Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial
Sun Young RhaDo‐Youn OhPatricio YañezYuxian BaiMin‐Hee RyuJeeyun LeeFernando RiveraGustavo Vasconcelos AlvesMarcelo GarridoKai‐Keen ShiuM. FernándezJin LiMaeve A. LoweryTimuçin ÇilFelipe Melo CruzShukui QinSuxia LuoHongming PanZev A. WainbergLina YinSonal BordiaPooja BhagiaLucjan WyrwiczGuillermo MéndezJuan Manuel O’ConnorAlvaro Yanzi CastillaJuan CundomDiego KaenRachel WongWeng NgMorteza AghmeshehMauricio PeressoniCarlos Eduardo Mattos da Cunha AndradeFábio FrankeGustavo R. AlvesFelipe Jose CruzKarina ViannaMaria Marcela MonteiroMichael J. RaphaelScott BerryRaymond Woo-Jun JangAnn TanJamil AsselahPatricio Yanez WeberMauricio MahaveCésar SánchezPamela SalmanYuxian BaiJin LiXiaochun ZhangTianshu LiuXiaoyan LinShukui QinJianwei YangSuxia LuoWěi LiJieer YingXi ChenShan ZengYanli QuLin YangLin ZhaoPing ChenHongming PanEnxiao LiFeng YeJianwei LuXinjun LiangQun ZhaoXianli YinJunhe LiLing YangGuoqing LvShouguo LiÁlvaro GuerreroJuan RubianoM. FernándezRay Manneh KoppAdrian Guzman RamirezLuis CorralesIleana Gonzalez HerreraBohuslav MelicharTomáš BüchlerTomáš SvobodaRadka ObermannováDavid VránaJakub CvekPer PfeifferLene BæksgaardMette YilmazValérie BoigeDaniel López‐TrabadaChristophe BorgDiane PannierSandrine HiretFrédéric Di FioreJean‐Philippe MetgesDirk ArnoldUwe M. MartensFlorian LordickAlexander SteinHugo R. CastroKarla Alejandra LopezJulio A. RamírezMynor AguilarMarco ChivalanWing‐Lok ChanAshley ChengWinnie YeoPeter ArkosyTibor CsösziErika HitreZsolt HorváthMaeve A. LoweryRay McDermottPatrick G. MorrisAyala HubertBaruch BrennerIrit Ben‐AharonEinat Shacham‐ShmueliSofia ManSharon Pelles AvrahamRonen BrennerMoshe MishaeliMaria Di BartolomeoNicola FazioSara LonardiCarlo GarufiTaroh SatohHiroki HaraShiro IwagamiHisateru YasuiMasahiro TsudaTatsu ShimoyamaHirokazu ShojiNaotoshi SugimotoNobuhiro ShibataKensei YamaguchiKenji AmagaiYasuhiro ChodaTaito EsakiHiroshi YabusakiTakashi OshimaAkihito TsujiHisato KawakamiAkihito KawazoeKenji IshidoShigenori KadowakiJorge Martinez RodriguezMarytere Herrera MartínezFidel Huitzil MelendezFrancisco Ramirez GodinezPaola BalancanDragan DamianovichVictor Castro OlidenJulio GradosCésar TorresLucjan WyrwiczPiotr J. WysockiŁukasz HajacJakub ŻołnierekBoguslawa KaraszewskaSun Young RhaJeeyun LeeMin‐Hee RyuDo‐Youn OhР. В. ОрловаS. TjulandinNatalia FadeevaYulia MakarychevaDmitry NosovMaria SmaginaSze Ham ChanConrad JacobsP KrausGregory LandersBarbara RobertsonPaul RuffElizabeth SchoemanJean-Marc MaurelM. Díez GarcíaPaula Jiménez FonsecaJavier GállegoF. Rivera HerreroJesús MirandaL. Layos RomeroRalph FritschSara BastianSun Young RhaSara De DossoThibaud KösslerKun‐Huei YehChia‐Jui YenYen‐Yang ChenJohnson LinMehmet BiliciMustafa ÖzgüroğluTimuçin ÇilBerna ÖksüzoğluHakan HarputluoğluAziz Karaoğluİlhan HacıbekiroğluBülent ErdoğanŞuayib YalçınHryhoriy AdamchukIgor BondarenkoOleksii KolesnikYuriy OstapenkoAnna KryzhanivskaLurii LeshchenkoIevgen IlinYaroslav ShparykDmytro TrukhinОлександр ВойткоRajarshi RoyAnna-Mary YoungLouise MedleyKai‐Keen ShiuPaul CelanoLindsay OvertonMoses S. RajRichard F. DunneZev A. WainbergFarshid DayyaniTimothy LarsonMark D. Kochenderfer
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Oxaliplatin-based chemotherapy has been associated with hepatic sinusoidal obstruction syndrome which is clinically characterized by portal hypertension, splenomegaly, subsequent thrombocytopenia and liver dysfunction. 1-5 • Although oxaliplatin is particularly incriminated for hepatic sinusoidal obstruction syndrome, fluoropyrimidines including 5-fluorouracil (5-FU), capecitabine and S-1 have been also suggested to result in sinusoidal dilatation or hepatic sinusoidal obstruction syndrome to a lesser extent. 6 • Purpose: To compare the severity and reversibility of hepatic sinusoidal obstruction syndrome, and its clinical significance in the aspect of chemotherapy dose intensity between two most commonly used oral fluoropyrimidines, S-1 and capecitabine when combined with oxaliplatin in patients with gastric cancer (GC). BACKGROUND CONCLUSIONS• S-1 seems to enhance oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients with clinical significance of higher incidences of splenomegaly, thrombocytopenia, increase of bilirubin, and dose reduction or delay of chemotherapy.• Given that hepatic sinusoidal injuries induced by either S-1 or capecitabine plus oxaliplatin are reversible after stopping chemotherapy, a better treatment strategy such as stop-and-go needs to be pursued in the palliative setting.• Further studies are needed to elucidate the underlying mechanisms for this phenomenon.
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Objective To investigate the efficacy and toxicity of Oxaliplatin combined with Capecitabine in treating advanced gastric cancer.Methods Oxaliplatin(130 mg/m2 ,intravenous infusion on day 1 for three hours) and Capecitabine(1000 mg/m2 ,per oral,twice daily for 14 days) were administered in a 21 days treatment course.All patients received at least two courses of treatment.Results Twenty-eight patients were enrolled in this study.All patients were included in the efficacy and adverse events analysis.There were no complete responses,twelve partial responses,giving an overall response rate of 42.8%.The major toxicity included myelotoxicity,peripheral neurotoxicity and hand-foot syndrome,all were generally mild.Conclusions Oxaliplatin combined with Capecitabine demonstrates clinical activity and an acceptable safety profile in patients with advanced gastric cancer.Clearly further investigation is warranted as we work.
Neurotoxicity
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Objective Comparative analysis the treatment effect of postoperation recurring gastric cancer about S1 and Capecitabine combined with Oxaliplatin. Methods The 26 patients which were postoperation recurring gastric cancer received and cured.Observed group (12 cases)cured with Oxaliplatin 30 mg/m2,D1, intravenous drip,S-1 selected 40mg～60mg/times about body surface area, 2 times/d, oral administration, D1~D14.Matched group (14 cases)cured with Oxaliplatin 30 mg/m2, D1, intravenous drip; Capecitabine applied 1500mg/times, 2 times/d, oral administration, D1~D14.Both the methods remedy cycles were 21 days.Effected assessment one times with two cycles, and follow-up visited the patients' condition.Results All the patients can be evaluated, the observed group's RR was 50% and the matched group's RR was 42.8%, they had no significant differences, but adverse effects and serious reactions of observed group were clearly under the matched group.Conclusion S-1 combined with Oxaliplatin was effective on advanced gastric cancer, and the adverse effects were tolerable.
Tegafur
Body surface area
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Objective To evaluate the efficacy and safety of Oxaliplatin in combination with capecitabine in treating advanced gastric cancer.Methods Thirty-five patients with advanced gastric cancer received chemotherapy: Oxaliplatin 100 mg/m~2 i.v,d1; combining oral capecitabine 2000mg/m~2.d (divided in two doses) d1-14; and repeated every 3 weeks.The efficacy and safety were assessed in every cycle.Results 2 cases (5.71%) achieved CR,13 cases (37.14%) had PR,10 cases (8.57%) had SD,10 cases (28.57%) had PD,with an overall response rate of 42.86%.The most common adverse effects were leucopenia,hand-foot syndrome,diarrhea and skin pigmentation.There was no treatment-related death.Conclusion Chemotherapy with oxaliplatin combined with capecitabine is effective and well-tolerated to the patients with advanced gastric cancer.
Combination chemotherapy
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Objective We evaluated the antitumour activity and toxicities of oxaliplatin and capecitabine as therapy in geriatric patients with advanced gastric cancer(AGC).Methods Patients were treated with capecitabine 1000mg/m2 p.o.twice daily on days 1-14 and oxaliplatin 120mg/m2 i.v.on day 1 every 3 weeks until disease progression or unacceptable toxicities.Results 1 patient showed complete response and 12 showed partial response.The overall response rate 56.4%.Major toxicity was myelosuppression,enteric reaction and hand-foot syndrome.Conclusion Oxaliplatin and capecitabine combination chemotherapy is active and highly tolerable as a therapy for geriatric patients with AGC.
Combination chemotherapy
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Objective To observe the efficacy and toxicity of the chemotherapy of Capecitabine combined with Oxaliplatin in treatment of patients with advanced gastric cancer.Methods 50 patients with advanced gastric cancer were randomly divided into group A and group B,with 25 cases respectively.Group A: Capecitabine 1 000 mg/m2,po,bid,d1-14;Oxaliplatin 130 mg/m2,ivgtt(2 h),d1;Group B: Leucovorin 200 mg/d,ivgtt(2 h),d1~5;Fluorouracil 750 mg/d,ivgtt(8 h),d1-5;Oxaliplatin 130 mg/m2,ivgtt(2 h),d1.They were repeated every 3 weeks.Results The differences in clinical efficacy were not obvious between the two groups(P 0.05).The toxicity of digestive systemtoxicity in group A was obviously milder than the toxicity in group B(P 0.01).Conclusion The chemotherapy of Capecitabine combined with Oxaliplatin is worthwhile to be applied widely in treatment of patients with advanced gastric cancer.
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Objective: To observe the safety and curative effects of treating advanced gastric cancer with combined capecitabine and oxaliplatin.Methods: Thirty two patients with advanced gastric cancer were treated with capecitabine and oxaliplatin for two courses to observe the curative effects,clinical profit,toxic reactions and side effects.Results: The total effective rate reached 56.3%.The patients who hade clinical profit were 84.3% and with slight toxic reactions and side effects,no patients dead for toxic reactions of chemotherapy. Conclusion: The chemotherapy with capecitabine and oxaliplatin combined has more advantages in treating advanced gastric cancer.It is more effective,more convenient and with slight toxic reactions and side effects is an effective chemotherapy regimen for advanced gastric cancer.
Regimen
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Objective: To investigate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of capecitabine plus oxaliplatin. Materials and Methods: Oxaliplatin was given by 2-hour iv infusion on days 1 and 8, and capecitabine was given orally, from day 1 to 14, every 3 weeks. We tested 4 levels of doses: 1) capecitabine 1650 mg/m2 + oxaliplatin 50 mg/m2; 2) capecitabine 2000 mg/m2 + oxaliplatin 50 mg/m2; 3) capecitabine 2000 mg/m2 + oxaliplatin 60 mg/m2; and 4) capecitabine 2500 mg/m2 + oxaliplatin 60 mg/m2. Patients with gastrointestinal neoplasm were eligible for the study. Results: Thirty-two patients were enrolled. At dose level 4, 3 patients had unacceptable toxicity (grade 3 diarrhea, grade 4 diarrhea, and grade 3 mucositis, respectively), thus, level 4 was the MTD. Apart from DLT, overall toxicity was mild: grade ≥3 nonhematological toxicity occurred in 3 patients, and hematological toxicity was sporadic. Conclusion: This study demonstrates that clinically relevant doses of capecitabine (2000 mg/m2 from day 1 to 14) plus oxaliplatin (60 mg/m2 on days 1 and 8) every 3 weeks can be given without causing unacceptable toxicity.
Mucositis
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Objective:To observe the curative effects and safety of treatment advanced gastric cancer in combined capecitabine and oxaliplatin.Methods:Thirty three patients with advanced gastric cancer were treated with capecitabine and oxaliplatin for two courses to observe the curative effects,clinicalprofit,toxic reactions and side effects.Results:The total effective rate was 63.6%.The clinical profits obtained from paients were 81.2%.Conclusions:Chemotherapy of oxaliplatin combined capecitabin is effective and well tolerated to the patients with advanced gastric cancer.
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