SpringerLink
Log in

Chemotherapy-induced neutropenia as a prognostic factor in patients with metastatic pancreatic cancer treated with gemcitabine

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Chemotherapy-induced neutropenia (CIN) is a common side effect of chemotherapy and an important dose-limiting factor. However, an association between CIN development and longer survival was recently reported in several solid cancers. In the present study, we aimed to assess whether CIN could be a prognostic factor and clarify other prognostic factors for patients with metastatic pancreatic cancer.

Methods

We retrospectively analyzed the medical records of 84 patients who received gemcitabine monotherapy as first-line chemotherapy for metastatic pancreatic cancer to assess whether CIN could be a prognostic factor. Potential prognostic factors of survival were examined by univariate and multivariate analyses using the log-rank test and Cox proportional hazard model, respectively.

Results

Median survival time was 170 days [95% confidence interval (CI), 147–193] in patients without CIN (grade 0), 301 days (95% CI, 152–450) in patients with grade 1–2 CIN, and 406 days (95% CI, 271–541) in patients with grade 3 CIN. The multivariate analysis revealed that a pretreatment C-reactive protein level of <0.50 mg/dL [hazard ratio (HR), 0.534; 95% CI, 0.323–0.758, P = 0.015] and grade 3 CIN (HR, 0.447; 95% CI, 0.228–0.875, P = 0.019) were independent favorable prognostic factors in patients with metastatic pancreatic cancer treated with gemcitabine.

Conclusions

Neutropenia during chemotherapy was associated with increased survival of patients with metastatic pancreatic cancer. Monitoring of CIN could be used to predict treatment responsiveness.

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 includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ito Y, Miyashiro I, Ito H, Hosono S, Chihara D, Nakata-Yamada K, Nakayama M, Matsuzaka M, Hattori M, Sugiyama H, Oze I, Tanaka R, Nomura E, Nishino Y, Matsuda T, Ioka A, Tsukuma H, Nakayama T, the J-CANSIS Research Group (2014) Long-term survival and conditional survival of cancer patients in Japan using population-based cancer registry data. Cancer Sci 105(11):1480–1486. doi:10.1111/cas.12525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Monitoring of cancer incidence in Japan—Survival 2003–2005 Report (Center for Cancer Control and Information Services, National Cancer Center, 2013). http://ganjoho.jp/professional/statistics/statistics.html

  3. Matsuda T, Ajiki W, Marugame T, Ioka A, Tsukuma H, Sobue T, Research Group of Population-Based Cancer Registries of Japan (2011) Population-based survival of cancer patients diagnosed between 1993 and 1999 in Japan: a chronological and international comparative study. Jpn J Clin Oncol 41(1):40–51. doi:10.1093/jjco/hyq167

    Article  PubMed  Google Scholar 

  4. Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan. http://ganjoho.jp/reg_stat/statistics/dl/index.html

  5. Cameron DA, Massie C, Kerr G, Leonard RCF (2003) Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Brit J Cancer 89(10):1837–1842. doi:10.1038/sj.bjc.6601366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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. doi:10.1016/S1470-2045(05)70255-2

    Article  CAS  PubMed  Google Scholar 

  7. Kishida Y, Kawahara M, Teramukai S, Kubota K, Komuta K, Minato K, Mio T, Fujita Y, Yonei T, Nakano K, Tsuboi M, Shibata K, Atagi S, Kawaguchi T, Furuse K, Fukushima M (2009) Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan multinational trial organization LC00-03. Brit J Cancer 101(9):1537–1542. doi:10.1038/sj.bjc.6605348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sunaga T, Suzuki S, Kago M, Kurihara T, Kaji S, Koike N, Harada N, Suzuki M, Kikuchi Y (2014) The association between neutropenia and prognosis in stage III colorectal cancer patients receiving adjuvant chemotherapy. Eur J Cancer Care 23(3):394–400. doi:10.1111/ecc.12120

    Article  CAS  Google Scholar 

  9. 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. Brit J Cancer 97(1):37–42. doi:10.1038/sj.bjc.6603831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mantovani A, Cassatella MA, Costantini C, Jaillo S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11(8):519–531. doi:10.1038/nri3024

    Article  CAS  PubMed  Google Scholar 

  11. Tanaka T, Ikeda M, Okusaka T, Ueno H, Morizane C, Hagihara A, Iwasa S, Kojima Y (2008) Prognostic factors in Japanese patients with advanced pancreatic cancer treated with single-agent gemcitabine as first-line therapy. Jpn J Clin Oncol 38(11):755–761. doi:10.1093/jjco/hyn098

    Article  PubMed  Google Scholar 

  12. Szkandera J, Stotz M, Absenger G, Stojakovic T, Samonigg H, Kornprat P, Schaberl-Moser R, AlZoughbi W, Lackner C, Ress AL, Seggewies FS, Gerger A, Hoefler G, Pichler M (2014) Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients. Brit J Cancer 110(1):183–188. doi:10.1038/bjc.2013.701

    Article  CAS  PubMed  Google Scholar 

  13. Inoue D, Ozaka M, Matsuyama M, Yamada I, Takano K, Saiura A, Ishii H (2015) Prognostic value of neutrophil-lymphocyte ratio and level of C-reactive protein in a large cohort of pancreatic cancer patients: a retrospective study in a single institute in Japan. Jpn J Clin Oncol 45(1):61–66. doi:10.1093/jjco/hyu159

    Article  PubMed  Google Scholar 

  14. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M (2007) Ann Oncol 18(2):317–323

    Article  CAS  PubMed  Google Scholar 

  15. Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, Fujita Y, Teramukai S, Fukushima M, Furuse K, Japan Multi-National Trial Organisation (2008) Lancet Oncol 9(12):1135–1142. doi:10.1016/S1470-2045(08)70261-4

    Article  CAS  PubMed  Google Scholar 

  16. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. doi:10.1056/NEJMoa1011923

    Article  CAS  PubMed  Google Scholar 

  17. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. doi:10.1056/NEJMoa1304369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rha SY, Jeung HC, Choi YH, Yang WI, Yoo JH, Kim BS, Roh JK, Chung HC (2007) An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. Oncologist 12(6):622–630. doi:10.1634/theoncologist.12-6-622

    Article  CAS  PubMed  Google Scholar 

  19. Tanaka M, Javle M, Dong X, Eng C, Abbruzzese JL, Li D (2010) Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer. Cancer 116(22):5325–5335. doi:10.1002/cncr.25282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Okazaki T, Javle M, Tanaka M, Abbruzzese JL, Li D (2010) Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity. Clin Cancer Res 16(1):320–329. doi:10.1158/1078-0432.CCR-09-1555

    Article  CAS  PubMed  Google Scholar 

  21. Green H, Hasmats J, Kupershmidt I, Edsgard D, de Petris L, Lewensohn R, Blackhall F, Vikingsson S, Besse B, Lindgren A, Branden E, Koyi H, Peterson C, Lundeberg J (2015) Using whole-exome sequencing to identify genetic markers for carboplatin and gemcitabine-induced toxicities. Clin Cancer Res 22(2):366–373. doi:10.1158/1078-0432.CCR-15-0964

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank all patients and medical staff who participated in this study.

Contributions of authors statement

A.O. and D.T. designed the study, analyzed the data, and wrote the manuscript. K.T., M.Y., H.N., M.O., and M.M. collected data. Y.K. analyzed the data. K.I. and K.H. reviewed the study design, protocol, and study report. K.I. approved the version to be published.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Aki Otake, Daiki Tsuji, Mari Yokoi, Harumi Nakamori, Marika Osada, Megumi Matsumoto, Kazuyuki Inoue, Keita Hirai & Kunihiko Itoh

  2. Department of Medical Oncology, Shizuoka General Hospital, 4-27-1 Kitaandou, Aoi-ku, Shizuoka, 420-8527, Japan

    Keisei Taku

  3. Department of Drug Evaluation & Informatics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Yohei Kawasaki

Authors
  1. Aki Otake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daiki Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keisei Taku
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yohei Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mari Yokoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Harumi Nakamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marika Osada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Megumi Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuyuki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keita Hirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kunihiko Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daiki Tsuji.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Otake, A., Tsuji, D., Taku, K. et al. Chemotherapy-induced neutropenia as a prognostic factor in patients with metastatic pancreatic cancer treated with gemcitabine. Eur J Clin Pharmacol 73, 1033–1039 (2017). https://doi.org/10.1007/s00228-017-2260-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-017-2260-0

Keywords

Search

Navigation