Continuous Intravenous Administration of Granulocyte-Colony-Stimulating Factors-A Breakthrough in the Treatment of Cancer Patients with Febrile Neutropenia

Călin Căinap, Sânziana Cetean-Gheorghe, Laura Ancuta Pop, Daniel Corneliu Leucuta, Doina Piciu, Andra Mester, Cătălin Vlad, Crişan Ovidiu, Alexandra Gherman, Cristina Crişan, Alina Bereanu, Ovidiu Bălăcescu, Anne Marie Constantin, Irina Dicu, Loredana Bălăcescu, Adina Stan, Patriciu Achimaş-Cadariu, Simona Căinap, Călin Căinap, Sânziana Cetean-Gheorghe, Laura Ancuta Pop, Daniel Corneliu Leucuta, Doina Piciu, Andra Mester, Cătălin Vlad, Crişan Ovidiu, Alexandra Gherman, Cristina Crişan, Alina Bereanu, Ovidiu Bălăcescu, Anne Marie Constantin, Irina Dicu, Loredana Bălăcescu, Adina Stan, Patriciu Achimaş-Cadariu, Simona Căinap

Abstract

(1) Background: Febrile neutropenia (FN) remains one of the most challenging problems in medical oncology and is a very severe side effect of chemotherapy. Its late consequences, when it is recurrent or of a severe grade, are dose reduction and therapy delays. Current guidelines allow the administration of granulocyte-colony-stimulating factors (G-CSF) for profound FN (except for the case when a pegylated form of G-CSF is administrated with prophylactic intention) in addition to antibiotics and supportive care. (2) Methods: This is a prospective study that included 96 patients with confirmed malignancy, treated with chemotherapy, who developed FN during their oncological therapy, and were hospitalized. They received standard treatment plus a dose of G-CSF of 16 µg/Kg/day IV continuous infusion. (3) Results: The gender distribution was almost symmetrical: Male patients made up 48.96% and 51.04% were female patients, with no significance on recovery from FN (p = 1.00). The patients who received prophylactic G-CSF made up 20.21%, but this was not a predictive or prognostic factor for the recovery time from aplasia (p = 0.34). The median chemotherapy line where patients with FN were included was two and the number of previous chemotherapy cycles before FN was three. The median serological number of neutrophils (PMN) was 450/mm3 and leucocytes (WBC) 1875/mm3 at the time of FN. Ten patients possess PMN less than 100/mm3. The median time to recovery was 25.5 h for 96 included patients, with one failure in which the patient possessed grade 5 FN. Predictive factors for shorter recovery time were lower levels of C reactive protein (p < 0.001) and procalcitonin (p = 0.002) upon hospital admission and higher WBC (p = 0.006) and PMN (p < 0.001) at the time of the provoking cycle of chemotherapy for FN. The best chance for a shorter duration of FN was a short history of chemotherapy regarding the number of cycles) (p < 0.0001). (4) Conclusions: Continuous IV administration of G-CSF could be an alternative salvage treatment for patients with profound febrile neutropenia, with a very fast recovery time for neutrophiles.

Keywords: G-CSF; cancer; chemotherapy; febrile; neutropenia.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chart of the resolution of FN for the included population.
Figure 2
Figure 2
Repartition of aplasia among the included patients.

References

    1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics. CA Cancer J. Clin. 2016;66:7–30. doi: 10.3322/caac.21332.
    1. Long B., Koyfman A. Oncologic Emergencies: The Fever with too Few Neutrophils. J. Emerg. Med. 2019;57:689–700. doi: 10.1016/j.jemermed.2019.08.009.
    1. Klastersky J., de Naurois J., Rolston K., Rapoport B., Maschmeyer G., Aapro M., Herrstedt J. Management of febrile neutropaenia: ESMO clinical practice guidelines. [(accessed on 1 April 2021)];Ann. Oncol. 2016 27:111–118. doi: 10.1093/annonc/mdw325. Available online: .
    1. Becker P.S., Griffiths E.A., Alwan L.M., Bachiashvili K., Brown A., Cool R., Curtin P., Dinner S., Gojo I., Hicks A., et al. NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020. [(accessed on 1 April 2021)];J. Natl. Compr. Cancer Netw. 2020 18:12–22. doi: 10.6004/jnccn.2020.0002. Available online: .
    1. Krzyzanski W., Wiczling P., Lowe P., Pigeolet E., Fink M., Berghout A., Balser S. Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations. J. Clin. Pharmacol. 2010;50:817–826. doi: 10.1177/0091270010376966.
    1. Bronchud M.H., Potter M.R., Morgenstern G., Blasco M.J., Scarffe J.H., Thatcher N., Crowther D., Souza L.M., Alton N.K., Testa N.G. In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients. Br. J. Cancer. 1988;58:64–69. doi: 10.1038/bjc.1988.163.
    1. Shah B., Burg N., Pillinger M.H. Neutrophils. 10th ed. Elsevier Inc.; Amsterdam, The Netherlands: 2017. pp. 169–188.e3. Kelley and Firestein’s Textbook of Rheumatology, 2-Volume Set.
    1. Foley C., Mackey M.C. Mathematical model for G-CSF administration after chemotherapy. J. Theor. Biol. 2009;257:27–44. doi: 10.1016/j.jtbi.2008.09.043.
    1. Campa C.C., Germena G., Ciraolo E., Copperi F., Sapienza A., Franco I., Ghigo A., Camporele A., DI Savino A., Martini M., et al. Rac signal adaptation controls neutrophil mobilization from the bone marrow. [(accessed on 1 April 2021)];Sci. Signal. 2016 9 Available online:
    1. Campa C.C., Hirsch E. Advances in Biological Regulation. Volume 63. Elsevier Inc.; Amsterdam, The Netherlands: 2017. [(accessed on 1 April 2021)]. Rab11 and phosphoinositides: A synergy of signal transducers in the control of vesicular trafficking; pp. 132–139. Available online:
    1. Köhler A., De Filippo K., Hasenberg M., Van Den Brandt C., Nye E., Hosking M.P., Lane T.E., Mann L., Ransohoff R.M., Hauser A.E., et al. G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands. Blood. 2011;117:4349–4357. doi: 10.1182/blood-2010-09-308387.
    1. Scholz M., Schirm S., Wetzler M., Engel C., Loeffler M. Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. Theor. Biol. Med. Model. 2012;9:32. doi: 10.1186/1742-4682-9-32.
    1. Smith T.J., Bohlke K., Lyman G.H., Carson K.R., Crawford J., Cross S.J., Goldberg J.M., Khatcheressian J.L., Leighl N.B., Perkins C.L., et al. Recommendations for the use of WBC growth factors: American society of clinical oncology clinical practice guideline update. J. Clin. Oncol. 2015;33:3199–3212. doi: 10.1200/JCO.2015.62.3488.
    1. Seicean A., Gheorghiu M., Zaharia T., Calinici T., Samarghitan A., Marcus B., Cainap S., Seicean R. Performance of the Standard 22G Needle for Endoscopic Ultrasound-guided Tissue Core Biopsy in Pancreatic Cancer. J. Gastrointest Liver Dis. 2016;25:213–218. doi: 10.15403/jgld.2014.1121.252.ugg.
    1. Cancer Care Ontario . Cancer Care Ontario GCSF Recommendations 2016. Cancer Care Ontario; Toronto, ON, Canada: 2016.
    1. Fagnani D., Isa L., Verga M.F., Nova P., Casartelli C., Filipazzi V., Danova M., Farina G., Pugliese P., Fava S., et al. Granulocyte colony-stimulating factors used in clinical practice: Polonord Registry-Based Cohort Italian Study. Tumori. 2014;100:491–498. doi: 10.1177/1660.18158.
    1. Yoshida M., Karasawa M., Naruse T., Fukuda M., Hirashima K., Oh H., Ninomiya H., Abe T., Saito K., Shishido H., et al. Effect of granulocyte-colony stimulating factor on empiric therapy with flomoxef sodium and tobramycin in febrile neutropenic patients with hematological malignancies. [(accessed on 1 April 2021)];Int. J. Hematol. 1999 69:81–88. Available online:
    1. Özkaynak M.F., Krailo M., Chen Z., Feusner J. Randomized comparison of antibiotics with and without granulocyte colony-stimulating factor in children with chemotherapy-induced febrile neutropenia: A report from the Children’s Oncology Group. Pediatr. Blood Cancer. 2005;45:274–280. doi: 10.1002/pbc.20366.
    1. Soda H., Oka M., Fukuda M., Kinoshita A., Sakamoto A., Araki J., Satoru F., Itoh N., Watanabe K., Kanda T., et al. Optimal schedule for administering granulocyte colony-stimulating factor in chemotherapy-induced neutropenia in non-small-cell lung cancer. Cancer Chemother. Pharmacol. 1996;38:9–12. doi: 10.1007/s002800050440.
    1. Soda H., Oka M., Fukuda M., Kinoshita A., Sakamoto A., Araki J., Satoru F., Itoh N., Watanabe K., Kanda T., et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: A multicenter randomized trial. J. Natl. Cancer Inst. 2001;93:31–38.
    1. Mhaskar R., Clark O.A.C., Lyman G., Botrel T.E.A., Paladini L.M., Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia (Review) summary of findings for the main comparison. Cochrane Database Syst. Rev. 2014 doi: 10.1002/14651858.CD003039.pub2.
    1. Neulasta European Medicines Agency. [(accessed on 1 April 2021)]; Available online: .
    1. Nivestim European Medicines Agency. [(accessed on 1 April 2021)]; Available online: .
    1. Shochat E., Rom-Kedar V. Novel strategies for granulocyte colony-stimulating factor treatment of severe prolonged neutropenia suggested by mathematical modeling. Clin. Cancer Res. 2008;14:6354–6363. doi: 10.1158/1078-0432.CCR-08-0807.
    1. Cornes P., Gascon P., Chan S., Hameed K., Mitchell C.R., Field P., Latymer M., Arantes L.H. Systematic Review and Meta-analysis of Short- versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia. [(accessed on 1 April 2021)];Adv. Ther. 2018 35:1816–1829. doi: 10.1007/s12325-018-0798-6. Available online: .
    1. Watts M.J., Addison I., Long S.G., Hartley S., Warrington S., Boyce M., Linch D.C. Crossover study of the haematological effects and pharmacokinetics of glycosylated and non-glycosylated G-CSF in healthy volunteers. Br. J. Haematol. 1997;98:474–479. doi: 10.1046/j.1365-2141.1997.2393053.x.
    1. Kröger N., Renges H., Sonnenberg S., Krüger W., Gutensohn K., Dielschneider T., Cortes-Dericks L., Zander A.R. Stem cell mobilisation with 16 μg/kg vs 10 μg/kg of G-CSF for allogeneic transplantation in healthy donors. Bone Marrow Transplant. 2002;29:727–730. doi: 10.1038/sj.bmt.1703509.
    1. Petros W.P., Rabinowitz J., Stuart A., Peters W.P. Clinical pharmacology of filgrastim following high-dose chemotherapy and autologous bone marrow transplantation. Clin. Cancer Res. 1997;3:705–711.
    1. Paul M., Ram R., Kugler E., Farbman L., Peck A., Leibovici L., Lahav M., Yeshurun M., Shpilberg O., Herscovici C., et al. Rac signal adaptation controls neutrophil mobilization from the bone marrow. Sci. Signal. 2016;9:ra124.
    1. Paul M., Ram R., Kugler E., Farbman L., Peck A., Leibovici L., Lahav M., Yeshurun M., Shpilberg O., Herscovici C., et al. Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-oncological patients: Randomized controlled trial. Am. J. Hematol. 2014;89:243–248. doi: 10.1002/ajh.23622.

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