Abstract
Purpose
Some cancer patients experience an increase in the leukocyte count, platelet count, and absolute neutrophil count compared to the baseline level after chemotherapy. We identify this phenomenon as "myelostimulation", which seems to go against the myelosuppression properties of chemotherapy drugs. However, the clinical value of "myelostimulation" that appears early after fluorouracil plus platinum-based neoadjuvant chemotherapy (NACT) in patients with locally advanced gastric cancer (LAGC) remains unclear.
Method
Patients with LAGC who underwent fluorouracil plus platinum-based NACT and radical resection from January 2010 to January 2015 were included. Patients were divided into an increased group and a decreased group based on the leukocyte count, platelet count, and absolute neutrophil count in the early stage after NACT, compared with the baseline blood routine examination results. The prognosis was compared between the increased group and the decreased group.
Results
The 3-year PFS and 5-year OS of the group with increased leukocyte count, platelet count, and absolute neutrophil count were significantly lower compared to those of the decreased group. Based on the multivariate analysis, increased absolute neutrophil count is an independent risk factor for 3-year PFS (P < 0.001, HR 3.003, 95% CI 1.639–5.495) and 5-year OS (P = 0.003, HR 2.611, 95% CI 1.374–4.950), and increased platelet count is an independent risk factor for 5-year OS (P = 0.037, HR 2.033, 95% CI 1.044–3.953).
Conclusion
The "myelostimulation" that occurs in patients with LAGC in the early stage (3–5 days) after fluorouracil plus platinum-based NACT is related to a poor prognosis, which is a simple and effective method to screen related patients with unfavored outcomes. Notably, the increase in absolute neutrophil count and platelet count has been proved to be an independent risk factor.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
References
Cancer statistics.WHO, GLOBOCAN 2018 Stomach. https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf. Accessed 19 Sept 2020
Yokoyama H, Nakanishi H, Kodera Y, Ikehara Y, Ohashi N, Ito Y, Koike M, Fujiwara M, Tatematsu M, Nakao A (2006) Biological significance of isolated tumor cells and micrometastasis in lymph nodes evaluated using a green fluorescent protein-tagged human gastric cancer cell line. Clin Cancer Res 12(2):361–368. https://doi.org/10.1158/1078-0432.CCR-05-1963
Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Geneve J, Lasser P, Rougier P (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29(13):1715–1721. https://doi.org/10.1200/JCO.2010.33.0597
Carey PJ (2003) Drug-induced myelosuppression: diagnosis and management. Drug Saf 26(10):691–706. https://doi.org/10.2165/00002018-200326100-00003
Di Maio M, Gridelli C, Gallo C, Shepherd F, Piantedosi FV, Cigolari S, Manzione L, Illiano A, Barbera S, Robbiati SF, Frontini L, Piazza E, Ianniello GP, Veltri E, Castiglione F, Rosetti F, Gebbia V, Seymour L, Chiodini P, Perrone F (2005) Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 6(9):669–677. https://doi.org/10.1016/S1470-2045(05)70255-2
Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M (2007) Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma. Br J Cancer 97(1):37–42. https://doi.org/10.1038/sj.bjc.6603831
Washington K (2010) 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol 17(12):3077–3079. https://doi.org/10.1245/s10434-010-1362-z
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(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545. https://doi.org/10.1016/S0140-6736(00)04046-0
Diakos CI, Charles KA, McMillan DC, Clarke SJ (2014) Cancer-related inflammation and treatment effectiveness. Lancet Oncol 15(11):e493-503. https://doi.org/10.1016/S1470-2045(14)70263-3
Kasi PM, Grothey A (2018) Chemotherapy-induced neutropenia as a prognostic and predictive marker of outcomes in solid-tumor patients. Drugs 78(7):737–745. https://doi.org/10.1007/s40265-018-0909-3
Templeton AJ, McNamara MG, Seruga B, Vera-Badillo FE, Aneja P, Ocana A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B, Tannock IF, Amir E (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106(6):dju124. https://doi.org/10.1093/jnci/dju124
Guthrie GJ, Roxburgh CS, Farhan-Alanie OM, Horgan PG, McMillan DC (2013) Comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer. Br J Cancer 109(1):24–28. https://doi.org/10.1038/bjc.2013.330
Wang Y, Chen Y, Yin H, Gu X, Shi Y, Dai G (2018) Timing of chemotherapy-induced neutropenia is a prognostic factor in patients with advanced gastric cancer undergoing first-line chemotherapy with oxaliplatin and capecitabine: a retrospective study. Cancer Med 7(4):997–1005. https://doi.org/10.1002/cam4.1308
Coffelt SB, Wellenstein MD, de Visser KE (2016) Neutrophils in cancer: neutral no more. Nat Rev Cancer 16(7):431–446. https://doi.org/10.1038/nrc.2016.52
Choi Y, Kim JW, Nam KH, Han SH, Kim JW, Ahn SH, Park DJ, Lee KW, Lee HS, Kim HH (2017) Systemic inflammation is associated with the density of immune cells in the tumor microenvironment of gastric cancer. Gastric Cancer 20(4):602–611. https://doi.org/10.1007/s10120-016-0642-0
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013
Petrie HT, Klassen LW, Kay HD (1985) Inhibition of human cytotoxic T lymphocyte activity in vitro by autologous peripheral blood granulocytes. J Immunol (Baltimore, Md: 1950) 134(1):230–234
Hag A, Clark RA (1987) Immunosuppression by activated human neutrophils. Dependence on the myeloperoxidase system. J Immunol (Baltimore, Md: 1950) 139(7):2406–2413
McCourt M, Wang JH, Sookhai S, Redmond HP (1999) Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg (Chicago, Ill: 1960) 134(12):1325–1331. https://doi.org/10.1001/archsurg.134.12.1325 ((discussion 1331–1322))
Di Carlo E, Forni G, Musiani P (2003) Neutrophils in the antitumoral immune response. Chem Immunol Allergy 83:182–203. https://doi.org/10.1159/000071561
McCourt M, Wang JH, Sookhai S, Redmond HP (2001) Activated human neutrophils release hepatocyte growth factor/scatter factor. Eur J Surg Oncol 27(4):396–403. https://doi.org/10.1053/ejso.2001.1133
Jabłońska E, Kiluk M, Markiewicz W, Piotrowski L, Grabowska Z, Jabłoński J (2001) TNF-alpha, IL-6 and their soluble receptor serum levels and secretion by neutrophils in cancer patients. Archivum immunologiae et therapiae experimentalis 49(1):63–69
Schaider H, Oka M, Bogenrieder T, Nesbit M, Satyamoorthy K, Berking C, Matsushima K, Herlyn M (2003) Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8. Int J Cancer 103(3):335–343. https://doi.org/10.1002/ijc.10775
Shamamian P, Schwartz JD, Pocock BJ, Monea S, Whiting D, Marcus SG, Mignatti P (2001) Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol 189(2):197–206. https://doi.org/10.1002/jcp.10014
Scapini P, Nesi L, Morini M, Tanghetti E, Belleri M, Noonan D, Presta M, Albini A (1950) Cassatella MA (2002) Generation of biologically active angiostatin kringle 1–3 by activated human neutrophils. J Immunol (Baltimore, Md: 1950) 168(11):5798–5804. https://doi.org/10.4049/jimmunol.168.11.5798
Granot Z (2019) Neutrophils as a therapeutic target in cancer. Front Immunol 10:1710. https://doi.org/10.3389/fimmu.2019.01710
Best MG, Sol N, In 't Veld S, Vancura A, Muller M, Niemeijer AN, Fejes AV, Tjon Kon Fat LA, Huis In 't Veld AE, Leurs C, Le Large TY, Meijer LL, Kooi IE, Rustenburg F, Schellen P, Verschueren H, Post E, Wedekind LE, Bracht J, Esenkbrink M, Wils L, Favaro F, Schoonhoven JD, Tannous J, Meijers-Heijboer H, Kazemier G, Giovannetti E, Reijneveld JC, Idema S, Killestein J, Heger M, de Jager SC, Urbanus RT, Hoefer IE, Pasterkamp G, Mannhalter C, Gomez-Arroyo J, Bogaard HJ, Noske DP, Vandertop WP, van den Broek D, Ylstra B, Nilsson RJA, Wesseling P, Karachaliou N, Rosell R, Lee-Lewandrowski E, Lewandrowski KB, Tannous BA, de Langen AJ, Smit EF, van den Heuvel MM, Wurdinger T (2017) Swarm intelligence-enhanced detection of non-small-cell lung cancer using tumor-educated platelets. Cancer Cell 32(2):238–252.e239. https://doi.org/10.1016/j.ccell.2017.07.004
Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, Ikeda Y, Hibi T, Inazawa J, Watanabe M (2002) Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 8(9):1011–1017
Knaus HA, Berglund S, Hackl H, Blackford AL, Zeidner JF, Montiel-Esparza R, Mukhopadhyay R, Vanura K, Blazar BR, Karp JE, Luznik L, Gojo I (2018) Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. JCI Insight. https://doi.org/10.1172/jci.insight.120974
Ireland AS, Oliver TG (2020) Neutrophils create an ImpeNETrable shield between tumor and cytotoxic immune cells. Immunity 52(5):729–731. https://doi.org/10.1016/j.immuni.2020.04.009
Funding
No external funding was used in the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
YL designed the work. YL, YC and LX analyzed and interpreted the patient data. YL and HW were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
None of the authors have a relevant financial relationship with a commercial interest.
Ethics approval
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. The exemption from informed consent requirement was permitted by The Affiliated Cancer Hospital of Xinjiang Medical University Institutional Review Board.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, Y., Cao, Y., Xiao, L. et al. Early myelostimulation in patients with locally advanced gastric cancer after fluorouracil plus platinum-based neoadjuvant chemotherapy is related to poor prognosis. Cancer Chemother Pharmacol 87, 701–710 (2021). https://doi.org/10.1007/s00280-021-04243-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-021-04243-z