Abstract
Purpose
Programmed cell death protein 1 (PD-1) inhibitor and apatinib have been utilized in metastatic gastric cancer patients. The current study aimed to further investigate the efficacy and safety of neoadjuvant S-1 plus oxaliplatin combined with PD-1 inhibitor and apatinib (SOXPA) in locally advanced gastric cancer (LAGC) patients.
Methods
This two-centered, prospective, cohort study analyzed 30 resectable LAGC patients receiving SOXPA as neoadjuvant therapy.
Results
Two (6.7%), 18 (60.0%), and 10 (33.3%) patients achieved complete response (CR), partial response (PR), and stable disease (SD), separately. The objective response rate (ORR) and disease control rate (DCR) were 66.7% and 100.0%, respectively. The R0 resection rate was 93.3%. Beyond that, 6 (20.0%), 18 (60.0%), and 6 (20.0%) patients achieved grade 1, 2, and 3 pathological responses. The pathological complete response (pCR) rate was 20%. The 1-year and 2-year disease-free survival (DFS) rates were 96.6% and 77.7% respectively; meanwhile, the 1-year and 2-year overall survival (OS) rates were 96.6% and 90.1%, separately. What’s more, better clinical response (P = 0.046); achievement of ORR (P = 0.014), and better pathological response (P = 0.020) were correlated with longer DFS. Besides, ORR achievement was linked with longer OS (P = 0.040). Most adverse events were relatively mild and manageable. Grade 3 adverse events included leukopenia, anemia, neutropenia, fatigue, hand-foot syndrome, nausea and vomiting. No grade 4 adverse events were witnessed.
Conclusion
SOXPA as neoadjuvant therapy achieves a satisfying clinical response, pathological response, survival profile, and tolerable safety in LAGC patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, Farjah F, Gerdes H, Gibson MK, Hochwald S, Hofstetter WL, Ilson DH, Keswani RN, Kim S, Kleinberg LR, Klempner SJ, Lacy J, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Outlaw D, Park H, Perry KA, Pimiento J, Poultsides GA, Reznik S, Roses RE, Strong VE, Su S, Wang HL, Wiesner G, Willett CG, Yakoub D, Yoon H, McMillian N, Pluchino LA (2022) Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 20:167–192. https://doi.org/10.6004/jnccn.2022.0008
Chen Y, He J, Liu D, Xiao J, Chen X, Tang H, Luo D, Shang C, Lian L, Peng J (2021) Triplet versus doublet neoadjuvant chemotherapy regimens for locally advanced gastric cancer: a propensity score matching analysis. BMC Cancer 21:1328. https://doi.org/10.1186/s12885-021-09093-9
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. https://doi.org/10.1016/j.ejca.2008.10.026
Global Burden of Disease Cancer C, Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, Abdelalim A, Abdoli A, Abdollahpour I, Abdulle ASM, Abebe ND, Abraha HN, Abu-Raddad LJ, Abualhasan A, Adedeji IA, Advani SM, Afarideh M, Afshari M, Aghaali M, Agius D, Agrawal S, Ahmadi A, Ahmadian E, Ahmadpour E, Ahmed MB, Akbari ME, Akinyemiju T, Al-Aly Z, AlAbdulKader AM, Alahdab F, Alam T, Alamene GM, Alemnew BTT, Alene KA, Alinia C, Alipour V, Aljunid SM, Bakeshei FA, Almadi MAH, Almasi-Hashiani A, Alsharif U, Alsowaidi S, Alvis-Guzman N, Amini E, Amini S, Amoako YA, Anbari Z, Anber NH, Andrei CL, Anjomshoa M, Ansari F, Ansariadi A, Appiah SCY, Arab-Zozani M, Arabloo J, Arefi Z, Aremu O, Areri HA, Artaman A, Asayesh H, Asfaw ET, Ashagre AF, Assadi R, Ataeinia B, Atalay HT, Ataro Z, Atique S, Ausloos M, Avila-Burgos L, Avokpaho E, Awasthi A, Awoke N, Ayala Quintanilla BP, Ayanore MA, Ayele HT, Babaee E, Bacha U, Badawi A, Bagherzadeh M, Bagli E, Balakrishnan S, Balouchi A, Barnighausen TW, Battista RJ, Behzadifar M, Behzadifar M, Bekele BB, Belay YB, Belayneh YM, Berfield KKS, Berhane A, Bernabe E, Beuran M, Bhakta N, Bhattacharyya K, Biadgo B, Bijani A, Bin Sayeed MS, Birungi C et al (2019) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol 5:1749–1768. https://doi.org/10.1001/jamaoncol.2019.2996
Hasegawa H, Shitara K, Takiguchi S, Takiguchi N, Ito S, Kochi M, Horinouchi H, Kinoshita T, Yoshikawa T, Muro K, Nishikawa H, Suna H, Kodera Y (2022) A multicenter, open-label, single-arm phase I trial of neoadjuvant nivolumab monotherapy for resectable gastric cancer. Gastric Cancer 25:619–628. https://doi.org/10.1007/s10120-022-01286-w
In H, Ravetch E, Langdon-Embry M, Palis B, Ajani JA, Hofstetter WL, Kelsen DP, Sano T (2018) The newly proposed clinical and post-neoadjuvant treatment staging classifications for gastric adenocarcinoma for the American Joint Committee on Cancer (AJCC) staging. Gastric Cancer 21:1–9. https://doi.org/10.1007/s10120-017-0765-y
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 (2021) 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 398:27–40. https://doi.org/10.1016/S0140-6736(21)00797-2
Japanese Gastric Cancer A (2011) Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 14: 101–112. https://doi.org/10.1007/s10120-011-0041-5
Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, Ryu MH, Rha SY, Chung IJ, Kim IH, Oh SC, Park YS, Son T, Jung MR, Heo MH, Kim HK, Park C, Yoo CH, Choi JH, Zang DY, Jang YJ, Sul JY, Kim JG, Kim BS, Beom SH, Cho SH, Ryu SW, Kook MC, Ryoo BY, Kim HK, Yoo MW, Lee NS, Lee SH, Kim G, Lee Y, Lee JH, Noh SH (2021) PRODIGY: a phase III study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 plus surgery and adjuvant S-1 versus surgery and adjuvant S-1 for resectable advanced gastric cancer. J Clin Oncol 39:2903–2913. https://doi.org/10.1200/JCO.20.02914
Kumagai Y, Futoh Y, Miyato H, Ohzawa H, Yamaguchi H, Saito S, Kurashina K, Hosoya Y, Lefor AK, Sata N, Kitayama J (2022) Effect of systemic or intraperitoneal administration of anti-PD-1 antibody for peritoneal metastases from gastric cancer. In Vivo 36:1126–1135. https://doi.org/10.21873/invivo.12811
Li T, Chen L (2011) Efficacy and safety of SOX regimen as neoadjuvant chemotherapy for advanced gastric cancer. Zhonghua Wei Chang Wai Ke Za Zhi 14:104–106
Li X, Huang Q, Lei Y, Zheng X, Dai S, Leng W, Liu M (2021) Locally advanced gastroesophageal junction cancer with pathological complete response to neoadjuvant therapy: a case report and literature review. Ann Transl Med 9:513. https://doi.org/10.21037/atm-21-434
Lin JX, Xu YC, Lin W, Xue FQ, Ye JX, Zang WD, Cai LS, You J, Xu JH, Cai JC, Tang YH, Xie JW, Li P, Zheng CH, Huang CM (2021) Effectiveness and safety of apatinib plus chemotherapy as neoadjuvant treatment for locally advanced gastric cancer: a nonrandomized controlled trial. JAMA Netw Open 4:e2116240. https://doi.org/10.1001/jamanetworkopen.2021.16240
Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R (2020) Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. https://doi.org/10.3390/ijms21114012
Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, Reck M, Wu YL, Brustugun OT, Crino L, Felip E, Fennell D, Garrido P, Huber RM, Marabelle A, Moniuszko M, Mornex F, Novello S, Papotti M, Perol M, Smit EF, Syrigos K, van Meerbeeck JP, van Zandwijk N, Yang JC, Zhou C, Vokes E (2017) The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC. J Thorac Oncol 12:194–207. https://doi.org/10.1016/j.jtho.2016.10.003
Quesada S, Samalin E, Thezenas S, Khellaf L, Mourregot A, Portales F, Mazard T, Ychou M, Adenis A (2022) Perioperative FOLFOX in patients with locally advanced oesogastric adenocarcinoma. Anticancer Res 42:185–193. https://doi.org/10.21873/anticanres.15472
Roviello G, Ravelli A, Fiaschi AI, Cappelletti MR, Gobbi A, Senti C, Zanotti L, Polom K, Reynolds AR, Fox SB, Generali D (2016) Apatinib for the treatment of gastric cancer. Expert Rev Gastroenterol Hepatol 10:887–892. https://doi.org/10.1080/17474124.2016.1209407
Sah BK, Zhang B, Zhang H, Li J, Yuan F, Ma T, Shi M, Xu W, Zhu Z, Liu W, Yan C, Li C, Liu B, Yan M, Zhu Z (2020) Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer. Nat Commun 11:6093. https://doi.org/10.1038/s41467-020-19965-6
Scott LJ (2018) Apatinib: a review in advanced gastric cancer and other advanced cancers. Drugs 78:747–758. https://doi.org/10.1007/s40265-018-0903-9
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Tang Z, Wang Y, Yu Y, Cui Y, Liang L, Xu C, Shen Z, Shen K, Wang X, Liu T, Sun Y (2022) Neoadjuvant apatinib combined with oxaliplatin and capecitabine in patients with locally advanced adenocarcinoma of stomach or gastroesophageal junction: a single-arm, open-label, phase 2 trial. BMC Med 20:107. https://doi.org/10.1186/s12916-022-02309-0
Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, Zhang J, Sun LY, Lin RB, Qiu H, Wang C, Qiu MZ, Cai MY, Wu Q, Liu H, Guan WL, Zhou AP, Zhang YJ, Liu TS, Bi F, Yuan XL, Rao SX, Xin Y, Sheng WQ, Xu HM, Li GX, Ji JF, Zhou ZW, Liang H, Zhang YQ, Jin J, Shen L, Li J, Xu RH (2021) The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (lond) 41:747–795. https://doi.org/10.1002/cac2.12193
Wang X, Zhao DB, Yang L, Chi Y, Zhao H, Jiang LM, Jiang J, Tang Y, Li N, Liu WY, Dou LZ, Zou SM, Xue LY, Ren JS, Tian YT, Che X, Guo CG, Bai XF, Sun YM, Wang SL, Song YW, Liu YP, Fang H, Li YX, Jin J (2022) Preoperative concurrent chemoradiotherapy versus neoadjuvant chemotherapy for locally advanced gastric cancer: phase II randomized study. Front Oncol 12:870741. https://doi.org/10.3389/fonc.2022.870741
Wang T, Wang N, Zhou H, Zhou A, Jin J, Chen Y, Zhao D (2020) Long-term survival results of patients with locally advanced gastric cancer and pathological complete response after neoadjuvant chemotherapy and resection. Transl Cancer Res 9:529–535. https://doi.org/10.21037/tcr.2019.11.37
Wei Q, Yuan X, Li J, Xu Q, Ying J (2020) PD-1 inhibitor combined with apatinib for advanced gastric or esophagogastric junction cancer: a retrospective study. Transl Cancer Res 9:5315–5322. https://doi.org/10.21037/tcr-20-1333
Xia Y, Tang W, Qian X, Li X, Cheng F, Wang K, Zhang F, Zhang C, Li D, Song J, Zhang H, Zhao J, Yao A, Wu X, Wu C, Ji G, Liu X, Zhu F, Qin L, Xiao X, Deng Z, Kong X, Li S, Yu Y, Xi W, Deng W, Qi C, Liu H, Pu L, Wang P, Wang X (2022) Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. J Immunother Cancer. https://doi.org/10.1136/jitc-2022-004656
Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A (2019) Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer 18:60. https://doi.org/10.1186/s12943-019-0974-6
Zhang Y, Zhang B, Yang J, Zhang J, Zhang W (2021) Perioperative safety and effectiveness of neoadjuvant therapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel plus apatinib in locally advanced gastric cancer. Cancer Manag Res 13:2279–2286. https://doi.org/10.2147/CMAR.S304093
Zheng Y, Wang Z, Yan C, Yan M, Hou Z, Zheng R, Zhu Z, Li C (2020) Protocol for a randomized controlled trial of perioperative S-1 plus oxaliplatin combined with apatinib and camrelizumab in patients with resectable, locally advanced gastric or gastroesophageal junction adenocarcinoma. Ann Transl Med 8:1684. https://doi.org/10.21037/atm-20-7802
Zhu ZG (2021) Current status and prospect of perioperative therapy for locally advanced gastric cancer. Zhonghua Wei Chang Wai Ke Za Zhi 24:101–106. https://doi.org/10.3760/cma.j.cn.441530-20210105-00003
Funding
This study was supported by National Natural Science Foundation of China (No. 81770601).
Author information
Authors and Affiliations
Contributions
HJ contributed to the study conception and design. Material preparation, data collection and analysis were performed by [CX] and [XX]. The first draft of the manuscript was written by [NK] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Ethics approval
The study was permitted by Ethics Committee of The Second Hospital of Hebei Medical University.
Consent to participate
The informed consent was signed by each patient.
Consent to publish
Not Applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Xu, C., Xie, X., Kang, N. et al. Neoadjuvant PD-1 inhibitor and apatinib combined with S-1 plus oxaliplatin for locally advanced gastric cancer patients: a multicentered, prospective, cohort study. J Cancer Res Clin Oncol 149, 4091–4099 (2023). https://doi.org/10.1007/s00432-022-04302-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-022-04302-9