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Journal of Cancer Research and Clinical Oncology

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Open Access 01-02-2018 | Original Article – Clinical Oncology

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy

Authors: Sibylle Schirm, Christoph Engel, Sibylle Loibl, Markus Loeffler, Markus Scholz

Published in: Journal of Cancer Research and Clinical Oncology | Issue 2/2018

Abstract

Purpose

Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients.

Methods

We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios.

Results

Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies ‘BEACOPP escalated’ (Hodgkin’s disease), ‘ETC’ (breast cancer), and risk-adapted schedules for ‘CHOP-14’ (aggressive non-Hodgkin’s lymphoma in elderly patients).

Conclusions

We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

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Altwairgi AK, Hopman WM, Mates M (2013) Real-world impact of granulocyte-colony stimulating factor on febrile neutropenia. Curr Oncol 20(3):9. https://doi.org/10.3747/co.20.1306 CrossRef

Bennett CL, Sinkule JA, Schilsky RL, Senekjian E, Choi KE (1987) Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer. Cancer Res 47(7):1952–1956PubMed

Bennett CL, Djulbegovic B, Norris LB, Armitage JO (2013) Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med 368(12):1131–1139. https://doi.org/10.1056/NEJMct1210890 PubMedPubMedCentralCrossRef

Blayney DW, LeBlanc ML, Grogan T, Gaynor ER, Chapman RA, Spiridonidis CH, Taylor SA, Bearman SI, Miller TP, Fisher RI (2003) Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: A phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 21(13):2466–2473. https://doi.org/10.1200/Jco.2003.06.137 PubMedCrossRef

Blayney DW, McGuire BW, Cruickshank SE, Johnson DH (2005) Increasing chemotherapy dose density and intensity: phase I trials in non-small cell lung cancer and non-Hodgkin’s lymphoma. Oncologist 10(2):138–149. https://doi.org/10.1634/theoncologist.10-2-138 PubMedCrossRef

Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A (2008) Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev (4):CD003189. 10.1002/14651858.CD003189.pub4

Bruno R, Riva A, Hille D, Lebecq A, Thomas L (1997) Pharmacokinetic and pharmacodynamic properties of docetaxel: results of phase I and phase II trials. Am J Health Syst Pharm Off J Am Soc Health Syst Pharm 54(24 Suppl 2):9

Chatta GS, Price TH, Allen RC, Dale DC (1994) Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers. Blood 84(9):2923–2929PubMed

Cheng C, Gallagher EM, Yeh J-Y, Earl MA (2014) Rates of febrile neutropenia with pegfilgrastim on same day versus next day of CHOP with or without rituximab. Anticancer Drugs 25(8):964–969. https://doi.org/10.1097/CAD.0000000000000115 PubMedCrossRef

Chua HL, Plett PA, Sampson CH, Katz BP, Carnathan GW, MacVittie TJ, Lenden K, Orschell CM (2014) Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors. Health Phys 106(1):21–38. https://doi.org/10.1097/HP.0b013e3182a4df10 PubMedCrossRef

Clark OAC, Lyman G, Castro AA, Clark LGO, Djulbegovic B (2003) Colony stimulating factors for chemotherapy induced febrile neutropenia. Cochrane Database Syst Rev (3):CD003039. 10.1002/14651858.CD003039

Clark OAC, Lyman GH, Castro AA, Clark LGO, Djulbegovic B (2005) Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 23(18):4198–4214. https://doi.org/10.1200/JCO.2005.05.645 PubMedCrossRef

Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A (1992) Modulation of granulocyte survival and programmed cell-death by cytokines and bacterial products. Blood 80(8):2012–2020PubMed

Cooper KL, Madan J, Whyte S, Stevenson MD, Akehurst RL (2011) Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer 11:404. https://doi.org/10.1186/1471-2407-11-404 PubMedPubMedCentralCrossRef

Craig M, Humphries AR, Nekka F, Belair J, Li J, Mackey MC (2015) Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: mathematical modelling guides dose optimisation to minimise neutropenia. J Theor Biol 385:77–89. https://doi.org/10.1016/j.jtbi.2015.08.015 PubMedCrossRef

Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, Kris M, Grous J, Picozzi V, Rausch G (1991) Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325(3):164–170. https://doi.org/10.1056/NEJM199107183250305 PubMedCrossRef

Crawford J, Kreisman H, Garewal H, Jones SE, Shoemaker D, Pupa MR, Armstrong S, Tomita D, Dziem G (1997) The impact of Filgrastim schedule variation on hematopoietic recovery post-chemotherapy. Ann Oncol 8(11):1117–1124PubMedCrossRef

Crawford J, Dale DC, Lyman GH (2004) Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 100(2):228–237. https://doi.org/10.1002/cncr.11882 PubMedCrossRef

Dale DC (2002) Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 62(Suppl 1):1–15PubMedCrossRef

Dale D (2003) Current management of chemotherapy-induced neutropenia: the role of colony-stimulating factors. Semin Oncol 30(4 Suppl 13):3–9PubMedCrossRef

Danova M, Chiroli S, Rosti G, Doan QV (2009) Cost-effectiveness of pegfilgrastim versus six days of filgrastim for preventing febrile neutropenia in breast cancer patients. Tumori 95(2):219–226PubMed

Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dorken B, Muller-Hermelink H, Duhmke E, Loeffler M, German Hodgkin’s Lymphoma Study Group [Nachname nicht vorhanden] (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 348(24):2386–2395. https://doi.org/10.1056/Nejmoa022473 PubMedCrossRef

Djulbegovic B, Norris LB, Bennett CL (2013) Colony-stimulating factors for febrile neutropenia. N Engl J Med 369(3):286. https://doi.org/10.1056/NEJMc1306109 PubMed

Engel C, Scholz M, Loeffler M (2004) A computational model of human granulopoiesis to simulate the hematotoxic effects of multicycle polychemotherapy. Blood 104(8):2323–2331. https://doi.org/10.1182/blood-2004-01-0306 PubMedCrossRef

Faber E, Pytlik R, Slaby J, Zapletalova J, Kozak T, Raida L, Papajik T, Zikesova E, Maresova I, Hamouzova M, Indrak K, Trneny M (2006) Individually determined dosing of filgrastim after autologous peripheral stem cell transplantation in patients with malignant lymphoma—results of a prospective multicentre controlled trial. Eur J Haematol 77(6):493–500. https://doi.org/10.1111/j.1600-0609.2006.00741.x PubMedCrossRef

Georgala A, Klastersky JA (2015) Prophylaxis of febrile neutropenia in adults receiving chemotherapy needs to be adapted to the risk. Expert Rev Hematol 8(1):115–121. https://doi.org/10.1586/17474086.2015.983470 PubMedCrossRef

Gross A, Schirm S, Scholz M (2014) Ycasd—a tool for capturing and scaling data from graphical representations. BMC Bioinform 15(219):219. https://doi.org/10.1186/1471-2105-15-219 CrossRef

Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2(3):214–221. https://doi.org/10.1038/nrd1033 PubMedCrossRef

Holmes FA, Jones SE, O’Shaughnessy J, Vukelja S, George T, Savin M, Richards D, Glaspy J, Meza L, Cohen G, Dhami M, Budman DR, Hackett J, Brassard M, Yang BB, Liang BC (2002) Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol Off J Eur Soc Med Oncol 13(6):903–909CrossRef

Houston AC, Stevens LA, Cour V (1999) Pharmacokinetics of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in healthy male volunteers. Brit J Clin Pharmacol 47(3):279–284CrossRef

Ishiguro H, Kitano T, Yoshibayashi H, Toi M, Ueno T, Yasuda H, Yanagihara K, Garbo CL, Fukushima M (2008) Prolonged neutropenia after dose-dense chemotherapy with pegfilgrastim. Ann Oncol 19(5):1019. https://doi.org/10.1093/annonc/mdn051 (author reply 1019–20) PubMedCrossRef

Iyer L, Ratain MJ (1999) 5-Fluorouracil pharmacokinetics: causes for variability and strategies for modulation in cancer chemotherapy. Cancer Investig 17(7):494–506CrossRef

Kloft C, Wallin J, Henningsson A, Chatelut E, Karlsson MO (2006) Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs. Clin Cancer Res Off J Am Assoc Cancer Res 12(18):5481–5490. https://doi.org/10.1158/1078-0432.CCR-06-0815 CrossRef

Kosaka Y, Rai Y, Masuda N, Takano T, Saeki T, Nakamura S, Shimazaki R, Ito Y, Tokuda Y, Tamura K (2015) Phase III placebo-controlled, double-blind, randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide chemotherapy. Support Care Cancer 23(4):1137–1143. https://doi.org/10.1007/s00520-014-2597-1 PubMedPubMedCentralCrossRef

Kota J, Machavaram KK, McLennan DN, Edwards GA, Porter CJ, Charman SA (2007) Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model. Drug Metab Dispos 35:2211–2217PubMedCrossRef

Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH (2006) Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106(10):2258–2266. https://doi.org/10.1002/cncr.21847 PubMedCrossRef

Kuderer NM, Dale DC, Crawford J, Lyman GH (2007) Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 25(21):3158–3167. https://doi.org/10.1200/Jco.2006.08.8823 PubMedCrossRef

Kuwabara T, Kato Y, Kobayashi S, Suzuki H, Sugiyama Y (1994) Nonlinear pharmacokinetics of a recombinant human granulocyte-colony-stimulating factor derivative (nartograstim)—species-differences among rats, monkeys and humans. J Pharmacol Exp Ther 271(3):1535–1543PubMed

Kuwabara T, Kobayashi S, Sugiyama Y (1996a) Kinetic analysis of receptor-mediated endocytosis of G-CSF derivative, nartograstim, in rat bone marrow cells. Am J Physiol 271(1 Pt 1):84

Kuwabara T, Kobayashi S, Sugiyama Y (1996b) Pharmacokinetics and pharmacodynamics of a recombinant human granulocyte colony-stimulating factor. Drug Metab Rev 28(4):625–658. https://doi.org/10.3109/03602539608994020 PubMedCrossRef

Lambertini M, Ferreira AR, Del Mastro L, Danesi R, Pronzato P (2015) Pegfilgrastim for the prevention of chemotherapy-induced febrile neutropenia in patients with solid tumors. Expert Opin Biol Ther 15(12):1799–1817. https://doi.org/10.1517/14712598.2015.1101063 PubMedCrossRef

Lee S, Knox A, Zeng ISL, Coomarasamy C, Blacklock H, Issa S (2013) Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost-benefit and quality of life analysis. Support Care Cancer 21(3):841–846. https://doi.org/10.1007/s00520-012-1589-2 PubMedCrossRef

Leonard RCF, Mansi JL, Keerie C, Yellowlees A, Crawford S, Benstead K, Matthew R, Adamson D, Chan S, Grieve R (2015) A randomised trial of secondary prophylaxis using granulocyte colony-stimulating factor (‘SPROG’ trial) for maintaining dose intensity of standard adjuvant chemotherapy for breast cancer by the Anglo-Celtic Cooperative Group and NCRN. Ann Oncol 26(12):2437–2441. https://doi.org/10.1093/annonc/mdv389 PubMed

Li Y, Klippel Z, Shih X, Reiner M, Wang H, Page JH (2016) Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies. Support Care Cancer. https://doi.org/10.1007/s00520-016-3277-0

Loibl S, Mueller V, von Minckwitz G, Conrad B, Koehne C-H, Kremers S, Forstbauer H, Linder M, Nekljudova V, Moebus V (2011) Comparison of pegfilgrastim on day 2 vs. day 4 as primary prophylaxis of intense dose-dense chemotherapy in patients with node-positive primary breast cancer within the prospective, multi-center GAIN study: (GBG 33). Support Care Cancer 19(11):1789–1795. https://doi.org/10.1007/s00520-010-1020-9 PubMedCrossRef

Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L, Dexter TM (1989) The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci USA 86(23):9499–9503PubMedPubMedCentralCrossRef

Lyman G, Lalla A, Barron R, Dubois RW (2009) Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin’s lymphoma receiving CHOP-21 in United States. Curr Med Res Opin 25(2):401–411. https://doi.org/10.1185/03007990802636817 PubMedCrossRef

Mackey MC, Aprikyan AA, Dale DC (2003) The rate of apoptosis in post mitotic neutrophil precursors of normal and neutropenic humans. Cell Prolif 36(1):27–34PubMedCrossRef

Masuda N, Tokuda Y, Nakamura S, Shimazaki R, Ito Y, Tamura K (2015) Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial. Support Care Cancer 23(10):2891–2898. https://doi.org/10.1007/s00520-015-2654-4 PubMedPubMedCentralCrossRef

Mhaskar R, Clark OAC, Lyman G, Engel Ayer Botrel T, Morganti Paladini L, Djulbegovic B (2014) Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev (10):CD003039. 10.1002/14651858.CD003039.pub2

Moebus V, Jackisch C, Lueck H-J, Du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M (2010) Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 28(17):2874–2880. https://doi.org/10.1200/JCO.2009.24.7643 PubMedCrossRef

Molineux G (2002) Pegylation: engineering improved pharmaceuticals for enhanced therapy. Cancer Treat Rev 28(Suppl A):13–16PubMedCrossRef

Pastor ML, Laffont CM, Gladieff L, Chatelut E, Concordet D (2015) Model-based approach to early predict prolonged high grade neutropenia in carboplatin-treated patients and guide G-CSF prophylactic treatment. Pharm Res 32(2):654–664. https://doi.org/10.1007/s11095-014-1493-1 PubMedCrossRef

Pettengell R, Gurney H, Radford JA, Deakin DP, James R, Wilkinson PM, Kane K, Bentley J, Crowther D (1992) Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin’s lymphoma: a randomized controlled trial. Blood 80(6):1430–1436PubMed

Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rube C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M (2004a) Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 104(3):634–641. https://doi.org/10.1182/blood-2003-06-2095 PubMedCrossRef

Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rube C, Loeffler M (2004b) Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104(3):626–633. https://doi.org/10.1182/blood-2003-06-2094 PubMedCrossRef

Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M, German High-Grade Non-Hodgkin Lymphoma Study Group (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20 + B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116. https://doi.org/10.1016/S1470-2045(08)70002-0 PubMedCrossRef

Quartino AL, Karlsson MO, Lindman H, Friberg LE (2014) Characterization of endogenous G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling. Pharm Res 31(12):3390–3403. https://doi.org/10.1007/s11095-014-1429-9 PubMedCrossRef

Rechenberg I (1973) Evolutionsstrategie. Optimierung technischer Systeme nach Prinzipien der biologischen Evolution. Frommann-Holzboog, Stuttgart

Rechenberg I (1994) Evolutionsstrategie 94. Frommann-Holzboog, Stuttgart

Roesch K, Hasenclever D, Scholz M (2014) Modelling lymphoma therapy and outcome. Bull Math Biol 76(2):401–430. https://doi.org/10.1007/s11538-013-9925-3 PubMedCrossRef

Rosch K, Scholz M, Hasenclever D (2016) Modeling combined chemo- and immunotherapy of high-grade non-Hodgkin lymphoma. Leuk Lymphoma 57(7):1697–1708. https://doi.org/10.3109/10428194.2015.1110746 PubMedCrossRef

Rushing DA, Raber SR, Rodvold KA, Piscitelli SC, Plank GS, Tewksbury DA (1994) The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. Cancer 74(3):834–841PubMedCrossRef

Sarkar CA, Lowenhaupt K, Wang PJ, Horan T, Lauffenburger DA (2003) Parsing the effects of binding, signaling, and trafficking on the mitogenic potencies of granulocyte colony-stimulating factor analogues. Biotechnol Prog 19(3):955–964. https://doi.org/10.1021/bp020017g PubMedCrossRef

Schirm S, Engel C, Loeffler M, Scholz M (2013) A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration. PLoS One 8(6):e65630. https://doi.org/10.1371/journal.pone.0065630 PubMedPubMedCentralCrossRef

Schirm S, Engel C, Loeffler M, Scholz M (2014a) A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment. Theor Biol Med Model 11:24. https://doi.org/10.1186/1742-4682-11-24 PubMedPubMedCentralCrossRef

Schirm S, Engel C, Loeffler M, Scholz M (2014b) Modelling chemotherapy effects on granulopoiesis. BMC Syst Biol 8(1):5. https://doi.org/10.1186/s12918-014-0138-7 CrossRef

Schmitz S, Franke H, Brusis J, Wichmann HE (1993) Quantification of the cell kinetic effects of G-CSF using a model of human granulopoiesis. Exp Hematol 21(6):755–760PubMed

Scholz M, Engel C, Loeffler M (2005) Modelling human granulopoiesis under poly-chemotherapy with G-CSF support. J Math Biol 50(4):397–439. https://doi.org/10.1007/s00285-004-0295-1 PubMedCrossRef

Scholz M, Engel C, Loeffler M, German High Grade Non-Hodgkin Lymphoma Study Group (2006) Model-based design of chemotherapeutic regimens that account for heterogeneity in leucopoenia. Br J Haematol 132(6):723–735. https://doi.org/10.1111/j.1365-2141.2005.05957.x PubMedCrossRef

Scholz M, Ackermann M, Engel C, Emmrich F, Loeffler M, Kamprad M (2009a) A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia. Cell Prolif 42(6):813–822. https://doi.org/10.1111/j.1365-2184.2009.00638.x PubMedCrossRef

Scholz M, Engel C, Apt D, Sankar SL, Goldstein E, Loeffler M (2009b) Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats. Cell Prolif 42(6):823–837. https://doi.org/10.1111/j.1365-2184.2009.00641.x PubMedCrossRef

Scholz M, Schirm S, Wetzler M, Engel C, Loeffler M (2012) Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. Theor Biol Med Model 9:32. https://doi.org/10.1186/1742-4682-9-32 PubMedPubMedCentralCrossRef

Sieber M, Bredenfeld H, Josting A, Reineke T, Rueffer U, Koch T, Naumann R, Boissevain F, Koch P, Worst P, Soekler M, Eich H, Muller-Hermelink HK, Franklin J, Paulus U, Wolf J, Engert A, Diehl V (2003) 14-Day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin’s lymphoma: results of a pilot study of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21(9):1734–1739. https://doi.org/10.1200/Jco.2003.06.028 PubMedCrossRef

Sulkes A, Collins JM (1987) Reappraisal of some dosage adjustment guidelines. Cancer Treat Rep 71(3):229–233PubMed

Sung L, Nathan PC, Alibhai SMH, Tomlinson GA, Beyene J (2007) Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med 147(6):400–411PubMedCrossRef

Trumper L, Zwick C, Ziepert M, Hohloch K, Schmits R, Mohren M, Liersch R, Bentz M, Graeven U, Wruck U, Hoffmann M, Metzner B, Hasenclever D, Loeffler M, Pfreundschuh M, German High-Grade Non-Hodgkin’s Lymphoma Study Group (2008) Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin’s lymphoma: I. A randomized dose escalation and feasibility study with bi- and tri-weekly regimens. Ann Oncol Off J Eur Soc Med Oncol 19(3):538–544. https://doi.org/10.1093/annonc/mdm497 CrossRef

Untch M, Fasching PA, Konecny GE, von Koch F, Conrad U, Fett W, Kurzeder C, Luck HJ, Stickeler E, Urbaczyk H, Liedtke B, Salat C, Harbeck N, Muller V, Schmidt M, Hasmuller S, Lenhard M, Schuster T, Nekljudova V, Lebeau A, Loibl S, von Minckwitz G, Arbeitsgemeinschaft Gynakologische Onkologie Prepare Investigators (2011a) PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery. Ann Oncol Off J Eur Soc Med Oncol 22(9):1988–1998. https://doi.org/10.1093/annonc/mdq709 CrossRef

Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Luck HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Muller V, Schmidt M, Hasmuller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA, Arbeitsgemeinschaft Gynakologische Onkologie Prepare Investigators (2011b) PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer—outcome on prognosis. Ann Oncol Off J Eur Soc Med Oncol 22(9):1999–2006. https://doi.org/10.1093/annonc/mdq713 CrossRef

Veronese FM, Mero A (2008) The impact of PEGylation on biological therapies. BioDrugs Clin Immunother Biopharm Gene Ther 22(5):315–329

Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, Neumann TA, Schwartzberg LS (2005) First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23(6):1178–1184. https://doi.org/10.1200/JCO.2005.09.102 PubMedCrossRef

Vose JM, Crump M, Lazarus H, Emmanouilides C, Schenkein D, Moore J, Frankel S, Flinn I, Lovelace W, Hackett J, Liang BC (2003) Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 21(3):514–519CrossRef

Wang XJ, Tang T, Farid M, Quek R, Tao M, Lim ST, Wee HL, Chan A (2016) Routine primary prophylaxis for febrile neutropenia with biosimilar granulocyte colony-stimulating factor (nivestim) or pegfilgrastim is cost effective in non-hodgkin lymphoma patients undergoing curative-intent R-CHOP chemotherapy. PLoS One 11(2):e0148901. https://doi.org/10.1371/journal.pone.0148901 PubMedPubMedCentralCrossRef

Whitworth JM, Matthews KS, Shipman KA, Numnum TM, Kendrick JE, Kilgore LC, Straughn JM Jr (2009) The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies. Gynecol Oncol 112(3):601–604. https://doi.org/10.1016/j.ygyno.2008.10.025 PubMedCrossRef

Yang BB, Lum PK, Hayashi MM, Roskos LK (2004) Polyethylene glycol modification of filgrastim results in decreased renal clearance of the protein in rats. J Pharm Sci 93(5):1367–1373. https://doi.org/10.1002/Jps.20024 PubMedCrossRef

Zagonel V, Babare R, Merola MC, Talamini R, Lazzarini R, Tirelli U, Carbone A, Monfardini S (1994) Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 5(Suppl 2):127–132PubMedCrossRef

Zamboni WC (2003) Pharmacokinetics of pegfilgrastim. Pharmacotherapy 23(8 Pt 2):9–14CrossRef

Zeynalova S, Ziepert M, Scholz M, Schirm S, Zwick C, Pfreundschuh M, Loeffler M, German High-Grade Non-Hodgkin Lymphoma Study Group (2013) Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma. Ann Hematol 92(12):1641–1652. https://doi.org/10.1007/s00277-013-1842-x PubMedCrossRef

Ziepert M, Schmits R, Trumper L, Pfreundschuh M, Loeffler M, German High-Grade Non-Hodgkin’s Lymphoma Study Group (2008) Prognostic factors for hematotoxicity of chemotherapy in aggressive non-Hodgkin’s lymphoma. Ann Oncol Off J Eur Soc Med Oncol 19(4):752–762. https://doi.org/10.1093/annonc/mdm541 CrossRef

Zwick C, Hartmann F, Zeynalova S, Poschel V, Nickenig C, Reiser M, Lengfelder E, Peter N, Schlimok G, Schubert J, Schmitz N, Loeffler M, Pfreundschuh M, German High-Grade Non-Hodgkin Lymphoma Study Group (2011) Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia. Ann Oncol Off J Eur Soc Med Oncol 22(8):1872–1877. https://doi.org/10.1093/annonc/mdq674 CrossRef

Title: Model-based optimization of G-CSF treatment during cytotoxic chemotherapy
Authors: Sibylle Schirm
Christoph Engel
Sibylle Loibl
Markus Loeffler
Markus Scholz
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 2/2018
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-017-2540-1

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