S E C T I O N A

Supportive care - Present use of biologicals in supportive care

Cesaro Simone

ey words: growth factors, G-CSF, Several studies showed a clear benefit of the use filgrastim, pegfilgrastim, erythropoietin, of G- CSF in terms of reduction of length of K darbepoetin, severe neutropenia, incidence of infections, use of intravenous antibiotic and duration of Dose and schedule are important factors in the hospitalizations. Overall, G-CSF facilitates the therapy of cancer. Animal model and clinical delivery on time of chemotherapy planned dose data show that there is a significant correlation but the high costs of acquisition raised the issue between dose-intensity and survival; moreover, of its appropriate use. The guidelines of The the shortening of interval between American Society of Clinical Oncology (ASCO), chemotherapy cycles prevents from tumor updated in 2000, indicated the settings where regrowth and maximize the effect of the use G-CSF is recommended on the basis of chemotherapy on cancer cells (Gregory SA, the available clinical data. In particular, G-CSF Trumper L, 2005). Most of anti-cancer drugs are is recommended as primary prophylaxis of non-selective and act indiscriminately on febrile neutropenia in patients with an expected dividing cells. Hematological toxicity is one of incidence of chemotherapy-induced neutropenia the most important limiting factor for the greater than or equal to 40%; in the treatment protocols that are based on the dose-escalation febrile neutropenia in patients at high risk of or the dose-density of chemotherapy. This result severe infections (sepsis, pneumonia, fungal in peripheral blood cytopenia (neutropenia, infections); after high-dose chemotherapy with anemia and thrombocytopenia), higher autologous progenitor stem-cell rescue; in the transfusion requirement, severe infectious mobilization of peripheral blood progenitor cells complications, prolonged hospitalization and (PBPCs); in patients with acute myeloid leukemia higher health care expenses. The use of to reduce the neutropenia of the post-induction hematopoietic growth factors such as the chemotherapy; and in patients with acute granulocyte colony-stimulating factors (G-CSF) lymphoblastic leukemia to reduce the filgrastim or lenograstim and erithropoietin neutropenia that follows the induction represented a step forward to reduce the chemotherapy. The adult indications of the use hematological toxicity of high-dose of G-CSF are generally extended to paediatric chemotherapy and to manage the frequent patients, though less data are available (Ozer et infectious complications. al, 2000). G-CSF Recently, new interest in G-CSF therapy has G-CSF is a natural cytokine that acts on been obtained with the introduction of committed myeloid progenitor cells. Its secretion pegfilgrastim, the pegylated form of filgrastim is stimulated by infections or by the reduction of (Waladkhani AR, 2004). Filgrastim, the mature myeloid cells, as a result of bacterial recombinant human G-CSF, is a relatively small lipolysaccharides and chemotherapy, protein that is rapidly eliminated from the body respectively (Lieschke GJ, Burgess AW, 1992); via the kidneys. The short half-life, about so the serum G-CSF concentration increase from 3.5.hours, requires its daily administration by approximately 25 pg/ml of healthy people to intravenous or subcutaneous injection until the 1,000 pg/ml of patients with severe infections or recovery to normal values of the absolute after stem-cell transplantation (Kawakami et al, neutrophil count. Pegfilgrastim consists of a 20- 1990). kDa polyehylene glycol molecule covalently

25 bound to the N-terminal amino group of filgrastim breast cancer patients who underwent molecule. Polyethylene glycol molecule are pH- moderately myelosuppressive chemotherapy neutral, non-toxic, water soluble polymers that regimen showed that the use of pegfilgrastim confers to pegfilgrastim a larger volume and a compared to placebo was associated to a lower slower renal clearance; as a result the half-life of incidence of febrile neutropenia (1% vs 17%), pegfilgrastim is 35 hours. The most important febrile-neutropenia-related hospitalization (1% vs route of elimination of pegfilgrastim is the so- 14%) and intravenous antibiotic use (2% vs 10%) called neuthrophil-mediated clearance: after These findings demonstrated that the use of binding with the G-CSF receptor on surface of pegfilgrastim reduced significantly the incidence neutrophils, the molecule is removed from of infectious complications also in the patients circulation and the resulting molecule-receptor with a moderate risk of febrile neutropenia (10- complex is internalized and metabolized. The 20%) and raised the issue of its use as primary neutrophil-mediated clearance is a process prophylaxis out of the current guidelines of ASCO slower than renal clearance and in healthy (Vogel et al, 2005). Phase II studies recently volunteers this molecule produced a sustained reported that pegfilgrastim was effective both in neutrophil count for 9-10 days (Molineux et al, mobilizing a sufficient number of CD34+ 1999). The study performed on neutropenic peripheral stem cell in patients with myeloma and cancer patients showed that pegfilgrastim lymphoma (Isidori et al, 2005; Steidl et al, 2004) reached a peak approximately 24 hours after and in decreasing the duration severe injection, remained high for all the neutropenic neutropenia and febrile neutropenia after period without daily fluctuation and declined as autologous peripheral blood stem cell the patient recovered the baseline count of transplantation (Staber et al, 2005). These data neutrophils. This favourable kinetic provides a deserve a further validation by prospective patient’s tailored protection from severe randomized study. In conclusion, pegfilgrastim neutropenia and a smooth recovery of neutrophil offers a simplified dosing regimen that is more levels. convenient for nurses and patients but its potentiality warrants further investigation Several phase II-III studies with pegfilgrastim has especially in setting where no data are still not been performed in lung cancer, breast cancer, available or conclusive (children, stem cell and lymphoma (Waladkhani AR, 2004; Biganzoli mobilization, autologous stem cell et al, 2004; Holmes et al, 2002; Green et al, 2003; transplantation). Siena et al, 2003) and the results are summarized as follows: a) the fixed dose of 6 mg (or 100 mg/ Erythropoietin (EPO) kg) of pegfilgrastim, administered once per Anemia is a common complication in patients chemotherapy cycle, is equivalent to the 5 mg/ treated with chemotherapy for cancer. Its kg-daily-dose of filgrastim, administered for 10- occurrence may delay the chemotherapy 11 days, with respect to the incidence and schedule, affect negatively the quality of life duration of severe neutropenia, and the median (QoL) and compromise the anti-tumour activity time to absolute neutrophil count recovery; b) of radiotherapy and chemotherapy (Ludwig H, no dose-limiting toxicities were observed with Fritz E, 1998; Crawford et al, 2002). Prior to pegfilgrastim, and the safety profile or the 1980s, the treatment od cancer-related anemia incidence of adverse events was similar to that was based only on red blood cell (RBC) of filgrastim, including bone pain; c) no effect of transfusion when the hemoglobin levels fell body weight was found on duration of severe below 8-9 g/dl. The introduction of recombinant neutropenia; d) a lower risk of febrile neutropenia human erythropoietin in the ‘80s gave the was observed in patients who received opportunity to reduce the need for RBC pegfilgrastim than those given daily filgrastim: transfusions and to improve overall QoL and 11% vs 19% (relative risk 0.56, C.I. 0.35-0.89, possibly prognosis of patients. EPO is a protein p< 0.005); f) a trend towards a lower risk of synthesised in the kidney and, to a lesser extent, hospitalization and use intravenous antibiotics in the liver that binds erythopoietin receptors on was observed in patients treated with surface of bone marrow red cell precursors pegfilgrastim. A recent randomized study in (BFU-e, CFU-e, erythroblasts) and promotes

26 S E C T I O N A erythropoiesis. This glycoprotein hormone has schedule not defined yet, slow onset of a molecular weight of 34 kDa and consists of response, costs, no clear impact on survival and 165 aminoacids; carbohydrates represent risk of thrombovascular events when used to around the 40% of the molecule. Three correct Hb levels beyond anemia. recombinant human EPO has been approved In conclusion, the development of long-acting for anemia in cancer: epoetin alfa, epoetin beta darbepoetin gives the opportunity to simplify the and darbepoetin alfa (Engert A, 2005). Evidence- management of chemotherapy-related anemia based guidelines have been published by ASCO but more data are needed to assess the real cost/ and EORTC about the use of the recombinant benefit ratio and impact on outcome. - human erythropoietin in patients with cancer. The major goals of the erythropoietin therapy is the References correction of chemotherapy-related anemia 1. Biganzoli L, Untch M, Skacel T, Pico JL. Neulast (defined as Hb level < 9-11g/dl), prevent (pegfilgrastim): a once-per-cycle option for the transfusions and possibly improve the QoL. The management of chemotherapy-induced neutropenia. recommended dose of epoetin alfa and beta is Sem Oncol 2004; 31(S8):27-34 150 IU/kg three times a week for a minimum of 4 2. Bohlius J, Langensiepen S, Schwarzer G, et al. weeks that can escalated to 300 IU/kg three Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive mata- times a week for other 4-8 weeks in those analysis. J Natl Cancer Inst 2005;97:489-98 patients who do not respond to the initial 3. Bokemeyer C, Aapro MS, Courdi A, et al. EORTC regimen. An alternative schedule is the guidelines for the use of erythropoietic proteins in administration of 30-40.000 IU once a week in anaemic patients with cancer. Eur J Cancer 2004; order to improve patient compliance (Rizzo et 40:2201-16 al, 2002; Bokemeyer et al, 2004). Darbepoetin 4. Crawford J, Cella D, Cleeland CS, et al. Relationship alfa is a biochemically distinct erythropoietin between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients characterized by an increased carbohydrate receiving epoetin therapy. Cancer 2002; 95:888-95 content, a major number of sialic acid molecules 5. Egert A. Recombinant human erythropoietin in oncology: and a higher molecular weight; these properties current status and further developments. Ann Oncol determine a longer hal-life (about 49 hours) and 2005; June 15 [epub ahead] an increased biological activity compared to 6. Glaspy JA, Jadeja JS, Justice G. Darbepoetin alfa given epoetin alfa or beta. The recommended dose of every 1 or 2 weeks alleviates anemia associated with cancer chemotherapy. Br J Cancer 2002; 87:268-76 darbepoetin is 2.25 ug/kg per week but a dose 7. Glaspy JA, Jadeja JS, Justice G, et al. A randomized, finding study in patients with solid tumours active control, pilot trial of front-loaded dosing regimens showed that the most effective weekly dose is of darbepoetin-alfa for the treatment of patients with 4.5ug/kg (Glaspy et al, 2002). In the same study, anemia during chemotherapy for maliignant disease. the administration of 9 ug/kg every 2 weeks had Cancer 2003;97:1317-20 a comparable efficacy to the weekly dose of 8. Gregory SA, Trumper L. Chemotherapy dose intensity 4.5ug/kg. Other authors found that the doses of in non-Hodgkin’s lymphoma: is dose intensity an emerging paradigm for better outcomes? Ann Oncol 12 ug/kg and 15 ug/kg of darbepoetin alfa allow 2005; 2 [epub ahead] to maintain the efficacy of darbepoetin despite 9. Green MD, Koebl H, Baselga J, et al. A randomized, a longer interval of administration, 3 and 4 weeks, double-blind, multicenter, phase 3 study of fixed-dose, respectively (Kotasek et al, 2002; Glaspy et al, single administration pegfilgrastin vs daily filgrastim in 2003). A recent meta-analyses including 27 patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29-35 prospective randomized trials published 10. Lieschke GJ, Burgess AW. Granulocyte colony- between 1985 and 2002 demonstrated that the stimulating factor and granulocyte-macrophage colony- use of recombinant human erythropoietin stimulating factor. N Engl J Med 1992;327:99–106 reduced significantly the risk of RBC transfusion, 11. Holmes FA, O’Shaughnessy J, Vukelja S, et al. Blinded, mainly in patients with solid tumours and gives randomized, multicenter study to evaluate single some evidence for improving QoL and survival administration of peg-filgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients (Bohlius et al, 2005). Despite these favourable with high-risk stage II or stage III/IV breast cancer. J Clin data, recombinant human erythropoietin is not Oncol 20, 727-31 routinely used in cancer patients for several 12. Ludwig H, Fritz E. Anemia in cancer patients. Semin reasons: limited data (children), best dosing Oncol 1998;25:2-6

27 13. Isidori A, Tani M, Bonifazi F, et al. Phase II study of a 19. Staber PB, Holub R, Linkesch W, et al. Fixed-dose single single pegfilgrastim injection as an adjunct to administration of pegfilgrastim vs daily filgrastim in chemotherapy to mobilize stem cells into the peripheral patients with haematological malignancies undergoing blood of pretreated lymphoma patients. Haematologica autologous peripheral blood stem cell trnaplantation. 2005; 90:225-31 Bone Marrow Transplant 2004;35:889-93 14. Kawakami M, Tsutsumi H, Kumakawa T, et al. Levels of 20. Steidl U, Fenk R, Bruns I, et al. Successful transplantation serum granulocyte colony-stimulating factor in patients of peripheral blood stem cells mobilized by with infections. Blood 1990;76:1962–64 chemotherapy and a single dose of pegylated G-CSF 15. Kotasek D, Albertsson M, John Mackey J, et al. in patients with multiple myeloma. Bone Marrow Randomized, double-blind, placebo-controlled, dose- Transplant 2005; 35:33-6 finding study of darbepoetin alfa administered every 3 21. Siena S, Piccart MJ, Holmes FA, et al. A combined (Q3W) or 4 (Q4W) weeks in patients with solid tumours. analysis of two pivotal randomized trials of a single dose Proc Am Soc Clin Oncol 2002; (abstr 1421) of pegfilgrastim per chemotherapy cycle and daily 16. Molineux G, Kinsler O, Briddel B, et al. A new form of filgrastim in patients with stage II-IV breast cancer. filgrastim with sustained duration of and enhanced ability Oncology Reports 2003;10:715-24 to mobilize PBPC in both mice and humans. 22. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and Experimental hematology 1999; 27:1724-34 subsequent cycle use of pegfilgrastim prevents febrile 17. Ozer H, Armitage JO, Bennett CL, et al. 2000 update of neutropenia in patients with breast cancer: a multicenter, recommendations for the use of hematopoietic colony- double-blind, placebo-controlled phase III study. J Clin stimulating factors: evidence-based, clinical practice Oncol 2005; 23:1178-84 guidelines. J Clin Oncol 2000;18:3558–3585 23. Waladkhani AW. Pegfilgrastim: a recent advance in the 18. Rizzo JD, Lichtin AE, Woolf SH, et al Use of epoetin in prophylaxis of chemotherapy-induced neutropenia. Eur patients with cancer:evidence-based clinical practice J Cancer care 2004;13:371-9 guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;19:4083-107

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