A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study

Menglong Zhou, Wang Yang, Yan Xuan, Wei Zou, Yaqi Wang, Zhiyuan Zhang, Jing Zhang, Miao Mo, Changming Zhou, Yuan Liu, Wenming Zhang, Zhaozhen Zhang, Yiping He, Weiwei Weng, Cong Tan, Lei Wang, Dan Huang, Weiqi Sheng, Huanhuan Li, Hui Zhu, Yan Wang, Lijun Shen, Hui Zhang, Juefeng Wan, Guichao Li, Hua Huang, Yanong Wang, Zhen Zhang, Xiaowen Liu, Fan Xia, Menglong Zhou, Wang Yang, Yan Xuan, Wei Zou, Yaqi Wang, Zhiyuan Zhang, Jing Zhang, Miao Mo, Changming Zhou, Yuan Liu, Wenming Zhang, Zhaozhen Zhang, Yiping He, Weiwei Weng, Cong Tan, Lei Wang, Dan Huang, Weiqi Sheng, Huanhuan Li, Hui Zhu, Yan Wang, Lijun Shen, Hui Zhang, Juefeng Wan, Guichao Li, Hua Huang, Yanong Wang, Zhen Zhang, Xiaowen Liu, Fan Xia

Abstract

Background: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC.

Methods: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy.

Discussion: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety.

Trial registration: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.

Keywords: Gastrectomy; Gastroesophageal junction adenocarcinoma; Immunotherapy; Locally advanced gastric cancer; Preoperative chemoradiation.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flow chart of the NeoRacing study
Fig. 2
Fig. 2
The treatment schedule of Arm A and Arm B in the NeoRacing study

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. doi: 10.3322/caac.21660.
    1. Wang Y, Li Z, Shan F, Miao R, Xue K, Li Z, Gao C, Chen N, Gao X, Li S, et al. Current status of diagnosis and treatment of early gastric cancer in China--Data from China Gastrointestinal Cancer Surgery Union. Zhonghua Wei Chang Wai Ke Za Zhi. 2018;21(2):168–174.
    1. Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71:264–279. doi: 10.3322/caac.21657.
    1. van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW, Henegouwen MIVB, Wijnhoven BPL, Richel DJ, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, et al. Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer. New Engl J Med. 2012;366(22):2074–2084. doi: 10.1056/NEJMoa1112088.
    1. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Konigsrainer A, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009;27(6):851–856. doi: 10.1200/JCO.2008.17.0506.
    1. Leong T, Smithers BM, Haustermans K, Michael M, Gebski V, Miller D, Zalcberg J, Boussioutas A, Findlay M, O'Connell RL, et al. TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol. 2017;24(8):2252–2258. doi: 10.1245/s10434-017-5830-6.
    1. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24(24):3953–3958. doi: 10.1200/JCO.2006.06.4840.
    1. Liu X, Li G, Long Z, Yin J, Zhu X, Sheng W, Huang D, Zhu H, Zhang Z, Cai H, et al. Phase II trial of preoperative chemoradiation plus perioperative SOX chemotherapy in patients with locally advanced gastric cancer. J Surg Oncol. 2018;117(4):692–698. doi: 10.1002/jso.24917.
    1. Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer. 2017;81:183–190. doi: 10.1016/j.ejca.2017.04.027.
    1. Wang XZ, Zeng ZY, Ye X, Sun J, Zhang ZM, Kang WM. Interpretation of the development of neoadjuvant therapy for gastric cancer based on the vicissitudes of the NCCN guidelines. World J Gastrointest Oncol. 2020;12(1):37–53. doi: 10.4251/wjgo.v12.i1.37.
    1. Liu X, Jin J, Cai H, Huang H, Zhao G, Zhou Y, Wu J, Du C, Long Z, Fang Y, et al. Study protocol of a randomized phase III trial of comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma: PREACT. BMC Cancer. 2019;19(1):606. doi: 10.1186/s12885-019-5728-8.
    1. Leong T, Smithers BM, Michael M, Gebski V, Boussioutas A, Miller D, Simes J, Zalcberg J, Haustermans K, Lordick F, et al. TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/EORTC/NCIC CTG) BMC Cancer. 2015;15:532. doi: 10.1186/s12885-015-1529-x.
    1. Slagter AE, Jansen E, van Laarhoven H, van Sandick JW, van Grieken N, Sikorska K, Cats A, Muller-Timmermans P, Hulshof M, Boot H, et al. CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. BMC Cancer. 2018;18(1):877. doi: 10.1186/s12885-018-4770-2.
    1. Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021;22(8):1081–1092. doi: 10.1016/S1470-2045(21)00297-7.
    1. Wang X, Li S, Xie T, Lu Y, Guo X, Lin C. Early results of the randomized, multicenter, controlled evaluation of S-1 and oxaliplatin as neoadjuvant chemotherapy for Chinese advanced gastric cancer patients (RESONANCE Trial) J Clin Oncol. 2020;38(4_suppl):280. doi: 10.1200/JCO.2020.38.4_suppl.280.
    1. Zhang L, Mai W, Jiang W, Geng Q. Sintilimab: A Promising Anti-Tumor PD-1 Antibody. Front Oncol. 2020;10:594558. doi: 10.3389/fonc.2020.594558.
    1. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC. AJCC Cancer Staging Manual. 8th edi. New York: Springer; 2017.
    1. Association JGC Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–112. doi: 10.1007/s10120-011-0041-5.
    1. Chuwa EW, Khin LW, Chan WH, Ong HS, Wong WK. Prognostic significance of peritoneal lavage cytology in gastric cancer in Singapore. Gastric Cancer. 2005;8(4):228–237. doi: 10.1007/s10120-005-0343-6.
    1. Okabe H, Ueda S, Obama K, Hosogi H, Sakai Y. Induction chemotherapy with S-1 plus cisplatin followed by surgery for treatment of gastric cancer with peritoneal dissemination. Ann Surg Oncol. 2009;16(12):3227–3236. doi: 10.1245/s10434-009-0706-z.
    1. Mezhir JJ, Shah MA, Jacks LM, Brennan MF, Coit DG, Strong VE. Positive peritoneal cytology in patients with gastric cancer: natural history and outcome of 291 patients. Ann Surg Oncol. 2010;17(12):3173–3180. doi: 10.1245/s10434-010-1183-0.
    1. Chiu CC, Lin MH, Huang WT. Prognostic significance of peritoneal washing cytology in patients with gastric cancer (Br J Surg 2012; 99: 397-403) Br J Surg. 2012;99(8):1166. doi: 10.1002/bjs.8855.
    1. Oh CA, Bae JM, Oh SJ, Choi MG, Noh JH, Sohn TS, Kim S. Long-term results and prognostic factors of gastric cancer patients with only positive peritoneal lavage cytology. J Surg Oncol. 2012;105(4):393–399. doi: 10.1002/jso.22091.
    1. Yamashita K, Ushiku H, Katada N, Hosoda K, Moriya H, Mieno H, Kikuchi S, Hoshi K, Watanabe M. Reduced preoperative serum albumin and absence of peritoneal dissemination may be predictive factors for long-term survival with advanced gastric cancer with positive cytology test. Eur J Surg Oncol. 2015;41(10):1324–1332. doi: 10.1016/j.ejso.2015.05.021.
    1. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). GASTRIC CENTER. 2017;20(1):1–19.
    1. Ajani JA, D Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, et al. Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J NATL COMPR CANC NE. 2022;20(2):167–92.
    1. Kodera Y, Ito S, Mochizuki Y, Ohashi N, Tanaka C, Kobayashi D, Kojima H, Matsui T, Kondo K, Fujiwara M. Long-term follow up of patients who were positive for peritoneal lavage cytology: final report from the CCOG0301 study. Gastric Cancer. 2012;15(3):335–337. doi: 10.1007/s10120-012-0156-3.
    1. Kodera Y, Ito S, Mochizuki Y, Kondo K, Koshikawa K, Suzuki N, Kojima H, Kojima T, Matsui T, Takase T, et al. 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;35(11):1158–1163. doi: 10.1016/j.ejso.2009.03.003.
    1. Okabe H, Hata H, Hosogi H, Ueda S, Ota S, Kinjo Y, Hoshino N, Hisamori S, Tsunoda S, Obama K, et al. A Phase 2 Study of Induction Chemotherapy Using Docetaxel, Cisplatin, and S-1 for Gastric Cancer with Peritoneal Metastasis (KUGC06) Ann Surg Oncol. 2019;26(6):1779–1786. doi: 10.1245/s10434-019-07229-7.
    1. Satoh S, Okabe H, Teramukai S, Hasegawa S, Ozaki N, Ueda S, Tsuji A, Sakabayashi S, Fukushima M, Sakai Y. Phase II trial of combined treatment consisting of preoperative S-1 plus cisplatin followed by gastrectomy and postoperative S-1 for stage IV gastric cancer. Gastric Cancer. 2012;15(1):61–69. doi: 10.1007/s10120-011-0066-9.
    1. Jamel S, Markar SR, Malietzis G, Acharya A, Athanasiou T, Hanna GB. Prognostic significance of peritoneal lavage cytology in staging gastric cancer: systematic review and meta-analysis. Gastric Cancer. 2018;21(1):10–18. doi: 10.1007/s10120-017-0749-y.
    1. Ryan R, Gibbons D, Hyland JM, Treanor D, White A, Mulcahy HE, O'Donoghue DP, Moriarty M, Fennelly D, Sheahan K. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005;47(2):141–146. doi: 10.1111/j.1365-2559.2005.02176.x.
    1. Takiguchi S, Shitara K, Takiguchi N, Ito S, Kochi M, Horinouchi H, Kinoshita T, Muro K, Yoshikawa T, Hasegawa H, et al. Neoadjuvant nivolumab monotherapy in patients with resectable gastric cancer: Preliminary results from a multicenter study. J Clin Oncol. 2021;39(15_suppl):4026. doi: 10.1200/JCO.2021.39.15_suppl.4026.
    1. Li N, Li Z, Fu Q, Zhang B, Zhang J, Wan X, Lu C, Wang J, Deng W, Wei C, et al. Phase II study of sintilimab combined with FLOT regimen for neoadjuvant treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2021;39(3_suppl):216. doi: 10.1200/JCO.2021.39.3_suppl.216.
    1. Wei J, Lu X, Liu Q, Fu Y, Liu S, Yang J, Wang M, Zheng L, Yang Y, Fan X, et al. SHARED: Efficacy and safety of sintilimab in combination with concurrent chemoradiotherapy (cCRT) in patients with locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2021;39(15_suppl):4040. doi: 10.1200/JCO.2021.39.15_suppl.4040.
    1. Sunakawa Y, Matoba R, Inoue E, Sakamoto Y, Kawabata R, Ishiguro A, Akamaru Y, Kito Y, Takahashi M, Matsuyama J, et al. Genomic pathway of gut microbiome to predict efficacy of nivolumab in advanced gastric cancer: DELIVER trial (JACCRO GC-08) J Clin Oncol. 2021;39(3_suppl):161. doi: 10.1200/JCO.2021.39.3_suppl.161.
    1. Oster P, Vaillant L, Riva E, McMillan B, Begka C, Truntzer C, Richard C, Leblond MM, Messaoudene M, Machremi E, et al. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut. 2022;71(3):457–466. doi: 10.1136/gutjnl-2020-323392.

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