SpringerLink
Log in

Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy.

Methods

The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves.

Results

During January 2017–June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0–34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0–16.6) and 4.0 (95% CI, 2.6–5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22–0.67; p = 0.001).

Conclusions

Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Napier KJ, Scheerer M, Misra S (2014) Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol 6:112–120. https://doi.org/10.4251/wjgo.v6.i5.112

    Article  Google Scholar 

  2. Koizumi S, Motoyama S, Iijima K (2018) Is the incidence of esophageal adenocarcinoma increasing in Japan? Trends from the data of a hospital-based registration system in Akita Prefecture, Japan. J Gastroenterol 53:827–833. https://doi.org/10.1007/s00535-017-1412-4

    Article  Google Scholar 

  3. National comprehensive cancer network clinical practice guidelines in oncology esophageal and esophagogastric junction cancers version 2.2021.

  4. Hayashi K, Ando N, Watanabe H, Ide H, Nagai K, Aoyama N, Takiyama W, Ishida K, Isono K, Makuuchi H, Imamura M, Shinoda M, Ikeuchi S, Kabuto T, Yamana H, Fukuda H (2001) Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan esophageal oncology group (JEOG) Trial (JCOG9407). Jpn J Clin Oncol 31:419–423. https://doi.org/10.1093/jjco/hye090

    Article  CAS  Google Scholar 

  5. Iizuka T, Kakegawa T, Ide H, Ando N, Watanabe H, Tanaka O, Takagi I, Isono K, Ishida K, Arimori M et al (1992) Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japanese esophageal oncology group trial. Jpn J Clin Oncol 22:172–176

    CAS  Google Scholar 

  6. Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y (2019) Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:1506–1517. https://doi.org/10.1016/s1470-2045(19)30626-6

    Article  CAS  Google Scholar 

  7. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP, KEYNOTE-181 Investigators, (2020) Randomized Phase III KEYNOTE-181 Study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol 38:4138–4148. https://doi.org/10.1200/jco.20.01888

    Article  CAS  Google Scholar 

  8. Laird BJ, Kaasa S, McMillan DC, Fallon MT, Hjermstad MJ, Fayers P (2013) Klepstad P (2013) Prognostic factors in patients with advanced cancer: a comparison of clinicopathological factors and the development of an inflammation-based prognostic system. Clin Cancer Res 19:5456–5464. https://doi.org/10.1158/1078-0432.Ccr-13-1066

    Article  CAS  Google Scholar 

  9. Hiam-Galvez KJ, Allen BM, Spitzer MH (2021) Systemic immunity in cancer. Nat Rev Cancer 21:345–359. https://doi.org/10.1038/s41568-021-00347-z

    Article  CAS  Google Scholar 

  10. Kudou K, Nakashima Y, Haruta Y, Nambara S, Tsuda Y, Kusumoto E, Ando K, Kimura Y, Hashimoto K, Yoshinaga K, Saeki H, Oki E, Sakaguchi Y, Kusumoto T, Ikejiri K, Shimokawa M, Mori M (2021) Comparison of inflammation-based prognostic scores associated with the prognostic impact of adenocarcinoma of esophagogastric junction and upper gastric cancer. Ann Surg Oncol 28:2059–2067. https://doi.org/10.1245/s10434-020-08821-y

    Article  Google Scholar 

  11. Wei XL, Wang FH, Zhang DS, Qiu MZ, Ren C, ** Y, Zhou YX, Wang DS, He MM, Bai L, Wang F, Luo HY, Li YH, Xu RH (2015) A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio. BMC Cancer 15:350. https://doi.org/10.1186/s12885-015-1379-6

    Article  Google Scholar 

  12. Kasymjanova G, MacDonald N, Agulnik JS, Cohen V, Pepe C, Kreisman H, Sharma R, Small D (2010) The predictive value of pre-treatment inflammatory markers in advanced non-small-cell lung cancer. Curr Oncol 17:52–58. https://doi.org/10.3747/co.v17i4.567

    Article  CAS  Google Scholar 

  13. Liao G, Zhao Z, Yang H, Chen M, Li X (2020) Can prognostic nutritional index be a prediction factor in esophageal cancer?: A meta-analysis. Nutr Cancer 72:187–193. https://doi.org/10.1080/01635581.2019.1631859

    Article  Google Scholar 

  14. Tanoue K, Tamura S, Kusaba H, Shinohara Y, Ito M, Tsuchihashi K, Shirakawa T, Otsuka T, Ohmura H, Isobe T, Ariyama H, Koreishi S, Matsushita Y, Shimokawa H, Tanaka R, Mitsugi K, Akashi K, Baba E (2021) Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab. Sci Rep 11:2741. https://doi.org/10.1038/s41598-021-82448-1

    Article  CAS  Google Scholar 

  15. Araki T, Tateishi K, Sonehara K, Shinohara Y, Ito M, Tsuchihashi K, Shirakawa T, Otsuka T, Ohmura H, Isobe T, Ariyama H, Koreishi S, Matsushita Y, Shimokawa H, Tanaka R, Mitsugi K, Akashi K, Baba E (2021) Clinical utility of the C-reactive protein:albumin ratio in non-small cell lung cancer patients treated with nivolumab. Thorac Cancer 12:603–612. https://doi.org/10.1111/1759-7714.13788

    Article  CAS  Google Scholar 

  16. Weide B, Martens A, Hassel JC, Berking C, Postow MA, Bisschop K, Simeone E, Mangana J, Schilling B, Di Giacomo AM, Brenner N, Kähler K, Heinzerling L, Gutzmer R, Bender A, Gebhardt C, Romano E, Meier F, Martus P, Maio M, Blank C, Schadendorf D, Dummer R, Ascierto PA, Hospers G, Garbe C, Wolchok JD (2016) Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496. https://doi.org/10.1158/1078-0432.CCR-16-0127

    Article  CAS  Google Scholar 

  17. Mezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, Ponce S, Ares LP, Leroy L, Audigier-Valette C, Felip E, Zerón-Medina J, Garrido P, Brosseau S, Zalcman G, Mazieres J, Caramela C, Lahmar J, Adam J, Chaput N, Soria JC, Besse B (2018) Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol 4:351–357. https://doi.org/10.1001/jamaoncol.2017.4771

    Article  Google Scholar 

  18. Lalani AA, **e W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, Duquette A, Bossé D, Bellmunt J, Van Allen EM, McGregor BA, Creighton CJ, Harshman LC, Choueiri TK (2018) Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 6:5. https://doi.org/10.1186/s40425-018-0315-0

    Article  Google Scholar 

  19. Peng L, Wang Y, Liu F, Qiu X, Zhang X, Fang C, Qian X, Li Y (2020) Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors. Cancer Immunol Immunother 69:1813–1822. https://doi.org/10.1007/s00262-020-02585-w

    Article  CAS  Google Scholar 

  20. Ogata T, Satake H, Ogata M, Hatachi Y, Inoue K, Hamada M, Yasui H (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

    Article  Google Scholar 

  21. Ota Y, Takahari D, Suzuki T, Osumi H, Nakayama I, Oki A, Wakatsuki T, Ichimura T, Ogura M, Shinozaki E, Suenaga M, Chin K, Yamaguchi K (2020) Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival. Cancer Chemother Pharmacol 85:265–272. https://doi.org/10.1007/s00280-019-04023-w

    Article  CAS  Google Scholar 

  22. Guo JC, Lin CC, Lin CY, Hsieh MS, Kuo HY, Lien MY, Hsu CH (2019) Neutrophil–to–lymphocyte ratio and use of antibiotics associated with prognosis in esophageal squamous cell carcinoma patients receiving immune checkpoint inhibitors. Anticancer Res 39(10):5675–5682

    Article  CAS  Google Scholar 

  23. Fairclough E, Cairns E, Hamilton J, Kelly C (2009) Evaluation of a modified early warning system for acute medical admissions and comparison with C-reactive protein/albumin ratio as a predictor of patient outcome. Clin Med (Lond) 9:30–33. https://doi.org/10.7861/clinmedicine.9-1-30

    Article  Google Scholar 

  24. Kudou K, Saeki H, Nakashima Y, Kamori T, Kawazoe T, Haruta Y, Fujimoto Y, Matsuoka H, Sasaki S, Jogo T, Hirose K, Hu Q, Tsuda Y, Kimura K, Ando K, Oki E, Ikeda T, Maehara Y (2019) C-reactive protein/albumin ratio is a poor prognostic factor of esophagogastric junction and upper gastric cancer. J Gastroenterol Hepatol 34:355–363. https://doi.org/10.1111/jgh.14442

    Article  CAS  Google Scholar 

  25. Matsunaga T, Miyata H, Sugimura K, Motoori M, Asukai K, Yanagimoto Y, Yano M (2019) Prognostic significance of sarcopenia and systemic inflammatory response in patients with esophageal cancer. Anticancer Res 39(1):449–458

    Article  CAS  Google Scholar 

  26. Tamagawa H, Aoyama T, Tamagawa A, Komori K, Maezawa Y, Kano K, Rino Y (2020) Influence of the preoperative C-reactive protein-to-albumin ratio on survival and recurrence in patients with esophageal cancer. Anticancer Res 40(4):2365–2371

    Article  CAS  Google Scholar 

  27. Ni XF, Wu J, Ji M, Shao YJ, Xu B, Jiang JT, Wu CP (2018) Effect of C-reactive protein/albumin ratio on prognosis in advanced non-small-cell lung cancer. Asia Pac J Clin Oncol 14:402–409. https://doi.org/10.1111/ajco.13055

    Article  Google Scholar 

  28. McKeown DJ, Brown DJ, Kelly A, Wallace AM, McMillan DC (2004) The relationship between circulating concentrations of C-reactive protein, inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer. Br J Cancer 91:1993–1995. https://doi.org/10.1038/sj.bjc.6602248

    Article  CAS  Google Scholar 

  29. Ara T, Declerck YA (2010) Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 46:1223–1231. https://doi.org/10.1016/j.ejca.2010.02.026

    Article  CAS  Google Scholar 

  30. Foran E, Garrity-Park MM, Mureau C, Newell J, Smyrk TC, Limburg PJ, Egan LJ (2010) Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res 8:471–481. https://doi.org/10.1158/1541-7786.MCR-09-0496

    Article  CAS  Google Scholar 

  31. Middleton K, Jones J, Lwin Z, Coward JI (2014) Interleukin-6: An angiogenic target in solid tumours. Crit Rev Oncol Hematol 89:129–139. https://doi.org/10.1016/j.critrevonc.2013.08.004

    Article  Google Scholar 

  32. Fujiwara H, Suchi K, Okamura S, Okamura H, Umehara S, Todo M, Shiozaki A, Kubota T, Ichikawa D, Okamoto K, Ochiai T, Kokuba Y, Sonoyama T, Otsuji E (2011) Elevated serum CRP levels after induction chemoradiotherapy reflect poor treatment response in association with IL-6 in serum and local tumor site in patients with advanced esophageal cancer. J Surg Oncol 103:62–68. https://doi.org/10.1002/jso.21751

    Article  CAS  Google Scholar 

  33. Wigmore SJ, Fearon KC, Maingay JP, Lai PB, Ross JA (1997) Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am J Physiol 273:E720-726. https://doi.org/10.1152/ajpendo.1997.273.4.E720

    Article  CAS  Google Scholar 

  34. Liu Z, Shi H, Chen L (2019) Prognostic role of pre-treatment C-reactive protein/albumin ratio in esophageal cancer: a meta-analysis. BMC Cancer 19:1161. https://doi.org/10.1186/s12885-019-6373-y

    Article  CAS  Google Scholar 

  35. Takahashi M, Kato K, Okada M, Chin K, Kadowaki S, Hamamoto Y, Doki Y, Kubota Y, Kawakami H, Ogata T, Hara H, Muto M, Nakashima Y, Ishihara R, Tsuda M, Motoyama S, Kodani M, Kitagawa Y (2021) Nivolumab versus chemotherapy in Japanese patients with advanced esophageal squamous cell carcinoma: a subgroup analysis of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3). Esophagus 18:90–99. https://doi.org/10.1007/s10388-020-00794-x

    Article  Google Scholar 

Download references

Acknowledgements

I am deeply grateful to Prof. Satake and the other co-authors for their guidance. We also thank Editage, which was responsible for English editing.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan

    Tatsuki Ikoma, Toshihiko Matsumoto, Hiroki Nagai & Hisateru Yasui

  2. Department of Medical Oncology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan

    Keitaro Doi, Takanobu Shimada & Takehiko Tsumura

  3. Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi,, Ube-shi, Yamaguchi-ken, 755-8505, Japan

    Mototsugu Shimokawa

  4. Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji-shi, Hyogo-ken, 670-8540, Japan

    Yusuke Kurioka & Masahiro Takatani

  5. Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan

    Tatsuki Ikoma, Toshihiko Matsumoto, Shogen Boku, Tomoyo Yasuda & Nobuhiro Shibata

  6. Department of Surgery, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno,, Himeji-shi, Hyogo-ken, 670-8540, Japan

    Tetsuji Nobuhisa

  7. Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan

    Tsutomu Namikawa, Hiroyuki Kitagawa & Kazuhiro Hanazaki

  8. Department of Gastroenterology and Hepatology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan

    Takehiko Tsumura & Hiroyuki Marusawa

  9. Department of Surgery, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho,, Tenouji-ku, Osaka-fu, 543-8555, Japan

    Seichiro Kanaya

  10. Department of Gastroenterology and Hepatology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan

    Shuko Morita & Tetsurou Inokuma

  11. Department of Medical Oncology, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan

    Hironaga Satake

Authors
  1. Tatsuki Ikoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mototsugu Shimokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiko Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shogen Boku
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoyo Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhiro Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Kurioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiro Takatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tetsuji Nobuhisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tsutomu Namikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroyuki Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kazuhiro Hanazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Keitaro Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Takanobu Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Takehiko Tsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hiroyuki Marusawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Seichiro Kanaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Shuko Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Tetsurou Inokuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Hiroki Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Hisateru Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hironaga Satake
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tatsuki Ikoma, Hironaga Satake, Mototsugu Shimokawa, Shogen Boku and other authors were involved in investigation, data curation, writing—review & editing and visualization. Tatsuki Ikoma, Hironaga Satake and Shogen Boku were involved in writing—original draft. Tatsuki Ikoma and Hironaga Satake performed conceptualization and methodology. Hironaga Satake was involved in supervision and project administration. Tatsuki Ikoma, Hironaga Satake and Mototsugu Shimokawa were involved in formal analysis.

Corresponding author

Correspondence to Hironaga Satake.

Ethics declarations

Conflict of interest

Hironaga Satake received research funding from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and honoraria from Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly Japan, Merck Bio Pharma, MSD, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical Co., Ltd., Takeda, and Yakult Honsha. However, those funding sources had no involvement with our study. The rest of the authors do not have any conflict of interest.

Ethics approval

This study was conducted in accordance with the Helsinki Declaration of 1964 and later versions, and with the Ethical Guidelines for Clinical Studies. This study was approved by the institutional review boards of all three participating institutions: Kobe City Medical Center General Hospital (approval no. zn210501), Kansai Medical University Hospital, Kochi Medical School, Himeji Red Cross Hospital, and Osaka Red Cross hospital.

Consent to participate

The requirement for informed consent was waived owing to the retrospective nature of the study.

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.

Supplementary file1 (PDF 923 KB)

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ikoma, T., Shimokawa, M., Matsumoto, T. et al. Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab. Cancer Immunol Immunother 72, 427–435 (2023). https://doi.org/10.1007/s00262-022-03265-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-022-03265-7

Keywords

Search

Navigation