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Retrospective analysis for the efficacy and safety of nivolumab in advanced gastric cancer patients according to ascites burden

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Abstract

Background

Nivolumab is a standard later-line therapy for advanced gastric cancer (AGC). However, few reports exist about its efficacy and safety in patients with massive ascites.

Methods

We retrospectively collected clinical data from 72 AGC patients who received nivolumab administration at least once from Oct 2017 to Feb 2019 and studied their clinical outcomes dividing into two groups: 50 patients with no or localized ascites in the pelvic cavity or liver surface (LAB: low ascites burden) and 22 patients with massive ascites (HAB: high ascites burden).

Results

Median overall survival (OS) was 5.3 months (95% CI 3.4–7.3) in the LAB group and 2.5 months (95% CI 0.0–5.0) in the HAB group. Multivariate Cox regression analysis for OS revealed blood neutrophil-to-lymphocyte ratio (hazard ratio 0.40, 95% CI 0.20–0.83, p = 0.013) as an independent prognostic factor. Response rates in the patients with measurable lesions were 16% (7/43) and 8% (1/12) in the LAB and HAB groups, respectively. Ascites decreased or disappeared in 6 HAB patients (27%) and these responders had a prolonged OS of median 9.7 months (95% CI 3.6–15.8). The median time to ascites response was 1.3 months (95% CI 0.8–1.9). These responders have lower neutrophil-to-lymphocyte ratios than 5.0 at the start of nivolumab. Immune-related adverse events occurred in 23% of HAB and 18% of LAB patients.

Conclusions

Nivolumab could improve massive ascites and confer survival benefit for some AGC patients. Considering a similar incidence of immune-related adverse events, it would be a recommended treatment option for AGC with massive ascites.

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References

  1. Dupont JB Jr, Lee JR, Burton GR et al (1978) Adenocarcinoma of the stomach: review of 1,497 cases. Cancer 41(3):941–947

    Article  Google Scholar 

  2. Bang YJ, Van Cutsem E, Feyereislova A et al (2010) 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 376(9742):687–697

    Article  CAS  Google Scholar 

  3. Cunningham D, Starling N, Rao S et al (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358(1):36–46

    Article  CAS  Google Scholar 

  4. Kang YK, Kang WK, Shin DB et al (2009) Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20(4):666–673

    Article  Google Scholar 

  5. Koizumi W, Narahara H, Hara T et al (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9(3):215–221

    Article  CAS  Google Scholar 

  6. Wilke H, Muro K, Van Cutsem E et al (2014) 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 15(11):1224–1235

    Article  CAS  Google Scholar 

  7. Kitayama J, Ishigami H, Kaisaki S et al (2010) Weekly intravenous and intraperitoneal paclitaxel combined with S-1 for malignant ascites due to advanced gastric cancer. Oncology 78(1):40–46

    Article  CAS  Google Scholar 

  8. Tahara M, Ohtsu A, Boku N et al (2001) Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with peritoneal dissemination: a retrospective study. Gastric Cancer 4(4):212–218

    Article  CAS  Google Scholar 

  9. Nakajima TE, Yamaguchi K, Boku N et al (2020) Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G). Gastric Cancer 23(4):677–688

    Article  CAS  Google Scholar 

  10. Shah MA, Bang YJ, Lordick F et al (2017) Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized cinical trial. JAMA Oncol 3(5):620–627

    Article  Google Scholar 

  11. Yoon HH, Bendell JC, Braiteh FS et al (2016) Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol 27(12):2196–2203

    Article  CAS  Google Scholar 

  12. Kang Y-K, Boku N, Satoh T et al (2017) 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. The Lancet 390(10111):2461–2471

    Article  CAS  Google Scholar 

  13. Matsumoto H, Kawazoe A, Shimada K et al (2018) A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites. BMC Cancer 18(1):120

    Article  Google Scholar 

  14. Capone M, Giannarelli D, Mallardo D et al (2018) Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer 6(1):74

    Article  Google Scholar 

  15. Cassidy MR, Wolchok RE, Zheng J et al (2017) Neutrophil to lymphocyte ratio is associated with outcome during ipilimumab treatment. EBioMedicine 18:56–61

    Article  Google Scholar 

  16. Ferrucci PF, Ascierto PA, Pigozzo J et al (2016) Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol 27(4):732–738

    Article  CAS  Google Scholar 

  17. Fukui T, Okuma Y, Nakahara Y et al (2019) Activity of nivolumab and utility of neutrophil-to-lymphocyte ratio as a predictive biomarker for advanced non-small-cell lung cancer: a prospective observational study. Clin Lung Cancer 20(3):208–214

    Article  CAS  Google Scholar 

  18. Sacdalan DB, Lucero JA, Sacdalan DL (2018) Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis. Oncol Targets Ther 11:955–965

    Article  Google Scholar 

  19. Baldini E, Lunghi A, Cortesi E et al (2020) Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with nivolumab: the Italian NSCLC expanded access program. Lung Cancer 140:59–64

    Article  Google Scholar 

  20. Judd J, Zibelman M, Handorf E et al (2017) Immune-related adverse events as a biomarker in non-melanoma patients treated with programmed cell death 1 inhibitors. Oncologist 22(10):1232–1237

    Article  CAS  Google Scholar 

  21. Masuda K, Shoji H, Nagashima K et al (2019) Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer 19(1):974

    Article  Google Scholar 

  22. Schvartsman G, Peng SA, Bis G et al (2020) Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-smallcell lung cancer. Lung Cancer 112:90–95

    Article  Google Scholar 

  23. Fang N, Zhang HQ, He B et al (2014) Clinicopathological characteristics and prognosis of gastric cancer with malignant ascites. Tumour Biol 35(4):3261–3268

    Article  CAS  Google Scholar 

  24. Lim B, Kim JH, Kim M et al (2016) Genomic and epigenomic heterogeneity in molecular subtypes of gastric cancer. World J Gastroenterol 22(3):1190–1201

    Article  CAS  Google Scholar 

  25. Marabelle A, Le DT, Ascierto PA et al (2020) 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 38(1):1–10

    Article  CAS  Google Scholar 

  26. Kim H, An JY, Noh SH et al (2011) High microsatellite instability predicts good prognosis in intestinal-type gastric cancers. J Gastroenterol Hepatol 26(3):585–592

    Article  CAS  Google Scholar 

  27. Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209

    Article  Google Scholar 

  28. Le DT, Uram JN, Wang H et al (2015) PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520

    Article  CAS  Google Scholar 

  29. Bagley SJ, Kothari S, Aggarwal C et al (2017) Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 106:1–7

    Article  Google Scholar 

  30. Ogata T, Satake H, Ogata M et al (2018) Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: a multicenter retrospective study. Oncotarget 9(77):34520–34527

    Article  Google Scholar 

  31. Ota Y, Takahari D, Suzuki T et al (2020) Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival. Cancer Chemother Pharmacol 85(2):265–272

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all the members of the Division of Gastroenterology at University of Tsukuba Hospital. The authors would also like to thank Dr. Bryan J. Mathis of the Medical English Communication Center, University of Tsukuba, for language revision of this manuscript.

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Authors and Affiliations

  1. Division of Gastroenterology, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba, Ibaraki, 305-8576, Japan

    Hirosumi Suzuki, Takeshi Yamada, Yoshiyuki Yamamoto, Toshikazu Moriwaki & Ichinosuke Hyodo

  2. Division of Gastroenterology, Ibaraki Prefectural Central Hospital, 6528, Koibuchi, Kasama, Ibaraki, Japan

    Akinori Sugaya

  3. Division of Gastroenterology, Tsuchiura Kyodo Hospital, 4-1-1, Ootsuno, Tsuchiura, Ibaraki, Japan

    Shunsuke Ueyama

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  1. Hirosumi Suzuki
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  4. Shunsuke Ueyama
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Correspondence to Takeshi Yamada.

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Conflict of interest

HS, TY, AS, SU, YY and TM declare that they have no conflict of interest. IH reports grants and personal fees from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., personal fees from Eli Lilly Japan K.K., Asahi Kasei Pharma Corp., and grants from Takeda Pharmaceutical Co., Ltd., unrelated to the present study.

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Suzuki, H., Yamada, T., Sugaya, A. et al. Retrospective analysis for the efficacy and safety of nivolumab in advanced gastric cancer patients according to ascites burden. Int J Clin Oncol 26, 370–377 (2021). https://doi.org/10.1007/s10147-020-01810-x

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  • DOI: https://doi.org/10.1007/s10147-020-01810-x

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