位、女性では大腸癌、肺癌、膵臓癌に次いで4位であった[5]
  1. 75歳未満の部位別がん年齢調整死亡率では男女とも年次推移で大きく減少傾向を示しており、男性では1995年に人口10万人対で28.9人(1位)から2016年に12.5人へ減少(肺癌、大腸癌に次いで3位)、女性では同年で12.1人(1位)から4.9人へ減少した(乳癌、大腸癌、肺癌に次いで4位)[6]
  1. 粘膜内、または粘膜下層にとどまるものを早期胃癌と定義する。
  1. 治療は外科的切除が主体であり、進行度などによって内視鏡的切除、腹腔鏡下手術、開腹手術などが行われる。
  1. 食道胃接合部癌は腫瘍の中心が食道胃接合部の上下2 cm以内に存在するものと定義する。海外ではSiewert分類が用いられておりType IIが相当する。
  1. 粘膜下層まで浸潤すれば10%以上の確率で所属リンパ節に転移するので、リンパ節郭清が必要と考えられている。
  1. リンパ行性、血行性、播種性のいずれのルートからも転移する、比較的悪性度の高い癌である。
  1. Stage II、IIIの場合の再発防止のための補助療法は有用である。補助療法としてS-1単剤、カペシタビン+オキサリプラチン、特にStage IIIの場合はS-1+ドセタキセル併用療法を行う。
  1. Stage IVの場合には、一般的に、化学療法、放射線療法、緩和手術、best supportive careのいずれか、あるいはその組み合わせで治療を行う。
  1. Stage IVのうち、個数が少なく他に遠隔転移のない肝転移例、少数の大動脈周囲リンパ節転移例、洗浄細胞診陽性例などは、外科的切除を含む集学的治療の適応である。
問診・診察のポイント  
問診:
  1. 胃癌に特異的な症状は少なく、無症状の場合もしばしばある。経口摂取が可能かどうか、最近の体重の変動、栄養状態などに気を配る必要がある。全身麻酔の手術において周術期に問題となりそうな既往歴、喫煙歴などを確認する。喫煙者には速やかに禁煙を指示する。

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文献 

Hayashi T, Senda M, Suzuki N, Nishikawa H, Ben C, Tang C, Nagase L, Inoue K, Senda T, Hatakeyama M.
Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins.
Cell Rep. 2017 Sep 19;20(12):2876-2890. doi: 10.1016/j.celrep.2017.08.080.
Abstract/Text Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.

Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PMID 28930683
Buas MF, Vaughan TL.
Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease.
Semin Radiat Oncol. 2013 Jan;23(1):3-9. doi: 10.1016/j.semradonc.2012.09.008.
Abstract/Text Gastroesophageal (GE) junction carcinoma is a rare but often lethal condition with increasing importance as a public health problem in recent decades. Whereas diagnosis of this disease has been complicated historically by the lack of uniform classification standards, available data from the Surveillance, Epidemiology, and End Results cancer registry program in the United States show an approximate 2.5-fold increase in the incidence of GE junction adenocarcinoma from 1973 to 1992, with rates stabilizing in the past 2 decades. Similar proportional trends are observed among subgroups defined by race and gender, but rates are significantly higher in males relative to females, and in white males relative to black males. Smoking, obesity, and GE reflux disease are significant risk factors for GE junction adenocarcinoma, and may account for a substantial fraction of total disease burden. Infection with Helicobacter pylori has been associated with reduced incidence, and high dietary fiber intake has also been linked to lower disease risk. Ongoing studies continue to explore a potential role for nonsteroidal anti-inflammatory drugs in chemoprevention.

Copyright © 2013 Elsevier Inc. All rights reserved.
PMID 23207041
Li L, Ying XJ, Sun TT, Yi K, Tian HL, Sun R, Tian JH, Yang KH.
Overview of methodological quality of systematic reviews about gastric cancer risk and protective factors.
Asian Pac J Cancer Prev. 2012;13(5):2069-79. doi: 10.7314/apjcp.2012.13.5.2069.
Abstract/Text BACKGROUND AND OBJECTIVE: A comprehensive overall review of gastric cancer (GC) risk and protective factors is a high priority, so we conducted the present study.
METHODS: Systematic searches in common medical electronic databases along with reference tracking were conducted to include all kinds of systematic reviews (SRs) about GC risk and protective factors. Two authors independently selected studies, extracted data, and evaluated the methodological qualities and the quality of evidence using R-AMSTAR and GRADE approaches.
RESULTS: Beta- carotene below 20 mg/day, fruit, vegetables, non-fermented soy-foods, whole-grain, and dairy product were GC protective factors, while beta-carotene 20 mg/day or above, pickled vegetables, fermented soy-foods, processed meat 30 g/d or above, or salty foods, exposure to alcohol or smoking, occupational exposure to Pb, overweight and obesity, helicobacter pylori infection were GC risk factors. So we suggested screening and treating H. pylori infection, limiting the amount of food containing risk factors (processed meat consumption, beta-carotene, pickled vegetables, fermented soy-foods, salty foods, alcohol), stopping smoking, avoiding excessive weight gain, avoidance of Pb, and increasing the quantity of food containing protective components (fresh fruit and vegetables, non-fermented soy-foods, whole-grain, dairy products).
CONCLUSIONS: The conclusions and recommendations of our study were limited by including SRs with poor methodological bases and low quality of evidence, so that more research applying checklists about assessing the methodological qualities and reporting are needed for the future.

PMID 22901173
New Global Cancer Data: GLOBOCAN 2018 [Internet]. Union Int Cancer Control. 2018. Available from: https://www.uicc.org/news/new-global-cancer-data-globocan-2018#
国立がん研究センターがん対策情報センター「最新がん統計」 [Internet]. Available from: https://ganjoho.jp/reg_stat/statistics/stat/summary.html
東京都福祉保健局 「がんの死亡率」. Available from: https://www.fukushihoken.metro.tokyo.lg.jp/smph/iryo/iryo_hoken/gan_portal/research/genjyou/sibouritu.html
Irino T, Sano T, Hiki N, Ohashi M, Nunobe S, Kumagai K, Ida S, Yamaguchi T.
Diagnostic staging laparoscopy in gastric cancer: a prospective cohort at a cancer institute in Japan.
Surg Endosc. 2018 Jan;32(1):268-275. doi: 10.1007/s00464-017-5673-z. Epub 2017 Jun 29.
Abstract/Text BACKGROUND: There have been many studies that describe the value of diagnostic staging laparoscopy (DSL) in gastric cancer. However, different studies use different indications, making study results difficult to compare. This study aimed to clarify the diagnostic feasibility of DSL for gastric cancer in a prospective manner and investigated the impact of DSL on clinical decision-making in gastric cancer treatment.
METHODS: The study was a prospective cohort study based at a single institution between January 2010 and December 2013. We treated 2213 patients with potentially resectable gastric cancer during this period. DSL was primarily indicated for asymptomatic patients with: (1) large Borrmann type 3 tumours ≥8 cm, (2) Borrmann type 4 tumours (linitis plastica), (3) bulky lymph nodes or paraaortic lymph node swelling, or (4) clinical suspicion of peritoneal disease. The primary outcome is change in treatment strategy, and the secondary outcomes are diagnostic accuracy of the indications and false negative rate of DSL.
RESULTS: DSL was performed on 156 (7%) of 2213 patients. Of these, peritoneal disease was found in 74 (47%) patients: (1) 56% for large type 3, (2) 54% for type 4, (3) 21% for bulky lymph nodes or paraaortic lymph node swelling, and (4) 20% for suspected peritoneal disease. The diagnostic accuracy of our indication for DSL was 92% for all patients and 74% for patients with cT3/T4 tumours. Among 82 patients without peritoneal disease, 66 patients (81%) underwent subsequent radical gastrectomy; peritoneal disease was discovered intraoperatively for 7 patients at laparotomy, indicating a false negative rate of 11%.
CONCLUSION: We confirmed that DSL performed according to our indication, in the context of gastric cancer, possesses diagnostic feasibility. Approximately half of the patients who underwent DSL consequently avoided unnecessary laparotomy and were able to receive appropriate alternative treatment.

PMID 28664424
Miki Y, Tokunaga M, Tanizawa Y, Bando E, Kawamura T, Terashima M.
Staging Laparoscopy for Patients with cM0, Type 4, and Large Type 3 Gastric Cancer.
World J Surg. 2015 Nov;39(11):2742-7. doi: 10.1007/s00268-015-3144-z.
Abstract/Text BACKGROUND: Staging laparoscopy (SL) is considered useful for detecting peritoneal metastasis, a task that is difficult using conventional imaging modalities. However, indications for the procedure remain unclear, with differences evident across reports. The present study aimed to clarify the effectiveness and limitations of SL for patients with type 4 and large type 3 gastric cancer.
METHODS: We included 88 patients with cM0, type 4 or large type 3 gastric cancer who underwent SL at the Shizuoka Cancer Center from August 2008 to June 2014, to determine the detection rate of peritoneal metastasis by SL. In addition, we calculated the false-negative rate of SL by recruiting patients who were diagnosed as P0 at SL and underwent laparotomy within 28 days after the SL.
RESULTS: P0CY0, P0CY1, P1CY0, and P1CY1 were diagnosed in 41 (46.6 %), 15 (17.0 %), 15 (17.0 %), and 17 (19.3 %) patients, respectively. Accordingly, clinically non-evident peritoneal metastasis was found in 36.3 % of patients, and 53.4 % of patients were diagnosed with stage IV. In addition, 29 patients diagnosed as P0 at SL underwent laparotomy within 28 days after the SL. Among them, peritoneal metastasis was found in five patients. Thus, the false-negative rate was 17.2 % (5/29, 95 % CI 7.6-34.6 %).
CONCLUSIONS: SL is useful for detecting previously unsuspected peritoneal metastasis and for avoiding unnecessary laparotomy, although the high false-negative rate cannot be ignored. Patients with cM0, type 4, and large type 3 gastric cancer are considered suitable candidates for SL.

PMID 26148519
Katai H, Ishikawa T, Akazawa K, Isobe Y, Miyashiro I, Oda I, Tsujitani S, Ono H, Tanabe S, Fukagawa T, Nunobe S, Kakeji Y, Nashimoto A; Registration Committee of the Japanese Gastric Cancer Association.
Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001-2007).
Gastric Cancer. 2018 Jan;21(1):144-154. doi: 10.1007/s10120-017-0716-7. Epub 2017 Apr 17.
Abstract/Text BACKGROUND: The aim of this retrospective study was to investigate the tumor characteristics, surgical details, and survival distribution of surgically resected cases of gastric cancer from the nationwide registry of the Japanese Gastric Cancer Association.
METHODS: Data from 118,367 patients with primary gastric carcinoma who underwent resection between 2001 and 2007 were included in the survival analyses. The 5-year survival rates were calculated for various subsets of prognostic factors.
RESULTS: The median age of the patients was 67 years. The proportions of patients with pathological stage (Japanese Gastric Cancer Association) IA, IB, II, IIIA, IIIB, and IV disease were 44.0%, 14.7%, 11.7%, 9.5%, 5.0%, and 12.4% respectively. The death rate within 30 days of operation was 0.5%. The 5-year overall survival rate in the 118,367 patients who were treated by resection was 71.1%. The 5-year overall survival rates of patients with pathological stage IA, IB, II, IIIA, IIIB, and IV disease were 91.5%, 83.6%, 70.6%, 53.6%, 34.8%, and 16.4% respectively. The 5-year disease-specific survival rates in the patients with pT1 (mucosa) disease after D1+ dissection of lymph node station no. 7 (D1 + α), D1+ dissection of lymph node station nos. 7, 8, and 9 (D1+ β), and D2 lymphadenectomy were 99.4%, 99.6%, and 99.1% respectively. The 5-year disease-specific survival rates in the patients with pT1 (submucosa) disease after D1 + α, D1 + β, and D2 lymphadenectomy were 97.3%, 98.1%, and 96.9% respectively.
CONCLUSION: Detailed analyses of the data from more than 100,000 patients show the recent trends of the outcomes of gastric cancer treatment in Japan and provide baseline information for use by medical communities around world.

PMID 28417260
Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P.
Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group.
Br J Cancer. 1999 Mar;79(9-10):1522-30. doi: 10.1038/sj.bjc.6690243.
Abstract/Text Controversy still exists on the optimal surgical resection for potentially curable gastric cancer. Much better long-term survival has been reported in retrospective/non-randomized studies with D2 resections that involve a radical extended regional lymphadenectomy than with the standard D1 resections. In this paper we report the long-term survival of patients entered into a randomized study, with follow-up to death or 3 years in 96% of patients and a median follow-up of 6.5 years. In this prospective trial D1 resection (removal of regional perigastric nodes) was compared with D2 resection (extended lymphadenectomy to include level 1 and 2 regional nodes). Central randomization followed a staging laparotomy. Out of 737 patients with histologically proven gastric adenocarcinoma registered, 337 patients were ineligible by staging laparotomy because of advanced disease and 400 were randomized. The 5-year survival rates were 35% for D1 resection and 33% for D2 resection (difference -2%, 95% CI = -12%-8%). There was no difference in the overall 5-year survival between the two arms (HR = 1.10, 95% CI 0.87-1.39, where HR > 1 implies a survival benefit to D1 surgery). Survival based on death from gastric cancer as the event was similar in the D1 and D2 groups (HR = 1.05, 95% CI 0.79-1.39) as was recurrence-free survival (HR = 1.03, 95% CI 0.82-1.29). In a multivariate analysis, clinical stages II and III, old age, male sex and removal of spleen and pancreas were independently associated with poor survival. These findings indicate that the classical Japanese D2 resection offers no survival advantage over D1 surgery. However, the possibility that D2 resection without pancreatico-splenectomy may be better than standard D1 resection cannot be dismissed by the results of this trial.

PMID 10188901
Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, Meyer S, Plukker JT, Van Elk P, Obertop H, Gouma DJ, van Lanschot JJ, Taat CW, de Graaf PW, von Meyenfeldt MF, Tilanus H; Dutch Gastric Cancer Group.
Extended lymph-node dissection for gastric cancer.
N Engl J Med. 1999 Mar 25;340(12):908-14. doi: 10.1056/NEJM199903253401202.
Abstract/Text BACKGROUND: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery.
METHODS: Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results.
RESULTS: Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent).
CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

PMID 10089184
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 May;11(5):439-49. doi: 10.1016/S1470-2045(10)70070-X. Epub 2010 Apr 19.
Abstract/Text BACKGROUND: Historical data and recent studies show that standardised extended (D2) lymphadenectomy leads to better results than standardised limited (D1) lymphadenectomy. Based on these findings, the Dutch D1D2 trial, a nationwide prospectively randomised clinical trial, was undertaken to compare D2 with D1 lymphadenectomy in patients with resectable primary adenocarcinoma of the stomach. The aim of the study was to assess the effect of D2 compared with D1 surgery on disease recurrence and survival in patients treated with curative intent.
METHODS: Between August, 1989, and July, 1993, patients were entered and randomised at 80 participating hospitals by means of a telephone call to the central data centre of the trial. The sequence of randomisation was in blocks of six with stratification for the participating centre. Eligibility criteria were a histologically proven adenocarcinoma of the stomach without evidence of distance metastasis, age younger than 85 years, and adequate physical condition for D1 or D2 lymphadenectomy. Patients were excluded if they had previous or coexisting cancer or had undergone gastrectomy for benign tumours. Strict quality control measures for pathological assessment were implemented and monitored. Analyses were by intention to treat. This study is registered with the NCI trial register, as DUT-KWF-CKVO-8905, EU-90003.
FINDINGS: A total of 1078 patients were entered in the study, of whom 996 were eligible. 711 patients underwent the randomly assigned treatment with curative intent (380 in the D1 group and 331 in the D2 group) and 285 had palliative treatment. Data were collected prospectively and all patients were followed up for a median time of 15.2 years (range 6.9-17.9 years). Analyses were done for the 711 patients treated with curative intent and were according to the allocated treatment group. Of the 711 patients, 174 (25%) were alive, all but one without recurrence. Overall 15-year survival was 21% (82 patients) for the D1 group and 29% (92 patients) for the D2 group (p=0.34). Gastric-cancer-related death rate was significantly higher in the D1 group (48%, 182 patients) compared with the D2 group (37%, 123 patients), whereas death due to other diseases was similar in both groups. Local recurrence was 22% (82 patients) in the D1 group versus 12% (40 patients) in D2, and regional recurrence was 19% (73 patients) in D1 versus 13% (43 patients) in D2. Patients who had the D2 procedure had a significantly higher operative mortality rate than those who had D1 (n=32 [10%] vs n=15 [4%]; 95% CI for the difference 2-9; p=0.004), higher complication rate (n=142 [43%] vs n=94 [25%]; 11-25; p<0.0001), and higher reoperation rate (n=59 [18%] vs n=30 [8%]; 5-15; p=0.00016).
INTERPRETATION: After a median follow-up of 15 years, D2 lymphadenectomy is associated with lower locoregional recurrence and gastric-cancer-related death rates than D1 surgery. The D2 procedure was also associated with significantly higher postoperative mortality, morbidity, and reoperation rates. Because a safer, spleen-preserving D2 resection technique is currently available in high-volume centres, D2 lymphadenectomy is the recommended surgical approach for patients with resectable (curable) gastric cancer.
FUNDING: Dutch Health Insurance Funds Council and The Netherlands Cancer Foundation.

2010 Elsevier Ltd. All rights reserved.
PMID 20409751
Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, Lui WY, Whang-Peng J.
Nodal dissection for patients with gastric cancer: a randomised controlled trial.
Lancet Oncol. 2006 Apr;7(4):309-15. doi: 10.1016/S1470-2045(06)70623-4.
Abstract/Text BACKGROUND: The survival benefit and morbidity after nodal dissection for gastric cancer remains controversial. We aimed to do a single-institution randomised trial to compare D1 (ie, level 1) lymphadenectomy with that of D3 (ie, levels 1, 2, and 3) dissection for gastric cancer in terms of overall survival and disease-free survival.
METHODS: From Oct 7, 1993, to Aug 12, 1999, 335 patients were registered. 221 patients were eligible, 110 of whom were randomly assigned D1 surgery and 111 of whom were randomly assigned D3 surgery, both with curative intent. Three participating surgeons had done at least 25 independent D3 dissections before the start of the trial, and every procedure was verified by pathological analyses. The primary endpoints were 5-year overall survival and 5-year disease-free survival. We also analysed risk of recurrence. Main analyses were done by intention to treat. This trial is registered at the US National Institute of Health website .
FINDINGS: Median follow-up for the 110 (50%) survivors was 94.5 months (range 62.9-135.1). Overall 5-year survival was significantly higher in patients assigned D3 surgery than in those assigned D1 surgery (59.5% [95% CI 50.3-68.7] vs 53.6% [44.2-63.0]; difference beteween groups 5.9% [-7.3 to 19.1], log-rank p=0.041). 215 patients who had R0 resection (ie, no microscopic evidence of residual disease) had recurrence at 5 years of 50.6% [41.1-60.2] for D1 surgery and 40.3% [30.9-49.7] for D3 surgery (difference between groups 10.3% [-3.2 to 23.7], log-rank p=0.197).
INTERPRETATION: D3 nodal dissection, compared with that of D1, offers a survival benefit for patients with gastric cancer when done by well trained, experienced surgeons.

PMID 16574546
Sano T, Sasako M, Yamamoto S, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, Yamamura Y, Okajima K.
Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501.
J Clin Oncol. 2004 Jul 15;22(14):2767-73. doi: 10.1200/JCO.2004.10.184. Epub 2004 Jun 15.
Abstract/Text PURPOSE: Radical gastrectomy with regional lymphadenectomy is the only curative treatment option for gastric cancer. The extent of lymphadenectomy, however, is controversial. The two European randomized trials only reported an increase in operative morbidity and mortality, but failed to show survival benefit, in the D2 lymphadenectomy group. We conducted a randomized controlled trial to compare the Japanese standard D2 and D2 + para-aortic nodal dissection.
PATIENTS AND METHODS: Only experienced surgeons in both procedures from 24 Japanese institutions participated in the study. Patients with potentially curable gastric adenocarcinoma (T2-subserosa, T3, or T4) who were surgically fit were intraoperatively randomized. Postoperative morbidity and hospital mortality were recorded prospectively in a fixed format and were compared between the two groups in this study.
RESULTS: A total of 523 patients were randomized between July 1995 and April 2001. Postoperative complications were reported in 24.5% of all patients. Although the morbidity for the extended surgery group (28.1%) was slightly higher than the standard group (20.9%), there was no difference in the incidence of four major complications (anastomotic leak, pancreatic fistula, abdominal abscess, pneumonia) between the two groups. Hospital mortality was reported at 0.80%: one patient in each group died of operative complications, while one from each group died of rapid progressive cancer while inpatient.
CONCLUSION: Specialized surgeons could safely perform gastrectomy with D2 lymphadenectomy in patients with low operative risks. Para-aortic lymphadenectomy could be added without increasing major surgical complications in this setting.

PMID 15199090
Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, Yamamura Y, Okajima K; Japan Clinical Oncology Group.
D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer.
N Engl J Med. 2008 Jul 31;359(5):453-62. doi: 10.1056/NEJMoa0707035.
Abstract/Text BACKGROUND: Gastrectomy with D2 lymphadenectomy is the standard treatment for curable gastric cancer in eastern Asia. Whether the addition of para-aortic nodal dissection (PAND) to D2 lymphadenectomy for stage T2, T3, or T4 tumors improves survival is controversial. We conducted a randomized, controlled trial at 24 hospitals in Japan to compare D2 lymphadenectomy alone with D2 lymphadenectomy plus PAND in patients undergoing gastrectomy for curable gastric cancer.
METHODS: Between July 1995 and April 2001, 523 patients with curable stage T2b, T3, or T4 gastric cancer were randomly assigned during surgery to D2 lymphadenectomy alone (263 patients) or to D2 lymphadenectomy plus PAND (260 patients). We did not permit any adjuvant therapy before the recurrence of cancer. The primary end point was overall survival.
RESULTS: The rates of surgery-related complications among patients assigned to D2 lymphadenectomy alone and those assigned to D2 lymphadenectomy plus PAND were 20.9% and 28.1%, respectively (P=0.07). There were no significant differences between the two groups in the frequencies of anastomotic leakage, pancreatic fistula, abdominal abscess, pneumonia, or death from any cause within 30 days after surgery (the rate of death was 0.8% in each group). The median operation time was 63 minutes longer and the median blood loss was 230 ml greater in the group assigned to D2 lymphadenectomy plus PAND. The 5-year overall survival rate was 69.2% for the group assigned to D2 lymphadenectomy alone and 70.3% for the group assigned to D2 lymphadenectomy plus PAND; the hazard ratio for death was 1.03 (95% confidence interval [CI], 0.77 to 1.37; P=0.85). There were no significant differences in recurrence-free survival between the two groups; the hazard ratio for recurrence was 1.08 (95% CI, 0.83 to 1.42; P=0.56).
CONCLUSIONS: As compared with D2 lymphadenectomy alone, treatment with D2 lymphadenectomy plus PAND does not improve the survival rate in curable gastric cancer. (ClinicalTrials.gov number, NCT00149279.)

2008 Massachusetts Medical Society
PMID 18669424
Hasuike N, Ono H, Boku N, Mizusawa J, Takizawa K, Fukuda H, Oda I, Doyama H, Kaneko K, Hori S, Iishi H, Kurokawa Y, Muto M; Gastrointestinal Endoscopy Group of Japan Clinical Oncology Group (JCOG-GIESG).
A non-randomized confirmatory trial of an expanded indication for endoscopic submucosal dissection for intestinal-type gastric cancer (cT1a): the Japan Clinical Oncology Group study (JCOG0607).
Gastric Cancer. 2018 Jan;21(1):114-123. doi: 10.1007/s10120-017-0704-y. Epub 2017 Feb 21.
Abstract/Text BACKGROUND: Endoscopic resection has been limited to intestinal-type gastric cancer (cT1a) with a low risk of lymph node metastasis (T1a ≤2 cm, without ulcers). This single-arm confirmatory trial evaluated the efficacy and safety of endoscopic submucosal dissection (ESD) for >2 cm ulcer-negative and ≤3 cm ulcer-positive intestinal-type gastric cancer (cT1a).
METHODS: The eligibility criteria included endoscopically diagnosed cT1a, a single primary intestinal-type gastric adenocarcinoma, an ulcer-negative lesion of any size or a ≤3 cm ulcer-positive lesion, cN0M0, and no prior treatment. If ESD resulted in noncurative resection, surgical resection was added. The primary endpoint was the 5-year overall survival (OS) (planned sample size was 470, with a one-sided alpha level of 2.5%). The threshold 5-year OS was 86.1%.
RESULTS: We enrolled 470 early gastric cancer patients [median tumor size, 25 (5-130) mm] from 29 institutions between June 2007 and October 2010. These patients had 152 ulcer-negative lesions (>2 and ≤3 cm), 111 ulcer-negative lesions (>3 cm), and 207 ulcer-positive lesions (≤3 cm). The success rate for en block resection was 99.1% (466/470). Additional gastrectomy was conducted in 131 patients (28%) who did not fulfill the curative resection criteria. The 5-year OS of all patients was 97.0% (95% confidence interval, 95.0-98.2%), which was higher than the threshold 5-year OS (86.1%). The 317 patients who satisfied the curative resection criteria had no recurrence. There were no ESD-related grade 4 adverse events.
CONCLUSION: ESD for early gastric cancers that met the expanded criteria for intestinal-type gastric cancer (cT1a) was acceptable and should be the standard treatment instead of gastrectomy.

PMID 28224238
Takizawa K, Ono H, Hasuike N, Takashima A, Minashi K, Boku N, Kushima R, Katayama H, Ogawa G, Fukuda H, Fujisaki J, Oda I, Yano T, Hori S, Doyama H, Hirasawa K, Yamamoto Y, Ishihara R, Tanabe S, Niwa Y, Nakagawa M, Terashima M, Muto M; Gastrointestinal Endoscopy Group (GIESG) and the Stomach Cancer Study Group (SCSG) of Japan Clinical Oncology Group.
A nonrandomized, single-arm confirmatory trial of expanded endoscopic submucosal dissection indication for undifferentiated early gastric cancer: Japan Clinical Oncology Group study (JCOG1009/1010).
Gastric Cancer. 2021 Mar;24(2):479-491. doi: 10.1007/s10120-020-01134-9. Epub 2020 Nov 8.
Abstract/Text BACKGROUND: While endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC.
METHODS: The key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC.
RESULTS: Three hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1-99.8).
CONCLUSIONS: ESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.

PMID 33161444
Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K; ACTS-GC Group.
Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.
N Engl J Med. 2007 Nov 1;357(18):1810-20. doi: 10.1056/NEJMoa072252.
Abstract/Text BACKGROUND: Advanced gastric cancer can respond to S-1, an oral fluoropyrimidine. We tested S-1 as adjuvant chemotherapy in patients with curatively resected gastric cancer.
METHODS: Patients in Japan with stage II or III gastric cancer who underwent gastrectomy with extended (D2) lymph-node dissection were randomly assigned to undergo surgery followed by adjuvant therapy with S-1 or to undergo surgery only. In the S-1 group, administration of S-1 was started within 6 weeks after surgery and continued for 1 year. The treatment regimen consisted of 6-week cycles in which, in principle, 80 mg of oral S-1 per square meter of body-surface area per day was given for 4 weeks and no chemotherapy was given for the following 2 weeks. The primary end point was overall survival.
RESULTS: We randomly assigned 529 patients to the S-1 group and 530 patients to the surgery-only group between October 2001 and December 2004. The trial was stopped on the recommendation of the independent data and safety monitoring committee, because the first interim analysis, performed 1 year after enrollment was completed, showed that the S-1 group had a higher rate of overall survival than the surgery-only group (P=0.002). Analysis of follow-up data showed that the 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% confidence interval, 0.52 to 0.87; P=0.003). Adverse events of grade 3 or grade 4 (defined according to the Common Toxicity Criteria of the National Cancer Institute) that were relatively common in the S-1 group were anorexia (6.0%), nausea (3.7%), and diarrhea (3.1%).
CONCLUSIONS: S-1 is an effective adjuvant treatment for East Asian patients who have undergone a D2 dissection for locally advanced gastric cancer. (ClinicalTrials.gov number, NCT00152217 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17978289
Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y.
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 Nov 20;29(33):4387-93. doi: 10.1200/JCO.2011.36.5908. Epub 2011 Oct 17.
Abstract/Text PURPOSE: The first planned interim analysis (median follow-up, 3 years) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival, the primary end point. The results were therefore opened at the recommendation of an independent data and safety monitoring committee. We report 5-year follow-up data on patients enrolled onto the ACTS-GC study.
PATIENTS AND METHODS: Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 after surgery or surgery only. S-1 (80 to 120 mg per day) was given for 4 weeks, followed by 2 weeks of rest. This 6-week cycle was repeated for 1 year. The primary end point was overall survival, and the secondary end points were relapse-free survival and safety.
RESULTS: The overall survival rate at 5 years was 71.7% in the S-1 group and 61.1% in the surgery-only group (hazard ratio [HR], 0.669; 95% CI, 0.540 to 0.828). The relapse-free survival rate at 5 years was 65.4% in the S-1 group and 53.1% in the surgery-only group (HR, 0.653; 95% CI, 0.537 to 0.793). Subgroup analyses according to principal demographic factors such as sex, age, disease stage, and histologic type showed no interaction between treatment and any characteristic.
CONCLUSION: On the basis of 5-year follow-up data, postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy.

PMID 22010012
Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, Nagao N, Takahashi M, Takagane A, Watanabe T, Kaji M, Okitsu H, Nomura T, Matsui T, Yoshikawa T, Matsuyama J, Yamada M, Ito S, Takeuchi M, Fujii M.
Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial.
J Clin Oncol. 2019 May 20;37(15):1296-1304. doi: 10.1200/JCO.18.01138. Epub 2019 Mar 29.
Abstract/Text PURPOSE: S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings.
PATIENTS AND METHODS: This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; β = .2).
RESULTS: The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable.
CONCLUSION: Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

PMID 30925125
Yoshikawa T, Terashima M, Mizusawa J, Nunobe S, Nishida Y, Yamada T, Kaji M, Fukushima N, Hato S, Choda Y, Yabusaki H, Yoshida K, Ito S, Takeno A, Yasuda T, Kawachi Y, Katayama H, Fukuda H, Boku N, Sano T, Sasako M.
Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104 [OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial.
Lancet Gastroenterol Hepatol. 2019 Mar;4(3):208-216. doi: 10.1016/S2468-1253(18)30383-2. Epub 2019 Jan 22.
Abstract/Text BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer.
METHODS: We did a phase 3, open-label, randomised controlled, non-inferiority trial at 59 hospitals in Japan. Patients aged 20-80 years with stage II adenocarcinoma of the stomach were randomly assigned (1:1) to eight courses or four courses of S-1. Randomisation was done by the Japan Clinical Oncology Group Data Center website, using a minimisation method with a random component using institution, stage (IIA vs IIB), age (<70 years vs ≥70 years), and mode of operation (open gastrectomy with bursectomy vs open gastrectomy without bursectomy vs laparoscopic gastrectomy) as adjustment factors. One course was 80 mg/day per m2 of S-1 administered for 4 weeks followed by a rest for 2 weeks. The primary endpoint was relapse-free survival, analysed by intention to treat, with a non-inferiority margin for the hazard ratio (HR) set at 1·37. This study is registered at UMIN-Clinical Trial Registry, number UMIN000007306.
FINDINGS: Between Feb 16, 2012, and March 19, 2017, 590 patients were enrolled (295 per group). 528 (89%) patients were analysed at the first planned interim analysis in March, 2017, at which time the point estimate of HR for the four-course group compared with the eight-course group was 2·52 (95% CI 1·11-5·77), which exceeded 1·37 and met the prespecified criteria for early termination. Predictive probability for showing non-inferiority at the final analysis was calculated to be 2·9%. The study was stopped for futility. Updated 3-year relapse-free survival analysed in May, 2017, was 93·1% (95% CI 87·8-96·1) for the eight-course group and 89·8% (84·2-93·5) for the four-course group (HR 1·84, 95% CI 0·93-3·63). The most common grade 3-4 adverse event was neutropenia, observed in 46 (16%) patients in the eight-course group and 51 (17%) patients in the four-course group.
INTERPRETATION: S-1 for 1 year should remain as standard adjuvant chemotherapy for stage II gastric cancer.
FUNDING: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund, Japan.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30679107
Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; CLASSIC trial investigators.
Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.
Lancet. 2012 Jan 28;379(9813):315-21. doi: 10.1016/S0140-6736(11)61873-4. Epub 2012 Jan 7.
Abstract/Text BACKGROUND: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer.
METHODS: The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229).
FINDINGS: 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294).
INTERPRETATION: Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer.
FUNDING: F Hoffmann-La Roche and Sanofi-Aventis.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22226517
Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, Kim HH, Choi JH, Kim HK, Yu W, Lee JI, Shin DB, Ji J, Chen JS, Lim Y, Ha S, Bang YJ; CLASSIC trial investigators.
Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.
Lancet Oncol. 2014 Nov;15(12):1389-96. doi: 10.1016/S1470-2045(14)70473-5. Epub 2014 Oct 15.
Abstract/Text BACKGROUND: The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial.
METHODS: CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229.
FINDINGS: We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0·58, 95% CI 0·47-0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51-0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis.
INTERPRETATION: Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer.
FUNDING: F Hoffmann La-Roche and Sanofi.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25439693
Yamaguchi T, Takashima A, Nagashima K, Makuuchi R, Aizawa M, Ohashi M, Tashiro K, Yamada T, Kinoshita T, Hata H, Kawachi Y, Kawabata R, Tsuji T, Hihara J, Sakamoto T, Fukagawa T, Katai H, Higuchi K, Boku N.
Efficacy of Postoperative Chemotherapy After Resection that Leaves No Macroscopically Visible Disease of Gastric Cancer with Positive Peritoneal Lavage Cytology (CY1) or Localized Peritoneum Metastasis (P1a): A Multicenter Retrospective Study.
Ann Surg Oncol. 2020 Jan;27(1):284-292. doi: 10.1245/s10434-019-07697-x. Epub 2019 Sep 18.
Abstract/Text BACKGROUND: Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy.
PATIENTS AND METHODS: Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery.
RESULTS: Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18).
CONCLUSIONS: Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.

PMID 31535301
Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A; 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 Nov;10(11):1063-9. doi: 10.1016/S1470-2045(09)70259-1. Epub 2009 Oct 7.
Abstract/Text BACKGROUND: The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer.
METHODS: We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062.
FINDINGS: All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group.
INTERPRETATION: S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

PMID 19818685
Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M.
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 Mar;9(3):215-21. doi: 10.1016/S1470-2045(08)70035-4. Epub 2008 Feb 20.
Abstract/Text BACKGROUND: Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone.
METHODS: In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670.
FINDINGS: 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group.
INTERPRETATION: S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

PMID 18282805
Narahara H, Iishi H, Imamura H, Tsuburaya A, Chin K, Imamoto H, Esaki T, Furukawa H, Hamada C, Sakata Y.
Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002).
Gastric Cancer. 2011 Mar;14(1):72-80. doi: 10.1007/s10120-011-0009-5. Epub 2011 Feb 23.
Abstract/Text BACKGROUND: Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer.
METHODS: Patients were randomly assigned to oral S-1 (80 mg/m² daily for 28 days every 6 weeks) or oral S-1 (80 mg/m² daily for 21 days every 5 weeks) plus irinotecan (80 mg/m² by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety.
RESULTS: The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy.
CONCLUSIONS: Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study.

PMID 21340666
Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, Hara T, Chung HC, Satoh T, Cho JY, Hosaka H, Tsuji A, Takagane A, Inokuchi M, Tanabe K, Okuno T, Ogura M, Yoshida K, Takeuchi M, Nakajima T; JACCRO and KCSG Study Group.
Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START).
J Cancer Res Clin Oncol. 2014 Feb;140(2):319-28. doi: 10.1007/s00432-013-1563-5. Epub 2013 Dec 24.
Abstract/Text PURPOSE: Cisplatin plus 5-fluorouracil has been globally accepted as a standard regimen for the treatment for advanced gastric cancer. However, cisplatin has several disadvantages, including renal toxicity and the need for admission. S-1 plus cisplatin has become a standard treatment for advanced gastric cancer in East Asia. This phase III study was designed to evaluate the potential benefits of adding docetaxel to S-1 without a platinum compound in patients with advanced gastric cancer.
METHODS: Patients were randomly assigned to receive docetaxel plus S-1 or S-1 alone. The docetaxel plus S-1 group received docetaxel on day 1 and oral S-1 on days 1-14 of a 21-day cycle. The S-1 alone group received oral S-1 on days 1-28 of a 42-day cycle. The primary end point was overall survival.
RESULTS: Of the 639 patients enrolled, 635 were eligible for analysis. The median overall survival was 12.5 months in the docetaxel plus S-1 group and 10.8 months in the S-1 alone group (p = 0.032). The median progression-free survival was 5.3 months in the docetaxel plus S-1 group and 4.2 months in the S-1 alone group (p = 0.001). As for adverse events, neutropenia was more frequent in the docetaxel plus S-1 group, but remained manageable.
CONCLUSION: As first-line treatment for advanced gastric cancer, docetaxel plus S-1 significantly improves median overall and progression-free survival as compared with S-1 alone. (ClinicalTrials.gov number: NCT00287768).

PMID 24366758
Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Hamada C, Hyodo I.
Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer.
Ann Oncol. 2015 Jan;26(1):141-148. doi: 10.1093/annonc/mdu472. Epub 2014 Oct 14.
Abstract/Text BACKGROUND: We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC).
PATIENTS AND METHODS: In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease.
RESULTS: Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%).
CONCLUSION: SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS.
CLINICAL TRIAL NUMBER: JapicCTI-101021.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PMID 25316259
Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI.
Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.
Ann Oncol. 2009 Apr;20(4):666-73. doi: 10.1093/annonc/mdn717. Epub 2009 Jan 19.
Abstract/Text BACKGROUND: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC).
PATIENTS AND METHODS: In this randomised, open-label, phase III study, patients received cisplatin (80 mg/m(2) i.v. day 1) plus oral capecitabine (1000 mg/m(2) b.i.d., days 1-14) (XP) or 5-FU (800 mg/m(2)/day by continuous infusion, days 1-5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS).
RESULTS: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63-1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64-1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%).
CONCLUSIONS: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.

PMID 19153121
Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA.
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.
Lancet. 2021 Jul 3;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5.
Abstract/Text BACKGROUND: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.
METHODS: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.
FINDINGS: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.
INTERPRETATION: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.
FUNDING: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 34102137
Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N.
Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol. 2022 Feb;23(2):234-247. doi: 10.1016/S1470-2045(21)00692-6. Epub 2022 Jan 11.
Abstract/Text BACKGROUND: The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer.
METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, phase 2-3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 [SOX] or oral capecitabine 1000 mg/m2 [CAPOX], twice daily on days 1-14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing.
FINDINGS: Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7-14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44-14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97-9·40) in the placebo plus chemotherapy group (hazard ratio [HR] 0·68; 98·51% CI 0·51-0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1-29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67-20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18-19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75-1·08; p=0·26). The most common treatment-related grade 3-4 adverse events were neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapy group vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 [5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease).
INTERPRETATION: Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients.
FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.

Copyright © 2022 Elsevier Ltd. All rights reserved.
PMID 35030335
Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J.
Phase III Trial Comparing Intraperitoneal and Intravenous Paclitaxel Plus S-1 Versus Cisplatin Plus S-1 in Patients With Gastric Cancer With Peritoneal Metastasis: PHOENIX-GC Trial.
J Clin Oncol. 2018 Jul 1;36(19):1922-1929. doi: 10.1200/JCO.2018.77.8613. Epub 2018 May 10.
Abstract/Text Purpose Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival. Patients and Methods This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (< 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m2 and intravenous paclitaxel 50 mg/m2 on days 1 and 8 plus S-1 80 mg/m2 per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m2 per day on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety. Results We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated. Conclusion This trial failed to show statistical superiority of intraperitoneal paclitaxel plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal paclitaxel for gastric cancer.

PMID 29746229
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lancet. 2010 Aug 28;376(9742):687-97. doi: 10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19.
Abstract/Text BACKGROUND: Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer.
METHODS: ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404.
FINDINGS: 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups.
INTERPRETATION: Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer.
FUNDING: F Hoffmann-La Roche.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20728210
Sawaki A, Ohashi Y, Omuro Y, Satoh T, Hamamoto Y, Boku N, Miyata Y, Takiuchi H, Yamaguchi K, Sasaki Y, Nishina T, Satoh A, Baba E, Tamura T, Abe T, Hatake K, Ohtsu A.
Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study.
Gastric Cancer. 2012 Jul;15(3):313-22. doi: 10.1007/s10120-011-0118-1. Epub 2011 Dec 17.
Abstract/Text BACKGROUND: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients.
METHODS: We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n = 51; chemotherapy, n = 50).
RESULTS: Median overall survival in the Japanese subgroup was 15.9 months (95% confidence interval 12-25) for trastuzumab plus chemotherapy and 17.7 months (95% confidence interval 12-24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59-1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36-1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios.
CONCLUSIONS: After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.

PMID 22179434
Kurokawa Y, Sugimoto N, Miwa H, Tsuda M, Nishina S, Okuda H, Imamura H, Gamoh M, Sakai D, Shimokawa T, Komatsu Y, Doki Y, Tsujinaka T, Furukawa H.
Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1).
Br J Cancer. 2014 Mar 4;110(5):1163-8. doi: 10.1038/bjc.2014.18. Epub 2014 Jan 28.
Abstract/Text BACKGROUND: S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.
METHODS: Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.
RESULTS: A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84-99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).
CONCLUSIONS: Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.

PMID 24473399
Shitara K, Morita S, Fujitani K, Kadowaki S, Takiguchi N, Hirabayashi N, Takahashi M, Takagi M, Tokunaga Y, Fukushima R, Munakata Y, Nishikawa K, Takagane A, Tanaka T, Sekishita Y, Sakamoto J, Tsuburaya A.
Combination chemotherapy with S-1 plus cisplatin for gastric cancer that recurs after adjuvant chemotherapy with S-1: multi-institutional retrospective analysis.
Gastric Cancer. 2012 Jul;15(3):245-51. doi: 10.1007/s10120-011-0101-x. Epub 2011 Oct 13.
Abstract/Text BACKGROUND: It is unclear whether S-1 plus cisplatin is effective for patients with recurrent gastric cancer after adjuvant S-1 chemotherapy.
METHODS: We retrospectively evaluated the efficacy of S-1 plus cisplatin in patients whose gastric cancer recurred after adjuvant S-1 chemotherapy.
RESULTS: In the 52 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 8.1 months, and the median recurrence-free interval (RFI) since the last administration of adjuvant S-1 was 6.4 months. Among the 36 patients with measurable lesions, 7 achieved a complete or partial response, and 13 were evaluated as having stable disease, for an overall response rate of 19.4% and a disease control rate of 55.6%. For all patients, the median progression-free survival (PFS) was 4.8 months, and the median overall survival (OS) was 12.2 months. Compared with patients with an RFI of <6 months (n = 25), patients with an RFI of ≥6 months (n = 27) had a significantly higher response rate (5.0 vs. 37.5%, respectively), longer PFS (2.3 vs. 6.2 months, respectively), and longer overall survival (7.3 vs. 16.6 months, respectively). According to a multivariate Cox model including performance status (PS) and reason for discontinuation of adjuvant S-1, an RFI of 6 months was still significantly associated with PFS and OS.
CONCLUSIONS: S-1 plus cisplatin is effective for patients with gastric cancer that recurs after adjuvant S-1 chemotherapy, especially for those with an RFI of ≥6 months.

PMID 21993850
Nishikawa K, Tsuburaya A, Yoshikawa T, Takahashi M, Tanabe K, Yamaguchi K, Yoshino S, Namikawa T, Aoyama T, Rino Y, Kawada J, Tsuji A, Taira K, Kimura Y, Kodera Y, Hirashima Y, Yabusaki H, Hirabayashi N, Fujitani K, Miyashita Y, Morita S, Sakamoto J.
A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial.
Gastric Cancer. 2018 Sep;21(5):811-818. doi: 10.1007/s10120-018-0815-0. Epub 2018 Feb 27.
Abstract/Text BACKGROUNDS: In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294).
METHODS: HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety.
RESULTS: Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6-5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0-17.7) and ORR was 8/30 (26.7%) (95% CI 14.2-44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%).
CONCLUSIONS: XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1.
TRIAL REGISTRATION: NCT01412294.

PMID 29488122
Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH.
Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.
J Clin Oncol. 2012 May 1;30(13):1513-8. doi: 10.1200/JCO.2011.39.4585. Epub 2012 Mar 12.
Abstract/Text PURPOSE: When designing this trial, there was no evidence that salvage chemotherapy (SLC) in advanced gastric cancer (AGC) resulted in substantial prolongation of survival when compared with best supportive care (BSC). However, SLC is often offered to pretreated patients with AGC for anecdotal reasons.
PATIENTS AND METHODS: Patients with AGC with one or two prior chemotherapy regimens involving both fluoropyrimidines and platinum and with an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned in a ratio of 2:1 to SLC plus BSC or BSC alone. Choice of SLC-either docetaxel 60 mg/m(2) every 3 weeks or irinotecan 150 mg/m(2) every 2 weeks-was left to the discretion of investigators. Primary end point was overall survival (OS).
RESULTS: Median OS was 5.3 months among 133 patients in the SLC arm and 3.8 months among 69 patients in the BSC arm (hazard ratio, 0.657; 95% CI, 0.485 to 0.891; one-sided P = .007). OS benefit for SLC was consistent in most of the prospectively defined subgroups, including age, PS, number of prior treatments, metastatic sites, hemoglobin levels, and response to prior chemotherapy. SLC was generally well tolerated, and adverse events were similar in the SLC and BSC arms. We found no median OS difference between docetaxel and irinotecan (5.2 v 6.5 months; P = .116).
CONCLUSION: To our knowledge, this is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

PMID 22412140
Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA; COUGAR-02 Investigators.
Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial.
Lancet Oncol. 2014 Jan;15(1):78-86. doi: 10.1016/S1470-2045(13)70549-7. Epub 2013 Dec 10.
Abstract/Text BACKGROUND: Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life (HRQoL). We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients.
METHODS: For this open-labelled, multicentre trial, we recruited patients aged 18 years or older from 30 UK centres. Patients were eligible if they had an advanced, histologically confirmed adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. Patients could have an Eastern Cooperative Oncology Group performance status of 0-2. We randomly assigned patients using a central, computerised minimisation procedure to receive docetaxel plus active symptom control, or active symptom control alone (1:1; stratified by disease status, disease site, duration of response to previous chemotherapy, and performance status). Docetaxel was given at a dose of 75 mg/m(2) by intravenous infusion every 3 weeks for up to six cycles. The primary endpoint was overall survival, analysed by intention to treat. This is the report of the planned final analysis. This study is an International Standardised Randomised Controlled Trial, number ISRCTN13366390.
FINDINGS: Between April 21, 2008, and April 26, 2012, we recruited 168 patients, allocating 84 to each treatment group. After a median follow-up of 12 months [IQR 10-21]) and 161 (96%) deaths (80 in the docetaxel group, 81 in the active symptom control group), median overall survival in the docetaxel group was 5.2 months (95% CI 4.1-5.9) versus 3.6 months (3.3-4.4) in the active symptom control group (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.01). Docetaxel was associated with higher incidence of grade 3-4 neutropenia (12 [15%] patients vs no patients), infection (15 [19%] patients vs two [3%] patients), and febrile neutropenia (six [7%] patients vs no patients). Patients receiving docetaxel reported less pain (p=0.0008) and less nausea and vomiting (p=0.02) and constipation (p=0.02). Global HRQoL was similar between the groups (p=0.53). Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (p=0.02) and abdominal pain (p=0.01).
INTERPRETATION: Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine.
FUNDING: Cancer Research UK.

Copyright © 2014 Ford et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
PMID 24332238
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators.
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.
Lancet. 2014 Jan 4;383(9911):31-39. doi: 10.1016/S0140-6736(13)61719-5. Epub 2013 Oct 3.
Abstract/Text BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.
METHODS: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384.
FINDINGS: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.
INTERPRETATION: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.
FUNDING: ImClone Systems.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24094768
Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I.
Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial.
J Clin Oncol. 2013 Dec 10;31(35):4438-44. doi: 10.1200/JCO.2012.48.5805. Epub 2013 Nov 4.
Abstract/Text PURPOSE: This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum.
PATIENTS AND METHODS: Patients were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy.
RESULTS: Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio [HR], 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001).
CONCLUSION: No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.

PMID 24190112
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
Lancet Oncol. 2014 Oct;15(11):1224-35. doi: 10.1016/S1470-2045(14)70420-6. Epub 2014 Sep 17.
Abstract/Text BACKGROUND: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel.
METHODS: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase.
FINDINGS: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]).
INTERPRETATION: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.
FUNDING: Eli Lilly and Company.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25240821
Bando H, Shimodaira H, Fujitani K, Takashima A, Yamaguchi K, Nakayama N, Takahashi T, Oki E, Azuma M, Nishina T, Hironaka S, Komatsu Y, Shitara K.
A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer.
Eur J Cancer. 2018 Mar;91:86-91. doi: 10.1016/j.ejca.2017.11.032. Epub 2018 Jan 30.
Abstract/Text BACKGROUND: Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility and does not need premedication to avoid infusion-related reactions associated with solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated advanced gastric cancer.
PATIENTS AND METHODS: Patients with unresectable advanced gastric cancer refractory to first-line chemotherapy were administered nab-paclitaxel 100 mg/m2 intravenously on days 1, 8 and 15, plus ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary end-point was Independent Review Committee (IRC)-assessed overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and quality of life (QOL).
RESULTS: Forty-five patients were enrolled; 43 received the study treatment. The ORR assessed by the IRC was 54.8% (90% confidence interval [CI] 41.0-68.0) and the primary end-point was met. The DCR was 92.9% (95% CI 80.5-98.5). The IRC-assessed median PFS was 7.6 months (95% CI 5.4-8.1). The median OS was not reached at the data cutoff. The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (76.7%), decreased white blood cell count (27.9%), anaemia (11.6%), decreased appetite (7.0%), febrile neutropenia (4.7%), hypertension (4.7%) and proteinuria (4.7%). No treatment-related deaths occurred. No QOL deterioration was observed during study treatment.
CONCLUSION: Nab-paclitaxel plus ramucirumab combination therapy shows promising activity and manageable toxicities and could be a useful second-line treatment option for patients with previously treated advanced gastric cancer.

Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
PMID 29353164
Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr.
Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.
J Clin Oncol. 2020 Jan 1;38(1):1-10. doi: 10.1200/JCO.19.02105. Epub 2019 Nov 4.
Abstract/Text PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.
PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.
RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.
CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

PMID 31682550
MSI-High固形癌:国際共同臨床試験成績:国際共同第Ⅱ相試験<KEYNOTE-158試験 [Internet]. Available from: https://www.msdconnect.jp/products/keytruda/msi-high-keynote-158.xhtml
Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6.
Abstract/Text BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens.
METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343.
FINDINGS: Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57-12·37) in the nivolumab group and 8·59 months (5·65-11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60-6·37) in the nivolumab group and 4·14 months (3·42-4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51-0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7-32·0) with nivolumab and 10·9% (6·2-17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.
INTERPRETATION: In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines.
FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28993052
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Cutsem EV, Winkler RE, Makris L, Ilson DH, Tabernero J.
Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol. 2018 Nov;19(11):1437-1448. doi: 10.1016/S1470-2045(18)30739-3. Epub 2018 Oct 21.
Abstract/Text BACKGROUND: Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population.
METHODS: TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed.
FINDINGS: Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1-4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group).
INTERPRETATION: Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need.
FUNDING: Taiho Oncology and Taiho Pharmaceutical.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 30355453
Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K; DESTINY-Gastric01 Investigators.
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.
N Engl J Med. 2020 Jun 18;382(25):2419-2430. doi: 10.1056/NEJMoa2004413. Epub 2020 May 29.
Abstract/Text BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group.
CONCLUSIONS: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32469182
Kodera Y, Ito S, Mochizuki Y, Kondo K, Koshikawa K, Suzuki N, Kojima H, Kojima T, Matsui T, Takase T, Tsuboi K, Fujiwara M, Nakao A; Chubu Clinical Oncology Group.
A phase II study of radical surgery followed by postoperative chemotherapy with S-1 for gastric carcinoma with free cancer cells in the peritoneal cavity (CCOG0301 study).
Eur J Surg Oncol. 2009 Nov;35(11):1158-63. doi: 10.1016/j.ejso.2009.03.003. Epub 2009 Mar 27.
Abstract/Text BACKGROUND: Patients with gastric cancer who have positive cytologic results for cancer cells in peritoneal washings (CY1) have poor outcomes, even in the absence of other distant metastases. A standard treatment for such patients remains to be established.
METHODS: We conducted a phase II trial with the 2-year survival rate as the primary endpoint. Patients who had gastric cancer with CY1 status but no other residual disease received postoperative chemotherapy with S-1 (1M tegafur-0.4M gimestat-1M otastat potassium) at a daily dose of 80mg/m(2) for 4 weeks, followed by 2 weeks of rest. This cycle was continued until disease progression or intolerable adverse events. D2 dissection was the recommended surgical procedure; splenectomy could be omitted at the discretion of the surgeon. Accrual of 50 patients was planned, and a 2-year survival rate of more than 36% was needed to exceed the historical control.
RESULTS: Forty-eight patients were enrolled, among whom 47 were assessable for survival and 46 for adverse reactions. Median overall survival was 705 days, and progression-free survival was 376 days. The 2-year survival rate was 47%. Median time to treatment failure was 288 days. Neutropenia was the commonest > or = grade 3 toxicity (6 patients), and anorexia was the most frequent > or = grade 2 non-hematologic toxicity (10 patients).
CONCLUSIONS: Gastrectomy followed by S-1 monotherapy resulted in survival that surpassed historical data and can serve as an active control treatment for future trials in patients who have gastric cancer with CY1 status in the Far East.

PMID 19328643
Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K, Oshita H, Ito S, Kawashima Y, Fukushima N.
Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer.
Br J Surg. 2009 Sep;96(9):1015-22. doi: 10.1002/bjs.6665.
Abstract/Text BACKGROUND: Locally advanced gastric cancer with extensive lymph node metastasis is usually considered unresectable and so treated by chemotherapy. This trial explored the safety and efficacy of preoperative chemotherapy followed by extended surgery in the management of locally advanced gastric adenocarcinoma.
METHODS: Patients with gastric cancer with extensive lymph node metastasis received two or three 28-day cycles of induction chemotherapy with irinotecan (70 mg/m(2) on days 1 and 15) and cisplatin (80 mg/m(2) on day 1), and then underwent gastrectomy with curative intent with D2 plus para-aortic lymphadenectomy. Primary endpoints were 3-year overall survival and incidence of treatment-related death.
RESULTS: The study was terminated because of three treatment-related deaths when 55 patients had been enrolled (mortality rate above 5 per cent). Two deaths were due to myelosuppression and one to postoperative complications. Clinical response and R0 resection rates were 55 and 65 per cent respectively. The pathological response rate was 15 per cent. Median overall survival was 14.6 months and the 3-year survival rate 27 per cent.
CONCLUSION: This multimodal treatment of locally advanced gastric cancer provides reasonable 3-year survival compared with historical data, but at a considerable cost in terms of morbidity and mortality.

(c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
PMID 19644974
Tsuburaya A, Mizusawa J, Tanaka Y, Fukushima N, Nashimoto A, Sasako M; Stomach Cancer Study Group of the Japan Clinical Oncology Group.
Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis.
Br J Surg. 2014 May;101(6):653-60. doi: 10.1002/bjs.9484. Epub 2014 Mar 25.
Abstract/Text BACKGROUND: Locally advanced gastric cancer with extensive regional and/or para-aortic lymph node (PAN) metastases is typically unresectable and associated with poor outcomes. This study investigated the safety and efficacy of S-1 plus cisplatin followed by extended surgery with PAN dissection for gastric cancer with extensive lymph node metastasis.
METHODS: Patients with gastric cancer with bulky lymph node metastasis along the coeliac artery and its branches and/or PAN metastasis received two or three 28-day cycles of S-1 plus cisplatin, followed by gastrectomy with D2 plus PAN dissection. The primary endpoint was the percentage of complete resections with clear margins in the primary tumour (R0 resection). A target sample size of 50 with one-sided α of 0.105 and β of approximately 0.2 corresponded to an expected R0 rate of 65 per cent and a threshold of 50 per cent.
RESULTS: Between February 2005 and June 2007, 53 patients were enrolled, of whom 51 were eligible. The R0 resection rate was 82 per cent. Clinical and pathological response rates were 65 and 51 per cent respectively. The 3- and 5-year overall survival rates were 59 and 53 per cent respectively. During chemotherapy, grade 3/4 neutropenia occurred in 19 per cent and grade 3/4 non-haematological adverse events in 15.4 per cent. The incidence of grade 3/4 adverse events related to surgery was 12 per cent. There were no reoperations or treatment-related deaths.
CONCLUSION: For locally advanced gastric cancer with extensive lymph node metastasis, 4-weekly S-1 plus cisplatin followed by surgery including PAN dissection was safe and effective for some patients. Further investigation of this treatment strategy is warranted.

© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.
PMID 24668391
Ito S, Sano T, Mizusawa J, Takahari D, Katayama H, Katai H, Kawashima Y, Kinoshita T, Terashima M, Nashimoto A, Nakamori M, Onaya H, Sasako M.
A phase II study of preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by gastrectomy with D2 plus para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis: JCOG1002.
Gastric Cancer. 2017 Mar;20(2):322-331. doi: 10.1007/s10120-016-0619-z. Epub 2016 Jun 14.
Abstract/Text BACKGROUND: Gastric cancer with extensive lymph node metastasis is commonly considered unresectable, with a poor prognosis. We previously reported the results of the use of cisplatin and S-1 as preoperative chemotherapy for gastric cancer with extensive lymph node metastasis; docetaxel, cisplatin, and S-1 (DCS) have now been investigated for the same purpose.
METHODS: Patients received two or three 28-day cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1, S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 plus para-aortic nodal dissection. After R0 resection, S-1 chemotherapy was given for 1 year. The primary end point was the response rate (RR) to preoperative chemotherapy determined by central peer review according to the Response Evaluation Criteria in Solid Tumors version 1.0. The planned sample size was 50, with one-sided alpha of 10 %, power of 80 %, expected RR of 80 %, and threshold of 65 %.
RESULTS: Between July 2011 and May 2013, 53 patients were enrolled, of whom 52 were eligible. The clinical RR was 57.7 % [30/52, 80 % confidence interval 47.9-67.1 %, p = 0.89], and R0 resection was achieved in 84.6 % of patients (44/52). Common grade 3 or grade 4 adverse events during DCS therapy were leukocytopenia (18.9 %), neutropenia (39.6 %), and hyponatremia (15.1 %). The common grade 3 or grade 4 surgical morbidity was abdominal infection (10.2 %). The pathological RR was 50.0 % (26/52).
CONCLUSIONS: Preoperative DCS therapy was feasible but did not show a sufficient RR. Preoperative cisplatin and S-1 therapy is still considered the tentative standard treatment for this population until survival results are known.

PMID 27299887
Shirasu H, Tsushima T, Kawahira M, Kawai S, Kawakami T, Kito Y, Yoshida Y, Hamauchi S, Todaka A, Yokota T, Machida N, Yamazaki K, Fukutomi A, Onozawa Y, Terashima M, Uesaka K, Yasui H.
Role of hepatectomy in gastric cancer with multiple liver-limited metastases.
Gastric Cancer. 2018 Mar;21(2):338-344. doi: 10.1007/s10120-017-0730-9. Epub 2017 Jun 2.
Abstract/Text BACKGROUND: Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM.
METHODS: We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015.
RESULTS: Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor.
CONCLUSIONS: Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy.

PMID 28577228
Oki E, Tokunaga S, Emi Y, Kusumoto T, Yamamoto M, Fukuzawa K, Takahashi I, Ishigami S, Tsuji A, Higashi H, Nakamura T, Saeki H, Shirabe K, Kakeji Y, Sakai K, Baba H, Nishimaki T, Natsugoe S, Maehara Y; Kyushu Study Group of Clinical Cancer.
Surgical treatment of liver metastasis of gastric cancer: a retrospective multicenter cohort study (KSCC1302).
Gastric Cancer. 2016 Jul;19(3):968-76. doi: 10.1007/s10120-015-0530-z. Epub 2015 Aug 11.
Abstract/Text BACKGROUND: The necessity of surgical treatment of liver metastases of gastric cancer is still controversial.
PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study of liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria.
RESULTS: Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival.
CONCLUSIONS: To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.

PMID 26260876
Markar SR, Mikhail S, Malietzis G, Athanasiou T, Mariette C, Sasako M, Hanna GB.
Influence of Surgical Resection of Hepatic Metastases From Gastric Adenocarcinoma on Long-term Survival: Systematic Review and Pooled Analysis.
Ann Surg. 2016 Jun;263(6):1092-101. doi: 10.1097/SLA.0000000000001542.
Abstract/Text OBJECTIVES: The objectives of this systematic review and pooled analysis were to examine long-term survival, morbidity, and mortality following surgical resection of gastric cancer hepatic metastases and to identify prognostic factors that improve survival.
BACKGROUND: Patients with hepatic metastases from gastric cancer are traditionally treated with palliative chemotherapy.
METHODS: A systematic literature search was undertaken (1990 to 2015). Publications were included if they studied more than 10 patients undergoing hepatectomy for hepatic metastasis from gastric adenocarcinoma in the absence of peritoneal disease or other distant organ involvement. The primary outcome was the hazard ratio (HR) for overall survival. The influence of liver metastasis related factors; multiple vs single and metachronous vs synchronous upon survival was also assessed.
RESULTS: The median number of resections for the 39 studies included was 21 (range 10 to 64). Procedures were associated with a median 30-day morbidity of 24% (0% to 47%) and mortality of 0% (0% to 30%). The median 1-year, 3-year, and 5-year survival were 68%, 31%, and 27%, respectively. Survival was improved in Far Eastern compared with Western studies; 1-year (73% vs 59%), 3-year (34% vs 24.5%), and 5-year (27.3% vs 16.5%). Surgical resection of hepatic metastases was associated with a significantly improved overall survival (HR = 0.50; P < 0.001). Meta-analysis confirmed the additional survival benefit of solitary compared with multiple hepatic metastases (odds ratio = 0.31; P = 0.011).
CONCLUSIONS: The observed improved survival rates following the resection of hepatic metastasis from gastric adenocarcinoma in selected patients merit a prospective study to formally address the survival benefits and the influence on quality of life of such approach.

PMID 26797324
Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, Iwasaki Y, Hyung WJ, Takagane A, Park DJ, Yoshikawa T, Hahn S, Nakamura K, Park CH, Kurokawa Y, Bang YJ, Park BJ, Sasako M, Tsujinaka T; REGATTA study investigators.
Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial.
Lancet Oncol. 2016 Mar;17(3):309-318. doi: 10.1016/S1470-2045(15)00553-7. Epub 2016 Jan 26.
Abstract/Text BACKGROUND: Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients.
METHODS: We did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20-75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m(2) per day on days 1-21 and cisplatin 60 mg/m(2) on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012.
FINDINGS: Between Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7-42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2-34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7-19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8-16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78-1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients [18%] vs two [3%]), anorexia (22 [29%] vs nine [12%]), nausea (11 [15%] vs four [5%]), and hyponatraemia (seven [9%] vs four [5%]). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery).
INTERPRETATION: Since gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours.
FUNDING: The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26822397
Yamaguchi K, Yoshida K, Tanahashi T, Takahashi T, Matsuhashi N, Tanaka Y, Tanabe K, Ohdan H.
The long-term survival of stage IV gastric cancer patients with conversion therapy.
Gastric Cancer. 2018 Mar;21(2):315-323. doi: 10.1007/s10120-017-0738-1. Epub 2017 Jun 14.
Abstract/Text PURPOSE: A retrospective study was performed to clarify the role of conversion therapy (surgery with a prospect of R0 resection performed in initially unresectable metastatic cancer that responded to the chemotherapy) in stage IV gastric cancer (GC).
PATIENTS AND METHODS: We treated 259 stage IV GC patients with systemic chemotherapy at Gifu and Hiroshima University Hospitals between 2001-2013. Of these, 84 patients who were subsequently treated by surgery were classified into four categories according to our previously published classification of stage IV GC, and short- and long-term outcomes were analyzed.
RESULTS: Surgery was performed in 84 patients, of which 7 were performed following the neoadjuvant chemotherapy, whereas the other 77 that excluded neoadjuvant chemotherapy cases were considered the conversion therapy. The postoperative mortality and morbidity were comparable with those reported clinical trials. The MSTs of the patients with/without surgery for each category were 28.3/5.8 months for category 1, 30.5/11.0 months for category 2, 31.0/18.5 months for category 3 and 24.7/10.0 months for category 4. The MST of the R0 resected patients (41.3 months) was far better than that of the R1-2 resected patients (21.2 months). The MSTs of the patients with R0/R1-2 resection were 56.2/16.3 months for category 2, 33.3/29.6 months for category 3 and 40.7/17.8 months for category 4.
CONCLUSION: There were long-term survivors who underwent conversion therapy for stage IV GC. Adequate selection of stage IV GC patients for conversion therapy may be an important role for the surgical oncologist in the new era.

PMID 28616743
Du R, Hu P, Liu Q, Zhang J.
Conversion Surgery for Unresectable Advanced Gastric Cancer: A Systematic Review and Meta-Analysis.
Cancer Invest. 2019;37(1):16-28. doi: 10.1080/07357907.2018.1551898. Epub 2019 Jan 11.
Abstract/Text For patients with unresectable advanced gastric cancer, induction chemotherapy could down-stage primary tumors, resulting in conversion surgery becoming possible. However, the feasibility and therapeutic benefit of conversion surgery remains controversial. Therefore, this meta-analysis aimed to systematically review and investigate the efficacy of conversion surgery followed by chemotherapy for unresectable AGC.

PMID 30632817
Xu Y, Tan Y, Wang Y, Xi C, Ye N, Xu X.
Proximal versus total gastrectomy for proximal early gastric cancer: A systematic review and meta-analysis.
Medicine (Baltimore). 2019 May;98(19):e15663. doi: 10.1097/MD.0000000000015663.
Abstract/Text BACKGROUND: Recently, the incidence of proximal early gastric cancer (EGC) has been rising rapidly. Prevalent surgical methods are proximal gastrectomy (PG) and total gastrectomy (TG); however, which method is superior remains controversial. We conducted a systematic review and meta-analysis of original articles to compare the short- and long-term clinical outcomes of PG with TG for proximal EGC.
METHODS: Databases, including PubMed, Embase, Web of Science, and Cochrane Library were searched up to October 2018. The Newcastle-Ottawa scale was utilized to conduct quality assessments, and publication bias was evaluated using Egger test. STATA version 14.0 was used to perform the meta-analysis.
RESULTS: A total of 2036 patients with proximal EGC in 18 studies were included in the meta-analysis. The results showed that PG was potentially superior to TG regarding operation time, intraoperative blood loss volume, and long-term nutritional status. Overall survival between the PG and TG groups was not significantly different. PG was associated with a high incidence of 2 kinds of postoperative complications: anastomotic stenosis and reflux esophagitis. However, the incidence of these complications associated with esophagojejunostomy with double-tract reconstruction (DTR) was comparable with that of TG.
CONCLUSIONS: PG has several advantages over TG for the treatment of proximal EGC, including surgical outcomes and long-term nutritional status. However, anastomotic stenosis and reflux esophagitis frequently occurred in patients undergoing PG. Esophagojejunostomy with DTR could offer a solution to reducing the incidence of these complications.

PMID 31083268
Takiguchi N, Takahashi M, Ikeda M, Inagawa S, Ueda S, Nobuoka T, Ota M, Iwasaki Y, Uchida N, Kodera Y, Nakada K.
Long-term quality-of-life comparison of total gastrectomy and proximal gastrectomy by postgastrectomy syndrome assessment scale (PGSAS-45): a nationwide multi-institutional study.
Gastric Cancer. 2015 Apr;18(2):407-16. doi: 10.1007/s10120-014-0377-8. Epub 2014 May 7.
Abstract/Text BACKGROUND: Although proximal gastrectomy (PG) is widely accepted as a function-preserving operation for early upper-third gastric cancer, postoperative disorders, such as reflux or gastric stasis, have often been pointed out. From the perspective of postoperative disorder, the choice of total gastrectomy (TG) or PG for such cancers is still controversial. By using the newly developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, the quality of life after TG and PG was compared.
METHODS: The PGSAS-45 consists of 45 items composed of the SF-8 and GSRS scales and 22 new items. The main outcomes are measured by seven subscales (SS) covering symptoms, physical and mental component summary (SF-8), meals (amount and quality), ability to work, dissatisfaction for daily life, and change in body weight. A total of 2,368 eligible questionnaires were acquired from 52 institutions. From these, 393 patients with TG and 193 patients with PG were selected and compared.
RESULTS: The PG was better than TG in terms of body weight loss (TG 13.8% vs. PG 10.9%; p = 0.003), necessity for additional meals (2.4 vs. 2.0; p < 0.001), diarrhea SS (2.3 vs. 2.0; p = 0.048), and dumping SS (2.3 vs. 2.0; p = 0.043). There were no differences in the other main outcome measures.
CONCLUSIONS: Proximal gastrectomy appears to be valuable as a function-preserving procedure for early upper-third gastric cancer.

PMID 24801198
Aizawa M, Honda M, Hiki N, Kinoshita T, Yabusaki H, Nunobe S, Shibasaki H, Matsuki A, Watanabe M, Abe T.
Oncological outcomes of function-preserving gastrectomy for early gastric cancer: a multicenter propensity score matched cohort analysis comparing pylorus-preserving gastrectomy versus conventional distal gastrectomy.
Gastric Cancer. 2017 Jul;20(4):709-717. doi: 10.1007/s10120-016-0644-y. Epub 2016 Sep 26.
Abstract/Text OBJECTIVE: This study aimed to clarify the oncological safety of pylorus-preserving gastrectomy (PPG) compared with conventional distal gastrectomy (DG).
METHODS: From three institutions specializing in cancer, the medical records for a cohort of 2898 consecutive patients who had undergone DG (n = 2208) or PPG (n = 690) for clinical stage I gastric cancer between January 2006 and December 2012 were analyzed. A propensity score for each patient was estimated on the basis of 38 preoperative clinical and tumor-related factors. After propensity score matching had been done, 1004 patients (502 DG patients, 502 PPG patients) were included in the analysis. The overall survival, relapse-free survival, and occurrence of secondary gastric cancer were then compared. The median observation period was 48.6 months (range 1-109.8 months).
RESULTS: The 5-year overall survival rate was 98.4 % for the PPG group and 96.6 % for the DG group (hazard ratio 0.48, 95 % confidence interval 0.21-1.09, P = 0.07). The 3-year relapse-free survival rate was 99.5 % for the PPG group and 98.0 % for the DG group (hazard ratio 0.39, 95 % confidence interval 0.12-1.33, P = 0.12). Postoperative secondary gastric cancer was encountered in eight patients (1.6 %) in the PPG group and four patients (0.8 %) in the DG group. No significant differences in either overall survival, relapse-free survival, or the occurrence of secondary gastric cancer were observed between the two groups.
CONCLUSIONS: Given the adequate estimation of the clinical tumor stage, the oncological safety of PPG for clinical T1N0 gastric cancer in the middle portion of the stomach was comparable to that of DG.

PMID 27672061
Namikawa T, Hiki N, Kinami S, Okabe H, Urushihara T, Kawahira H, Fukushima N, Kodera Y, Yumiba T, Oshio A, Nakada K.
Factors that minimize postgastrectomy symptoms following pylorus-preserving gastrectomy: assessment using a newly developed scale (PGSAS-45).
Gastric Cancer. 2015 Apr;18(2):397-406. doi: 10.1007/s10120-014-0366-y. Epub 2014 Apr 24.
Abstract/Text BACKGROUND: Pylorus-preserving gastrectomy (PPG) is sometimes performed as a function-preserving surgery for the treatment of early gastric cancer. The aim of this study was to use an integrated assessment scale for postgastrectomy syndrome to determine the appropriate indicators and optimal methods for PPG.
METHODS: The Postgastrectomy Syndrome Assessment Study (PGSAS) is a multicenter survey based on an integrated questionnaire (PGSAS-45) consisting of 45 items. Questionnaire responses were retrieved from a total of 2,520 patients, each of whom had undergone one of six different types of gastrectomy procedures; 313 responses from patients who had received PPG were analyzed here.
RESULTS: The size of the proximal gastric remnant (less than one-quarter, about one-third, or more than one-half of the original size) significantly influenced the change in body weight, the scores for dissatisfaction at the meal, and dissatisfaction for daily life subscale (P = 0.030, P = 0.005, P = 0.034, respectively). The nausea score in patients who underwent hand-sewn anastomosis was significantly lower than in those who underwent anastomosis with a linear stapler (P = 0.006). The scores for diarrhea subscale, increased passage of stools, and sense of foods sticking differed significantly depending on the length of the preserved pyloric cuff (P = 0.047, P = 0.021, P = 0.046, respectively).
CONCLUSIONS: The results suggest that preservation of a sufficient proximal gastric remnant is recommended when utilizing PPG as function-preserving surgery.

PMID 24760336
Katai H, Mizusawa J, Katayama H, Takagi M, Yoshikawa T, Fukagawa T, Terashima M, Misawa K, Teshima S, Koeda K, Nunobe S, Fukushima N, Yasuda T, Asao Y, Fujiwara Y, Sasako M.
Short-term surgical outcomes from a phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage IA/IB gastric cancer: Japan Clinical Oncology Group Study JCOG0912.
Gastric Cancer. 2017 Jul;20(4):699-708. doi: 10.1007/s10120-016-0646-9. Epub 2016 Oct 7.
Abstract/Text BACKGROUNDS: No confirmatory randomized controlled trials (RCTs) have evaluated the efficacy of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG). We performed an RCT to confirm that LADG is not inferior to ODG in efficacy.
METHODS: We conducted a multi-institutional RCT. Eligibility criteria included histologically proven gastric adenocarcinoma in the middle or lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to ODG or LADG. This study is now in the follow-up stage. The primary endpoint is relapse-free survival (RFS) and the primary analysis is planned in 2018. Here, we compared the surgical outcomes of the two groups. This trial was registered at the UMIN Clinical Trials Registry as UMIN000003319.
RESULTS: Between March 2010 and November 2013, 921 patients (LADG 462, ODG 459) were enrolled from 33 institutions. Operative time was longer in LADG than in ODG (median 278 vs. 194 min, p < 0.001), while blood loss was smaller (median 38 vs. 115 ml, p < 0.001). There was no difference in the overall proportion with in-hospital grade 3-4 surgical complications (3.3 %: LADG, 3.7 %: ODG). The proportion of patients with elevated serum AST/ALT was higher in LADG than in ODG (16.4 vs. 5.3 %, p < 0.001). There was no operation-related death in either arm.
CONCLUSIONS: This trial confirmed that LADG was as safe as ODG in terms of adverse events and short-term clinical outcomes. LADG may be an alternative procedure in clinical IA/IB gastric cancer if the noninferiority of LADG in terms of RFS is confirmed.

PMID 27718137
Katai H, Mizusawa J, Katayama H, Morita S, Yamada T, Bando E, Ito S, Takagi M, Takagane A, Teshima S, Koeda K, Nunobe S, Yoshikawa T, Terashima M, Sasako M.
Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer (JCOG0912): a multicentre, non-inferiority, phase 3 randomised controlled trial.
Lancet Gastroenterol Hepatol. 2020 Feb;5(2):142-151. doi: 10.1016/S2468-1253(19)30332-2. Epub 2019 Nov 19.
Abstract/Text BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) is increasingly being used as an alternative to open distal gastrectomy (ODG) for gastric cancer treatment. Retrospective studies have shown equivalent survival with the two procedures, but these studies are limited by selection bias because LADG is more technically difficult than ODG. We aimed to evaluate whether LADG was non-inferior to ODG in terms of long-term survival outcomes.
METHODS: We did an open-label, multicentre, non-inferiority, phase 3 randomised controlled trial at 33 institutions in Japan. Patients aged 20-80 years with histologically confirmed gastric adenocarcinoma (T1N0, T1N1, or T2[MP]N0), clinical stage I, in the middle or lower third of the stomach, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with a body-mass index of less than 30 kg/m2, were randomly assigned (1:1) to receive ODG or LADG. Randomisation was done by telephone, fax, or with a web-based system in the Japan Clinical Oncology Group Data Center; a minimisation method with a random component was used to adjust for institution and clinical stage (IA or IB). Only study-accredited surgeons performed ODG and LADG. The primary endpoint was relapse-free survival and was analysed according to the intention-to-treat principle. The non-inferiority margin (LADG vs ODG) was set at a hazard ratio (HR) of 1·54. The trial was registered with the UMIN Clinical Trials Registry, UMIN000003319.
FINDINGS: Between March 15, 2010, and Nov 29, 2013, 921 patients were enrolled and randomly assigned to receive ODG (n=459) or LADG (n=462). 912 (99%) participants had the assigned surgery. 5-year relapse-free survival was 94·0% (95% CI 91·4-95·9) in the ODG group and 95·1% (92·7-96·8) in the LADG group. LADG was non-inferior to ODG for relapse-free survival (HR 0·84 [90% CI 0·56-1·27]), p=0·0075). The most common grade 3 or 4 adverse event was bowel obstruction, occurring in 11 (2%) of 455 patients in the ODG group and five (1%) of 457 patients in the LADG group. There were no treatment-related deaths.
INTERPRETATION: This trial supports the non-inferiority of LADG compared with ODG for clinical stage I gastric cancer relapse-free survival, suggesting that LADG should be considered a standard treatment option when performed by experienced surgeons.
FUNDING: Japan National Cancer Center, Ministry of Health, Labour and Welfare of Japan, Japan Agency for Medical Research and Development.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 31757656
Katai H, Mizusawa J, Katayama H, Kunisaki C, Sakuramoto S, Inaki N, Kinoshita T, Iwasaki Y, Misawa K, Takiguchi N, Kaji M, Okitsu H, Yoshikawa T, Terashima M; Stomach Cancer Study Group of Japan Clinical Oncology Group.
Single-arm confirmatory trial of laparoscopy-assisted total or proximal gastrectomy with nodal dissection for clinical stage I gastric cancer: Japan Clinical Oncology Group study JCOG1401.
Gastric Cancer. 2019 Sep;22(5):999-1008. doi: 10.1007/s10120-019-00929-9. Epub 2019 Feb 20.
Abstract/Text BACKGROUNDS: Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer is safe and feasible. In contrast, no prospective study evaluating the safety and efficacy of laparoscopy-assisted total gastrectomy (LATG) or laparoscopy-assisted proximal gastrectomy (LAPG) has been completed. We conducted a single-arm confirmatory trial to evaluate the safety of LATG/LAPG for clinical stage I (T1N0/T1N1/T2N0) proximal gastric cancer.
METHODS: The extent of lymphadenectomy was selected based on the Japanese Gastric Cancer Treatment Guidelines. The mini-laparotomy incision was required to be ≤ 6 cm. The primary endpoint was the proportion of grade 2-4 (CTCAE ver. 4.0) esophagojejunal anastomotic leakage. The planned sample size was 245 considering a threshold of 8% and one-sided alpha of 2.5%.
RESULTS: Between April 2015 and February 2017, 244 eligible patients were enrolled. LATG/LAPG was performed in 195/49. The proportion of conversions was 1.7%. Clinical T1N0/T1N1/T2N0 was 212/9/23. The extents of lymphadenectomy were as follows: D1+: 229; D2: 15. The median operation time was 309 min (IQR 265-353). The median blood loss was 30 ml (IQR 10-86). Grade 2-4 esophagojejunal anastomotic leakage was 2.5% (6/244; 95% CI 0.9-5.3). The overall proportion of in-hospital grade 3-4 adverse events was 29% (71/244). The proportions of intraabdominal abscess and pancreatic fistula were 3.7% and 2.0%, respectively. There were no treatment-related deaths.
CONCLUSIONS: This trial confirmed the safety of LATG/LAPG. After the non-inferiority of LADG is confirmed in our phase III trial (JCOG0912), LATG/LAPG is expected to be established as one of the standard treatments for clinical stage I gastric cancer.

PMID 30788750
Inaki N, Etoh T, Ohyama T, Uchiyama K, Katada N, Koeda K, Yoshida K, Takagane A, Kojima K, Sakuramoto S, Shiraishi N, Kitano S.
A Multi-institutional, Prospective, Phase II Feasibility Study of Laparoscopy-Assisted Distal Gastrectomy with D2 Lymph Node Dissection for Locally Advanced Gastric Cancer (JLSSG0901).
World J Surg. 2015 Nov;39(11):2734-41. doi: 10.1007/s00268-015-3160-z.
Abstract/Text BACKGROUND: The efficacy and safety outcomes of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection for locally advanced gastric cancer remain unclear. Therefore, we conducted a randomized, controlled phase II trial to confirm the feasibility of LADG in terms of technical safety, and short-term surgical outcomes were investigated.
METHODS: Eligibility criteria included pre-operatively diagnosed advanced gastric cancer that could be treated by distal gastrectomy with D2 lymph node dissection; MP, SS, and SE without involvement of other organs; and N0-2 and M0. Patients aged 20-80 years were pre-operatively randomized.
RESULTS: In total, 180 patients were registered and randomized to the open (89 patients) and laparoscopic arms (91 patients). Among 91 patients in the laparoscopic arm, 86 underwent laparoscopic gastrectomy according to the study protocol. Regarding the primary endpoint of the phase II trial, the proportion of patients with either anastomotic leakage or pancreatic fistula was 4.7 % (4/86). The grade 3 or higher morbidity rate, including systemic and local complications, was 5.8 %. Conversion to open surgery was required for 1 patient (1.2 %), without any intra-operative complication. The post-operative mortality rate was 0, and no patient required readmission for surgical complications within 6 months after initial discharge.
CONCLUSIONS: The technical safety of LADG with D2 lymph node dissection for locally advanced gastric cancer was demonstrated. A phase III trial to confirm the non-inferiority of this procedure to open gastrectomy in terms of long-term outcomes is ongoing. Registered Number: UMIN 000003420 ( www.umin.ac.jp/ctr/).

PMID 26170158
Kim HH, Han SU, Kim MC, Kim W, Lee HJ, Ryu SW, Cho GS, Kim CY, Yang HK, Park DJ, Song KY, Lee SI, Ryu SY, Lee JH, Hyung WJ; Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS) Group.
Effect of Laparoscopic Distal Gastrectomy vs Open Distal Gastrectomy on Long-term Survival Among Patients With Stage I Gastric Cancer: The KLASS-01 Randomized Clinical Trial.
JAMA Oncol. 2019 Apr 1;5(4):506-513. doi: 10.1001/jamaoncol.2018.6727.
Abstract/Text IMPORTANCE: Laparoscopic distal gastrectomy is gaining popularity over open distal gastrectomy for gastric cancer because of better early postoperative outcomes. However, to our knowledge, no studies have proved whether laparoscopic distal gastrectomy is oncologically equivalent to open distal gastrectomy.
OBJECTIVE: To examine whether the long-term survival among patients with stage I gastric cancer undergoing laparoscopic distal gastrectomy is noninferior to that among patients undergoing open distal gastrectomy.
DESIGN: The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS) group, which includes 15 surgeons from 13 institutes, conducted a phase 3, multicenter, open-label, noninferiority, prospective randomized clinical trial (KLASS-01) of patients with histologically proven, preoperative clinical stage I gastric adenocarcinoma from January 5, 2006, to August 23, 2010. Survival and recurrence status of the patients was determined in December 2016.
INTERVENTIONS: Patients were randomly assigned (1:1) to laparoscopic distal gastrectomy (n = 705) or open distal gastrectomy (n = 711). Of these patients, 85 received a surgical approach opposite the one to which they were randomized (63 randomized to the open surgery group and 22 to the laparoscopic group).
MAIN OUTCOMES AND MEASURES: Difference in 5-year overall survival between the laparoscopic and open distal gastrectomy groups. The noninferiority margin was prespecified as -5% (corresponding hazard ratio of 1.54), with an assumed survival of 90% after 5 years in the open surgery group.
RESULTS: Among the 1416 patients (mean [SD] age, 57.3 [11.1] years; 940 [66.4%] male) included in the study, the 5-year overall survival rates were 94.2% in the laparoscopic group and 93.3% in the open surgery group (log-rank P = .64). Intention-to-treat analysis confirmed the noninferiority of the laparoscopic approach compared with the open approach (difference, 0.9 percentage points; 1-sided 97.5% CI, -1.6 to infinity). The 5-year cancer-specific survival rates were similar between the 2 groups (97.1% in the laparoscopic group and 97.2% in the open surgery group, log-rank P = .91; difference, -0.03 percentage points; 1-sided 97.5% CI, -1.8 to infinity). Per-protocol analysis results were consistent with the intention-to-treat results for overall and cancer-specific survival rates.
CONCLUSIONS AND RELEVANCE: The KLASS-01 trial revealed similar overall and cancer-specific survival rates between patients receiving laparoscopic and open distal gastrectomy. Laparoscopic distal gastrectomy is an oncologically safe alternative to open surgery for stage I gastric cancer.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00452751.

PMID 30730546
Hu Y, Huang C, Sun Y, Su X, Cao H, Hu J, Xue Y, Suo J, Tao K, He X, Wei H, Ying M, Hu W, Du X, Chen P, Liu H, Zheng C, Liu F, Yu J, Li Z, Zhao G, Chen X, Wang K, Li P, Xing J, Li G.
Morbidity and Mortality of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: A Randomized Controlled Trial.
J Clin Oncol. 2016 Apr 20;34(12):1350-7. doi: 10.1200/JCO.2015.63.7215. Epub 2016 Feb 22.
Abstract/Text PURPOSE: The safety and efficacy of radical laparoscopic distal gastrectomy (LG) with D2 lymphadenectomy for the treatment of advanced gastric cancer (AGC) remain controversial. We conducted a randomized controlled trial to compare laparoscopic and conventional open distal gastrectomy with D2 lymph node dissections for AGC.
PATIENTS AND METHODS: Between September 2012 and December 2014, 1,056 patients with clinical stage T2-4aN0-3M0 gastric cancer were eligible for inclusion. They were randomly assigned to either the LG with D2 lymphadenectomy group (n = 528) or the open gastrectomy (OG) with D2 lymphadenectomy group (n = 528). Fifteen experienced surgeons from 14 institutions in China participated in the study. The morbidity and mortality within 30 days after surgery between the LG (n = 519) and the OG (n = 520) groups were compared on the basis of the modified intention-to-treat principle. Postoperative complications were stratified according to the Clavien-Dindo classification.
RESULTS: The compliance rates of D2 lymphadenectomy were similar between the LG and OG groups (99.4% v 99.6%; P = .845). The postoperative morbidity was 15.2% in the LG group and 12.9% in OG group with no significant difference (difference, 2.3%; 95% CI, -1.9 to 6.6; P = .285). The mortality rate was 0.4% for the LG group and zero for the OG group (difference, 0.4%; 95% CI, -0.4 to 1.4; P = .249). The distribution of severity was similar between the two groups (P = .314).
CONCLUSION: Experienced surgeons can safely perform LG with D2 lymphadenectomy for AGC.

© 2016 by American Society of Clinical Oncology.
PMID 26903580
Lee HJ, Hyung WJ, Yang HK, Han SU, Park YK, An JY, Kim W, Kim HI, Kim HH, Ryu SW, Hur H, Kong SH, Cho GS, Kim JJ, Park DJ, Ryu KW, Kim YW, Kim JW, Lee JH, Kim MC; Korean Laparo-endoscopic Gastrointestinal Surgery Study (KLASS) Group.
Short-term Outcomes of a Multicenter Randomized Controlled Trial Comparing Laparoscopic Distal Gastrectomy With D2 Lymphadenectomy to Open Distal Gastrectomy for Locally Advanced Gastric Cancer (KLASS-02-RCT).
Ann Surg. 2019 Dec;270(6):983-991. doi: 10.1097/SLA.0000000000003217.
Abstract/Text OBJECTIVE: The aim of the study was to evaluate the short-term outcomes of KLASS-02-RCT, a multicenter randomized controlled trial comparing laparoscopic distal gastrectomy (LDG) with D2 lymphadenectomy with open distal gastrectomy (ODG).
SUMMARY BACKGROUND DATA: Although several benefits of laparoscopic gastric cancer surgery have been reported, strong evidence is still limited, especially in locally advanced gastric cancer which requires extensive lymph node dissection.
METHODS: Enrollment criteria included histologically confirmed cT2-4a and N0-1 gastric adenocarcinoma. Thirty-day morbidity, 90-day mortality, postoperative pain, and recovery were compared between LDG and ODG groups.
RESULTS: A total of 1050 patients were randomly assigned to LDG (n = 526) or ODG group (n = 524) between November 2011 and April 2015. After excluding patients who received bypass or no surgery, 1011 patients were analyzed as actual treatment group. Mean number of totally retrieved lymph nodes was similar in both groups (LDG = 46.6 vs ODG = 47.4, P = 0.451). Early morbidity rate was significantly lower after LDG (16.6%) than after ODG (24.1%; P = 0.003). Postoperative analgesics use and patients' reported pain score were significantly lower after LDG. First day of flatus was earlier after LDG (3.5 vs 3.7 d, P = 0.025) and postoperative hospital stay was shorter in LDG group (8.1 vs 9.3 d, P = 0.005). Ninety days' mortality rate was similar in both groups (LDG = 0.4% vs ODG = 0.6%, P = 0.682).
CONCLUSIONS: Laparoscopic distal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer shows benefits in terms of lower complication rate, faster recovery, and less pain compared with open surgery.

PMID 30829698
Yu J, Huang C, Sun Y, Su X, Cao H, Hu J, Wang K, Suo J, Tao K, He X, Wei H, Ying M, Hu W, Du X, Hu Y, Liu H, Zheng C, Li P, Xie J, Liu F, Li Z, Zhao G, Yang K, Liu C, Li H, Chen P, Ji J, Li G; Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group.
Effect of Laparoscopic vs Open Distal Gastrectomy on 3-Year Disease-Free Survival in Patients With Locally Advanced Gastric Cancer: The CLASS-01 Randomized Clinical Trial.
JAMA. 2019 May 28;321(20):1983-1992. doi: 10.1001/jama.2019.5359.
Abstract/Text IMPORTANCE: Laparoscopic distal gastrectomy is accepted as a more effective approach to conventional open distal gastrectomy for early-stage gastric cancer. However, efficacy for locally advanced gastric cancer remains uncertain.
OBJECTIVE: To compare 3-year disease-free survival for patients with locally advanced gastric cancer after laparoscopic distal gastrectomy or open distal gastrectomy.
DESIGN, SETTING, AND PATIENTS: The study was a noninferiority, open-label, randomized clinical trial at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 2012 to December 2014. Final follow-up was on December 31, 2017.
INTERVENTIONS: Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histology to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy.
MAIN OUTCOMES AND MEASURES: The primary end point was 3-year disease-free survival with a noninferiority margin of -10% to compare laparoscopic distal gastrectomy with open distal gastrectomy. Secondary end points of 3-year overall survival and recurrence patterns were tested for superiority.
RESULTS: Among 1056 patients, 1039 (98.4%; mean age, 56.2 years; 313 [30.1%] women) had surgery (laparoscopic distal gastrectomy [n=519] vs open distal gastrectomy [n=520]), and 999 (94.6%) completed the study. Three-year disease-free survival rate was 76.5% in the laparoscopic distal gastrectomy group and 77.8% in the open distal gastrectomy group, absolute difference of -1.3% and a 1-sided 97.5% CI of -6.5% to ∞, not crossing the prespecified noninferiority margin. Three-year overall survival rate (laparoscopic distal gastrectomy vs open distal gastrectomy: 83.1% vs 85.2%; adjusted hazard ratio, 1.19; 95% CI, 0.87 to 1.64; P = .28) and cumulative incidence of recurrence over the 3-year period (laparoscopic distal gastrectomy vs open distal gastrectomy: 18.8% vs 16.5%; subhazard ratio, 1.15; 95% CI, 0.86 to 1.54; P = .35) did not significantly differ between laparoscopic distal gastrectomy and open distal gastrectomy groups.
CONCLUSIONS AND RELEVANCE: Among patients with a preoperative clinical stage indicating locally advanced gastric cancer, laparoscopic distal gastrectomy, compared with open distal gastrectomy, did not result in inferior disease-free survival at 3 years.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01609309.

PMID 31135850
Hyung WJ, Yang HK, Park YK, Lee HJ, An JY, Kim W, Kim HI, Kim HH, Ryu SW, Hur H, Kim MC, Kong SH, Cho GS, Kim JJ, Park DJ, Ryu KW, Kim YW, Kim JW, Lee JH, Han SU; Korean Laparoendoscopic Gastrointestinal Surgery Study Group.
Long-Term Outcomes of Laparoscopic Distal Gastrectomy for Locally Advanced Gastric Cancer: The KLASS-02-RCT Randomized Clinical Trial.
J Clin Oncol. 2020 Oct 1;38(28):3304-3313. doi: 10.1200/JCO.20.01210. Epub 2020 Aug 20.
Abstract/Text PURPOSE: It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated.
PATIENTS AND METHODS: A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups.
RESULTS: From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7% v 23.4%, respectively; P = .0027) and late complications (4.7% v 9.5%, respectively; P = .0038), particularly intestinal obstruction (2.0% v 4.4%, respectively; P = .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank P = .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank P = .827; P for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank P = .900; P for noninferiority = .030).
CONCLUSION: Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.

PMID 32816629
Uyama I, Suda K, Nakauchi M, Kinoshita T, Noshiro H, Takiguchi S, Ehara K, Obama K, Kuwabara S, Okabe H, Terashima M.
Clinical advantages of robotic gastrectomy for clinical stage I/II gastric cancer: a multi-institutional prospective single-arm study.
Gastric Cancer. 2019 Mar;22(2):377-385. doi: 10.1007/s10120-018-00906-8. Epub 2018 Dec 3.
Abstract/Text BACKGROUND: Robotic gastrectomy (RG) for gastric cancer (GC) has been increasingly performed for a decade; however, evidence for its use as a standard treatment has not yet been established. The present study aimed to determine the safety, feasibility, and effectiveness of RG for GC.
METHODS: This multi-institutional, single-arm prospective study, which included 330 patients from 15 institutions, was designed to compare morbidity rate of RG with that of a historical control (conventional laparoscopic gastrectomy, LG). This trial was approved for Advanced Medical Technology ("Senshiniryo") B. The included patients were operable patients with cStage I/II GC. The primary endpoint was morbidity (Clavien-Dindo Grade ≥ IIIa). The specific hypothesis was that RG could reduce the morbidity rate to less than half of that with LG (6.4%). A sample size of 330 was considered sufficient (one-sided alpha 0.05, power 80%).
RESULTS: Among the 330 study patients, the protocol treatment was suspended in 4 patients. Thus, 326 patients fully enrolled and completed the study. The median patient age and BMI were 66 years and 22.4 kg/m2, respectively. Distal gastrectomy was performed in 253 (77.6%) patients. The median operative time and estimated blood loss were 313 min and 20 mL, respectively. No 30-day mortality was seen, and morbidity showed a significant reduction to 2.45% with RG (p = 0.0018).
CONCLUSIONS: RG for cStage I/II GC is safe and feasible. It may be effective in reducing morbidity with LG.

PMID 30506394
Yu W, Choi GS, Chung HY.
Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer.
Br J Surg. 2006 May;93(5):559-63. doi: 10.1002/bjs.5353.
Abstract/Text BACKGROUND: Preservation or removal of the spleen during total gastrectomy for proximal gastric cancer is a matter of debate.
METHODS: A randomized clinical trial included patients with gastric adenocarcinoma who underwent total gastrectomy either with (104 patients) or without (103) splenectomy. Postoperative outcome in the two groups was compared, including morbidity, mortality and survival.
RESULTS: Gastrectomy combined with splenectomy tended to be associated with slightly higher morbidity and mortality rates, a slightly greater incidence of lymph node metastasis at the splenic hilum and along the splenic artery, and marginally better survival, but there were no statistically significant differences between the groups. Splenectomy had no impact on survival in patients with metastatic lymph nodes at the hilum of the spleen or in those with metastatic lymph nodes along the splenic artery.
CONCLUSION: These results do not support the use of prophylactic splenectomy to remove macroscopically negative lymph nodes near the spleen in patients undergoing total gastrectomy for proximal gastric cancer.

PMID 16607678
Sano T, Sasako M, Mizusawa J, Yamamoto S, Katai H, Yoshikawa T, Nashimoto A, Ito S, Kaji M, Imamura H, Fukushima N, Fujitani K; Stomach Cancer Study Group of the Japan Clinical Oncology Group.
Randomized Controlled Trial to Evaluate Splenectomy in Total Gastrectomy for Proximal Gastric Carcinoma.
Ann Surg. 2017 Feb;265(2):277-283. doi: 10.1097/SLA.0000000000001814.
Abstract/Text OBJECTIVE: To clarify the role of splenectomy in total gastrectomy for proximal gastric cancer.
BACKGROUNDS: Splenectomy in total gastrectomy is associated with increased operative morbidity and mortality, but its survival benefit is unclear. Previous randomized controlled trials were underpowered and inconclusive.
METHODS: We conducted a multiinstitutional randomized controlled trial. Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not invading the greater curvature was eligible. During the operation, surgeons confirmed that R0 resection was possible with negative lavage cytology, and patients were randomly assigned to either splenectomy or spleen preservation. The primary endpoint was overall survival (OS) and the secondary endpoints were relapse-free survival, operative morbidity, operation time, and blood loss. The trial was designed to confirm noninferiority of spleen preservation to splenectomy in OS with a noninferiority margin of the hazard ratio as 1.21 and 1-sided alpha of 5%.
RESULTS: Between June 2002 and March 2009, 505 patients (254 splenectomy, 251 spleen preservation) were enrolled from 36 institutions. Splenectomy was associated with higher morbidity and larger blood loss, but the operation time was similar. The 5-year survivals were 75.1% and 76.4% in the splenectomy and spleen preservation groups, respectively. The hazard ratio was 0.88 (90.7%, confidence interval 0.67-1.16) (<1.21); thus, the noninferiority of spleen preservation was confirmed (P = 0.025).
CONCLUSIONS: In total gastrectomy for proximal gastric cancer that does not invade the greater curvature, splenectomy should be avoided as it increases operative morbidity without improving survival.

PMID 27280511
Sasako M, Sano T, Yamamoto S, Sairenji M, Arai K, Kinoshita T, Nashimoto A, Hiratsuka M; Japan Clinical Oncology Group (JCOG9502).
Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial.
Lancet Oncol. 2006 Aug;7(8):644-51. doi: 10.1016/S1470-2045(06)70766-5.
Abstract/Text BACKGROUND: Because of the inaccessibility of mediastinal nodal metastases, the left thoracoabdominal approach (LTA) has often been used to treat gastric cancer of the cardia or subcardia. In a randomised phase III study, we aimed to compare LTA with the abdominal-transhiatal approach (TH) in the treatment of these tumours.
METHODS: Between July, 1995, and December, 2003, 167 patients were enrolled from 27 Japanese hospitals and randomly assigned to TH (n=82) or LTA (n=85). The primary endpoint was overall survival, and secondary endpoints were disease-free survival, postoperative morbidity and hospital mortality, and postoperative symptoms and change of respiratory function. The projected sample size was 302. After the first interim analysis, the predicted probability of LTA having a significantly better overall survival than TH at the final analysis was only 3.65%, and the trial was closed immediately. Analysis was by intention to treat. This study is registered with , number NCT00149266.
FINDINGS: 5-year overall survival was 52.3% (95% CI 40.4-64.1) in the TH group and 37.9% (26.1-49.6) in the LTA group. The hazard ratio of death for LTA compared with TH was 1.36 (0.89-2.08, p=0.92). Three patients died in hospital after LTA but none after TH. Morbidity was worse after LTA than after TH.
INTERPRETATION: Because LTA does not improve survival after TH and leads to increased morbidity in patients with cancer of the cardia or subcardia, LTA cannot be justified to treat these tumours.

PMID 16887481
Kurokawa Y, Takeuchi H, Doki Y, Mine S, Terashima M, Yasuda T, Yoshida K, Daiko H, Sakuramoto S, Yoshikawa T, Kunisaki C, Seto Y, Tamura S, Shimokawa T, Sano T, Kitagawa Y.
Mapping of Lymph Node Metastasis From Esophagogastric Junction Tumors: A Prospective Nationwide Multicenter Study.
Ann Surg. 2021 Jul 1;274(1):120-127. doi: 10.1097/SLA.0000000000003499.
Abstract/Text OBJECTIVE: The aim of the study was to determine the optimal extent of lymph node dissection for the 2 histological types of esophagogastric junction (EGJ) tumors based on the incidence of metastasis in a prospective nationwide multicenter study.
BACKGROUND: Because most previous studies were retrospective, the optimal surgical procedure for EGJ tumors has not been standardized.
METHODS: Patients with cT2-T4 adenocarcinoma or squamous cell carcinoma located within 2.0 cm of the EGJ were enrolled before surgery. Surgeons dissected all lymph nodes prespecified in the protocol, using either the abdominal transhiatal or right transthoracic approach. The primary endpoint was the metastasis rate of each lymph node. Lymph nodes were classified according to metastasis rate, as follows: category-1 (strongly recommended for dissection), rate more than 10%; category-2 (weakly recommended for dissection), rate from 5% to 10%; and category-3 (not recommended for dissection), rate less than 5%.
RESULTS: Between 2014 and 2017, 1065 patients with EGJ tumor were screened, and 371 were enrolled. Among 358 patients who underwent surgical resection, category-1 nodes included abdominal stations 1, 2, 3, 7, 9, and 11p, whereas category-2 nodes included abdominal stations 8a, 19, and lower mediastinal station 110. If esophageal involvement exceeded 2.0 cm, station 110 was assigned to category-1. Among 98 patients who had either adenocarcinoma with esophageal involvement over 3.0 cm or squamous cell carcinoma, there were no category-1 nodes in the upper/middle mediastinal field, whereas category-2 nodes included upper mediastinal station 106recR and middle mediastinal station 108. When esophageal involvement exceeded 4.0 cm, station 106recR was assigned to category-1.
CONCLUSION: The study accurately identified the distribution of lymph node metastases from EGJ tumors and the optimal extent of subsequent lymph node dissection.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
PMID 31404008
Yamashita H, Seto Y, Sano T, Makuuchi H, Ando N, Sasako M; Japanese Gastric Cancer Association and the Japan Esophageal Society.
Results of a nation-wide retrospective study of lymphadenectomy for esophagogastric junction carcinoma.
Gastric Cancer. 2017 Mar;20(Suppl 1):69-83. doi: 10.1007/s10120-016-0663-8. Epub 2016 Oct 28.
Abstract/Text BACKGROUND: Esophagogastric junction (EGJ) carcinoma has attracted considerable attention because of the marked increase in its incidence globally. However, the optimal extent of esophagogastric resection for this tumor entity remains highly controversial.
METHODS: This was a questionnaire-based national retrospective study undertaken in an attempt to define the optimal extent of lymph node dissection for EGJ cancer. Data from patients with EGJ carcinoma, less than 40 mm in diameter, who underwent R0 resection between January 2001 and December 2010 were reviewed.
RESULTS: Clinical records of 2807 patients without preoperative therapy were included in the analysis. There are distinct disparities in terms of the nodal dissection rate according to histology and the predominant tumor location. Nodal metastases frequently involved the abdominal nodes, especially those at the right and left cardia, lesser curvature and along the left gastric artery. Nodes along the distal portion of the stomach were much less often metastatic, and their dissection seemed unlikely to be beneficial. Lower mediastinal node dissection might contribute to improving survival for patients with esophagus-predominant EGJ cancer. However, due to low dissection rates for nodes of the middle and upper mediastinum, no conclusive result was obtained regarding the optimal extent of nodal dissection in this region.
CONCLUSIONS: Complete nodal clearance along the distal portion of the stomach offers marginal survival benefits for patients with EGJ cancers less than 4 cm in diameter. The optimal extent of esophageal resection and the benefits of mediastinal node dissection remain issues to be addressed in managing patients with esophagus-predominant EGJ cancers.

PMID 27796514
Kurokawa Y, Doki Y, Mizusawa J, Terashima M, Katai H, Yoshikawa T, Kimura Y, Takiguchi S, Nishida Y, Fukushima N, Iwasaki Y, Kaji M, Hirao M, Katayama H, Sasako M.
Bursectomy versus omentectomy alone for resectable gastric cancer (JCOG1001): a phase 3, open-label, randomised controlled trial.
Lancet Gastroenterol Hepatol. 2018 Jul;3(7):460-468. doi: 10.1016/S2468-1253(18)30090-6. Epub 2018 Apr 28.
Abstract/Text BACKGROUND: The role of bursectomy, in which the peritoneal lining covering the pancreas and the anterior plane of the transverse mesocolon are dissected, has long been controversial for preventing peritoneal metastasis. We investigated the survival benefit of bursectomy in patients with resectable gastric cancer.
METHODS: This phase 3, open-label, randomised controlled trial was done at 57 hospitals in Japan. Patients aged 20-80 years who had cT3(SS)-cT4a(SE) histologically proven gastric adenocarcinoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 and body-mass index less than 30 kg/m2 and who did not have distant metastasis or bulky lymph nodes were randomly assigned (1:1) during surgery to receive omentectomy alone (non-bursectomy) or bursectomy. Randomisation was done by telephone or website to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component to adjust for institution, cT status (T3 vs T4a), and type of gastrectomy (distal vs total). Both groups had total or distal gastrectomy with D2 lymphadenectomy. The primary endpoint was overall survival, analysed in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000003688.
FINDINGS: Between June 1, 2010, and March 30, 2015, 1503 patients were enrolled based on preoperative inclusion and exclusion criteria. Intraoperative inclusion and exclusion criteria were met in 1204 patients, of which 602 were allocated to the non-bursectomy group and 602 were allocated to the bursectomy group. At the planned second interim analysis on Sept 17, 2016, the JCOG Data and Safety Monitoring Committee independently reviewed the results and recommended their early publication on the basis of futility because overall survival was lower in the bursectomy group than the non-bursectomy group, and because the predictive probability of overall survival being significantly higher in bursectomy than non-bursectomy patients at the final analysis was only 12·7%. 5-year overall survival was 76·7% (95% CI 72·0-80·6) in the non-bursectomy group and 76·9% (72·6-80·7) in the bursectomy group (hazard ratio 1·05, 95% CI 0·81-1·37, one-sided p=0·65). 64 (11%) of 601 in the non-bursectomy group and 77 (13%) of 600 patients in the bursectomy group had grade 3-4 operative morbidity. Pancreatic fistula was significantly more common in the bursectomy group than in the non-bursectomy group (29 [5%] vs 15 [2%]; p=0·032). Six deaths occurred either in hospital or within 1 month of surgery: five in the non-bursectomy group and one in the bursectomy group.
INTERPRETATION: Bursectomy did not provide a survival advantage over non-bursectomy. D2 dissection with omentectomy alone should be done as a standard surgery for resectable cT3-T4a gastric cancer.
FUNDING: Japan Agency for Medical Research and Development, the Ministry of Health, Labour and Welfare of Japan, and the National Cancer Centre Research and Development Fund.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29709558
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、渡邉裕次、井ノ口岳洋、梅田将光および日本医科大学多摩永山病院 副薬剤部長 林太祐による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
井ノ口幹人 : 特に申告事項無し[2025年]
監修:杉原健一 : 特に申告事項無し[2025年]

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