Guidelines have been issued for the use of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) (1,2). The stimulus for the development of these guidelines followed the 1991 Food and Drug Administration (FDA) approval for the clinical use of rHuG-CSF and rHuGM-CSF in the United States. The uptake and use of these agents was rapid and deep. By 1994, use of colony-stimulating factors (CSFs) had expanded to 10% of some United States-based hospital budgets and, of concern, survival rate among the patients so treated did not seem to have improved. The widespread use of these agents and the subsequent economic impact stimulated the American Society of Clinical Oncology (ASCO) to publish its first clinical practice guidelines in 1994 (3). These guidelines were updated in 1996 (4) and in 2000 (1). The European Society for Medical Oncology (ESMO) recommendations for the use of these hematopoietic growth factors (HGFs) appeared in 2001 (2).

The more frequent use of these HGFs has been in either primary or secondary prevention of febrile neutropenia or the treatment of febrile neutropenia. These indications

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

are independent of its use in other conditions, such as the mobilization of peripheral blood progenitor cells (PBPCs) to support high-dose chemotherapy regimes.

Febrile neutropenia has been a dose-limiting effect for a wide range of chemotherapies. The magnitude of neutropenia and infection has been related to chemotherapy intensity, although host-related and disease-related factors have a role. In general, febrile neutropenia has been treated by hospitalization and the administration of empiric antibiotic therapy, often for several days. In the initial randomized clinical trial used for FDA licensing in the United States, the observed incidence of febrile neu-tropenia was approx 40% (5). Based on this information, a guideline for the use of CSFs was formulated and stated that with such a rate of febrile neutropenia, use of CSFs for primary prophylaxis was warranted.

The 40% rate of febrile neutropenia related to a series of patients with small-cell lung cancer (SCLC) treated with cyclophosphamide 1 g/m2, doxorubicin 50 mg/m2, and etopo-side 120 mg/m2 on d 1,2, and 3 of the chemotherapy cycle. Patients were randomized to receive either rHuG-CSF or placebo after chemotherapy. The incidence of neutropenia with fever in the patients receiving placebo was 57%, and in the rHuG-CSF-treated patients it was 28%. The median duration of a neutrophil count < 0.5 x 109/L was 6 d in the patients receiving placebo and 3 d in patients treated with rHuG-CSF; the duration of fever with neutropenia was 5 d in patients receiving placebo and 4 d in patients treated with rHuG-CSF. Patients receiving placebo had 4 d of hospitalization compared with 2 d for patients receiving rHuG-CSF. An analysis for cost effectiveness was in favor of the use of rHuG-CSF in primary prevention. It was concluded that there was a 50% reduction in the incidence of febrile neutropenia, antibiotic use, and hospitalization and that these reductions offered substantial economic as well as clinical benefit. This study was pivotal in the FDA approval process for rHuG-CSF; however, the cytotoxic doses used in the Crawford et al. (5) study are higher than those used in contemporary regimes.

The 2000 update of recommendations by the ASCO describes a number of the commonly used chemotherapy regimes and the reported rates of neutropenia, fever, and sepsis. The guideline note that many new chemotherapeutic agents, which include the taxanes, topoisomerase 1 inhibitors, and vinorelbine, have been used as part of these regimes in the latter part of the 1990s. The guidelines emphasize that a few of the commonly used combination drug regimes produce significant complications relating to neutropenia. The exception, of course, is when relapsed or refractory disease was being treated.

The basic thrust of the updated recommendations is that the routine use of CSFs for primary prophylaxis is not justified on the basis of cost savings with any of the current routine chemotherapy regimes. It notes that cost analyses have shown that CSFs save money when the risk of febrile neutropenia is greater than 40% but that no routine regimes have rates greater than 15%. (This excludes induction treatment of acute leukemia.) This analysis is based on economic modeling using costs of hospitalization for episodes of febrile neutropenia at US $10,000. The guidelines suggest that CSFs could be routinely used with justification if they cost substantially less.

The guidelines note that for secondary prophylaxis, the rate of febrile neutropenia could be on the order of 40% and would justify use of CSFs but suggest that dose modification would be a medically acceptable alternative on the basis that major clinical benefit of maintaining delivery of previously toxic levels of chemotherapy with CSF has not been demonstrated.

Similarly, the ESMO recommendations note that despite relatively high rates of low neutrophil counts during standard-dose chemotherapy regime (apart from acute leukemia), the rates of febrile neutropenia and other complications and mortality rates are relatively low for most standard chemotherapies. ESMO similarly concludes that these rates do not justify the routine use of HSFs.

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