Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
권호 표지
DOI QR코드

DOI QR Code

Neoadjuvant PD-1 Inhibitor Plus Apatinib and Chemotherapy Versus Apatinib Plus Chemotherapy in Treating Patients With Locally Advanced Gastric Cancer: A Prospective, Cohort Study

  • Chunjing Wang (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University) ;
  • Zhen Wang (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University) ;
  • Yue Zhao (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University) ;
  • Fujing Wang (Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University)
  • Received : 2022.11.21
  • Accepted : 2023.01.28
  • Published : 2023.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: This study aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death-1 (PD-1) inhibitors plus apatinib and chemotherapy (PAC) in patients with locally advanced gastric cancer (LAGC). Materials and Methods: Seventy-three patients with resectable LAGC were enrolled and named the PAC group (n=39) or apatinib plus chemotherapy (AC) group (n=34) based on the treatment they chose. Neoadjuvant therapy was administered in a 21-day cycle for 3 consecutive cycles, after which surgery was performed. Results: The PAC group exhibited a higher objective response rate than the AC group (74.4% vs. 58.8%, P=0.159). Moreover, the PAC group showed a numerically better response profile than the AC group (P=0.081). Strikingly, progression-free survival (PFS) (P=0.019) and overall survival (OS) (P=0.049) were prolonged, whereas disease-free survival (DFS) tended to be longer in the PAC group than in the AC group (P=0.056). Briefly, the 3-year PFS, DFS, and OS rates were 76.1%, 76.1%, and 86.7% in the PAC group and 46.9%, 49.9%, and 70.3% in the AC group, respectively. Furthermore, PAC (vs. AC) treatment (hazard ratio=0.286, P=0.034) was independently associated with prolonged PFS in multivariate Cox regression analyses. The incidence of adverse events did not differ between the two groups (all P>0.05), where leukopenia, anemia, hypertension, and other adverse events were commonly observed in the PAC group. Conclusions: Neoadjuvant PAC therapy may achieve a preferable pathological response, delayed progression, and prolonged survival compared to AC therapy with a similar safety profile in patients with LAGC; however, further validation is warranted.

Keywords

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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. https://doi.org/10.3322/caac.21660
  2. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol 2020;18:534-542. https://doi.org/10.1016/j.cgh.2019.07.045
  3. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet 2020;396:635-648. https://doi.org/10.1016/S0140-6736(20)31288-5
  4. Pelcovits A, Almhanna K. Locoregional gastric cancer: a narrative review of multidisciplinary management. Ann Transl Med 2020;8:1108.
  5. Tokunaga M, Sato Y, Nakagawa M, Aburatani T, Matsuyama T, Nakajima Y, et al. Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives. Surg Today 2020;50:30-37. https://doi.org/10.1007/s00595-019-01896-5
  6. Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, et al. 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 2021;39:2903-2913. https://doi.org/10.1200/JCO.20.02914
  7. Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, et al.; RESOLVE study group. 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;22:1081-1092. https://doi.org/10.1016/S1470-2045(21)00297-7
  8. Makuku R, Khalili N, Razi S, Keshavarz-Fathi M, Rezaei N. Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy. J Immunol Res 2021;2021:6661406.
  9. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 2021;16:223-249. https://doi.org/10.1146/annurev-pathol-042020-042741
  10. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. 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;398:27-40. https://doi.org/10.1016/S0140-6736(21)00797-2
  11. Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, et al. 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;23:234-247. https://doi.org/10.1016/S1470-2045(21)00692-6
  12. Scott LJ. Apatinib: a review in advanced gastric cancer and other advanced cancers. Drugs 2018;78:747-758. https://doi.org/10.1007/s40265-018-0903-9
  13. Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (Lond) 2021;41:747-795. https://doi.org/10.1002/cac2.12193
  14. Xu C, Xie X, Kang N, Jiang H. 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. Forthcoming 2022.
  15. Su L, Zhao S, Yin Y, Huang F, Zhu J, Chen L, et al. POF (paclitaxel/oxaliplatin/5-fluorouracil/leucovorin) vs. SOX/CAPOX/FOLFOX as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer: Study protocol for a randomized controlled trial, FNF-014 trial. Front Med (Lausanne) 2022;9:861777.
  16. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101-112. https://doi.org/10.1007/s10120-011-0041-5
  17. In H, Ravetch E, Langdon-Embry M, Palis B, Ajani JA, Hofstetter WL, et al. The newly proposed clinical and post-neoadjuvant treatment staging classifications for gastric adenocarcinoma for the American Joint Committee on Cancer (AJCC) staging. Gastric Cancer 2018;21:1-9. https://doi.org/10.1007/s10120-017-0765-y
  18. Jing C, Wang J, Zhu M, Bai Z, Zhao B, Zhang J, et al. Camrelizumab combined with apatinib and S-1 as second-line treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study. Cancer Immunol Immunother 2022;71:2597-2608. https://doi.org/10.1007/s00262-022-03174-9
  19. Wei Q, Yuan X, Li J, Xu Q, Ying J. PD-1 inhibitor combined with apatinib for advanced gastric or esophagogastric junction cancer: a retrospective study. Transl Cancer Res 2020;9:5315-5322. https://doi.org/10.21037/tcr-20-1333
  20. Li LH, Chen WC, Wu G. Feasibility and tolerance of apatinib plus PD-1 inhibitors for previously treated advanced gastric cancer: a real-world exploratory study. Dis Markers 2022;2022:4322404.
  21. Chen H, Jiang T, Lin F, Guan H, Zheng J, Liu Q, et al. PD-1 inhibitor combined with apatinib modulate the tumor microenvironment and potentiate anti-tumor effect in mice bearing gastric cancer. Int Immunopharmacol 2021;99:107929.
  22. Ho TT, Nasti A, Seki A, Komura T, Inui H, Kozaka T, et al. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis. J Immunother Cancer 2020;8:e001367.
  23. Kim W, Chu TH, Nienhuser H, Jiang Z, Del Portillo A, Remotti HE, et al. PD-1 signaling promotes tumor-infiltrating myeloid-derived suppressor cells and gastric tumorigenesis in mice. Gastroenterology 2021;160:781-796. https://doi.org/10.1053/j.gastro.2020.10.036
  24. Zheng B, Ren T, Huang Y, Guo W. Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3. Biochem Biophys Res Commun 2018;495:1695-1701. https://doi.org/10.1016/j.bbrc.2017.12.032
  25. Kawai S, Shimoda T, Nakajima T, Terashima M, Omae K, Machida N, et al. Pathological response measured using virtual microscopic slides for gastric cancer patients who underwent neoadjuvant chemotherapy. World J Gastroenterol 2019;25:5334-5343. https://doi.org/10.3748/wjg.v25.i35.5334
  26. Guc ZG, Turgut B, Avci A, Cengiz F, Eren Kalender M, Alacacioglu A. Predicting pathological response and overall survival in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy: the role of PET/computed tomography. Nucl Med Commun 2022;43:560-567. https://doi.org/10.1097/MNM.0000000000001534
  27. Chen YH, Xiao J, Chen XJ, Wang HS, Liu D, Xiang J, et al. Nomogram for predicting pathological complete response to neoadjuvant chemotherapy in patients with advanced gastric cancer. World J Gastroenterol 2020;26:2427-2439. https://doi.org/10.3748/wjg.v26.i19.2427
  28. Xiang R, Rong Y, Ge Y, Song W, Ren J, Fu T. Cell differentiation trajectory predicts patient potential immunotherapy response and prognosis in gastric cancer. Aging (Albany NY) 2021;13:5928-5945. https://doi.org/10.18632/aging.202515
  29. Lopes N, Bergsland C, Bruun J, Bjornslett M, Vieira AF, Mesquita P, et al. A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis. Gastric Cancer 2020;23:811-823. https://doi.org/10.1007/s10120-020-01064-6
  30. Arima Y, Nobusue H, Saya H. Targeting of cancer stem cells by differentiation therapy. Cancer Sci 2020;111:2689-2695. https://doi.org/10.1111/cas.14504
  31. Ishak RS, Aad SA, Kyei A, Farhat FS. Cutaneous manifestations of anti-angiogenic therapy in oncology: review with focus on VEGF inhibitors. Crit Rev Oncol Hematol 2014;90:152-164. https://doi.org/10.1016/j.critrevonc.2013.11.007
  32. Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG, et al. Holistic approach to immune checkpoint inhibitor-related adverse events. Front Immunol 2022;13:804597.