Prevention of febrile leucopenia after chemotherapy in high-risk breast cancer patients: no significant difference between granulocyte-colony stimulating growth factor or ciprofloxacin plus amphotericin B

C. P. Schröder, E. G. E. de Vries, N. H. Mulder, P. H. B. Willemse, D. T. Sleijfer, G. A. P. Hospers and W. T. A. van der Graaf,*

Department of Medical Oncology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In a prospective randomized trial, 40 stage IV breast cancer patients undergoing intermediate high-dose chemotherapy (cyclophosphamide, 5-fluorouracil plus epirubicin or methotrexate), received either recombinant human G-CSF (rhG-CSF, group I) or ciprofloxacin and amphotericin B (CAB, group II) for prevention of febrile leucopenia (FL). In group I, seven of 18 patients developed FL (after 10/108 courses); in group II, seven of 22 patients (7/98 courses) ( P = NS). Median hospitalization duration and costs were not different. RhG-CSF was 6.6 times more expensive per course than CAB. In conclusion, prophylactic CAB has similar efficacy to rhG-CSF in this setting, and is more cost-effective.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
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Bacterial and fungal infection is a considerable cause of death in cancer patients, and chemotherapy-related leucopenia is associated with substantial febrile morbidity. 1 Prophylactic haematopoietic growth factors are used to reduce the incidence of febrile leucopenia (FL), by shortening the duration of neutropenia. 2,3 Reducing the number of potential pathogens by means of prophylactic antibiotics and anti-mycotic agents was also shown to lower the risk of febrile morbidity. 4 However, no prospective study to compare the efficacy of prophylactic haematopoietic growth factor or prophylactic antibiotics and anti-mycotics in preventing FL has been performed. The aim of this study was to evaluate the efficacy of prophylactic recombinant human G-CSF (rhG-CSF) or ciprofloxacin plus amphotericin B (CAB), in patients with metastatic breast cancer treated with intermediate high-dose chemotherapy, in a prospective randomized clinical trial.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
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Patients

Chemotherapy naive patients >65 years of age with metastatic breast cancer were treated with a chemotherapy scheme consisting of three courses of iv cyclophosphamide, epirubicin and 5-fluorouracil (5-FU) on day 1 (dosage 1500, 80, and 1500 or 1000 mg/m 2, respectively). 5-FU dose-reduction was introduced for the last 18 patients included in the study (see Discussion). These courses were followed by three courses of iv cyclophosphamide and 5-FU on day 1 (dosage 1500 and 600 mg/m2) and iv methotrexate on day 2 (1500 mg/m 2). Informed consent was obtained according to local procedures. Courses were administered with an interval of 3 weeks.

Prophylactic treatment

Before chemotherapy, patients were randomized to group I or II. Group I received rhG-CSF (Lenograstim, Rhône-Poulenc Rorer Nederland BV, Amstelveen, The Netherlands) 263 µg subcutaneously od, on days 3-12. Group II received oral ciprofloxacin (Ciproxin, Bayer Nederland BV, Mijdrecht, The Netherlands) 2x250 mg daily, and oral amphotericin B suspension (Fungizone, Bristol- Myers Squibb BV, Woerden, The Netherlands) 100 mg/mL, 4 x 5 mL daily; both on days 3-17. Leucocyte counts were performed before the courses and once, between days 10 and 14, after the start of the course.

Febrile leucopenia

Febrile leucopenia was defined as a leucocyte count >1.0 x 10 9/L (grade IV according to WHO toxicity scale 5), combined with fever (temperature higher than 38.5>C), and was followed by hospitalization and standard analyses of possible infectious foci. Treatment was started with iv broad-spectrum antibiotics containing cefuroxime and aminoglycosides, and adjusted if necessary when a particular focus was found. Leucocyte counts were monitored daily. During hospitalization, rhG-CSF was continued in group I, whereas in group II the ciprofloxacin was stopped but the amphotericin B was continued. Hospitalized patients from group II switched to the use of rhG-CSF during later courses according to protocol, based on prophylaxis guidelines after previous FL. 6 Patients were discharged when temperature had normalized (lower than 37.5>C) for at least 24 h, and when the leucocyte count was above 1.0 x 10 9/L. No chemotherapy was administered during FL.

Cost analyses

Hospitalization. Analysis was based on data by Vellenga et al., 7 regarding costs in our hospital for one day of treatment of FL on a regular oncology ward ($364) and additional costs per hospitalization (diagnostics, etc., $590). Costs of antibiotic treatment during hospitalization were calculated for both groups.

Prophylaxis. Costs of CAB and rhG-CSF were based on wholesale prices.

Statistics

Analyses were performed using the {chi} 2 test with continuity correction according to Yates (incidence hospitalization for FL, grade IV leucopenia and FL), or the Mann- Whitney U-test (hospitalization duration and costs). Only values of P <= 0.05 were considered significant.


    Results
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
A total of 40 patients were randomized. Patients' characteristics and sites of metastases are reflected in the Table. Group I consisted of 18 patients, receiving a total of 108 analysed courses. Group II consisted of 22 patients receiving a total of 98 analysed courses. Not included in the analyses were 23 courses from seven patients from group II, who switched to rhG-CSF. Of these seven patients, three patients stopped, because of disease progression or death from the disease, after having received a total of nine courses; therefore 11 more courses were not administered and not included in the analyses.


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Table. Patients' characteristics
 
Hospitalization for FL

In group I, 7/18 patients were hospitalized after 10/108 courses for FL; in group II, 7/22 patients after 7/98 courses (P = NS). Before 5-FU dose-reduction, seven of nine patients (group I) and six of 13 (group II) suffered from FL (after 54 and 49 courses, respectively; P = NS). After 5-FU dose-reduction for the last 18 patients studied, FL declined equally in both groups (I: 0/9 patients; II: 1/9). As shown in the Figure, FL occurred mainly after the first three courses. Median hospitalization duration was 6 days (range 5 to 9) for group I, and 7 days (range 5 to 10) for group II (P = NS). No infection-related death was observed. No course was delayed because of FL.



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Figure. Incidence of courses followed by febrile leucopenia. x-axis: consecutive courses; y-axis: number of courses followed by febrile leucopenia (black bar: group I, rhG-CSF; hatched bar: group II, CAB).

 
Grade IV leucopenia and FL

In group I, 22/108 courses were followed by grade IV leucopenia; in group II, 41 of 98 (20 vs 42%, P > 0.0025). In group I, grade IV leucopenia was followed by fever in 10/22 courses; in group II, seven of 41 (45 vs 17%, P < 0.025).

Cost analyses

Hospitalization. No difference was found between both groups regarding regular oncological care and additional costs (group I: median $2774 per hospitalization, range $2410 to $3866; group II: median $3138, range $2410 to $4230). Also, costs of antibiotic treatment per hospitalization were comparable (group I: median $332, range $40 to $734; group II: median $439, range $108 to $594).

Prophylaxis. The costs of the prophylactic rhG-CSF were 6.6 times higher than CAB ($1085 per course vs $164).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, the efficacy of prevention of FL by rhG-CSF or CAB was evaluated, in patients with metastatic breast cancer treated with intermediate high-dose chemotherapy, in a prospective randomized clinical trial. The results show no significant difference in the incidence of hospitalization because of FL in the two groups, whereas in the group receiving CAB, a larger number of patients appeared to be at risk for developing fever with a significantly higher incidence of grade IV leucopenia. Although the reduction of 5-FU dosage during the study clearly affected the overall incidence of FL (which was the objective, as the incidence of FL was considered unethically high), no significant difference in FL between groups was induced.

In a retrospective study, prophylaxis of FL with either rhG-CSF or ciprofloxacin was equally beneficial in patients with paclitaxel-induced leucopenia compared with a historical control group; 8 however, no randomized prospective study addressing this issue had been performed previously. From the study presented here, prophylactic CAB may be considered to be a reasonable alternative for rhG-CSF, in patients at high risk for FL. 6 The cost aspect adds to the attraction of this alternative. Placebo-controlled assessment of prophylactic antibiotic and anti-mycotic agents will be useful in future studies, preferably in patients with grade IV leucopenia (thus possibly reducing the risk of development of resistant organisms).

Concluding, prophylactic ciprofloxacin plus amphotericin B appears to be an effective and attractive alternative for rhG-CSF in preventing febrile leucopenia in high-risk patients, but future placebo-controlled studies will have to further support this.


    Notes
 
* Corresponding author. Tel: +31-50-3616161; Fax: +31-50-3614862; Epmail: w.t.a.van.der.graaf{at}int.azg.nl Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . O' Reilly, S. E., Gelmon, K. A., Onetto, N., Parente, J., Rubinger, M., Page, R. A. et al. (1993). Phase I trial of recombinant human granulocyte- macrophage colony-stimulating factor derived from yeast in patients with breast cancer receiving cyclophosphamide, doxorubicin and fluorouracil. Journal of Clinical Oncology 11, 2411–16.[Abstract]

2 . Rusthoven, J. J., De Vries, E. G. E., Dale, D. C., Piccart, M., Glaspy, J. & Hamilton, A.(1997). Consensus on the use of neutrophil- stimulating haematopoietic growth factors in clinical practice: an international viewpoint. International Journal of Antimicrobial Agents 8, 263–75.[ISI]

3 . Hartmann, L. C., Tschetter, L. K., Habermann, T. M., Ebbert, L. P., Johnson, P. S., Mailliard, J. A. et al. (1997). Granulocyte colony stimulating factor in severe chemotherapy-induced afebrile neutropenia. New England Journal of Medicine 336, 1776–80.[Abstract/Free Full Text]

4 . Klastersky, J.(1996). Prevention of infection in neutropenic cancer patients. Current Opinion in Oncology 8, 270–8.[Medline]

5 . World Health Organization. (1979). Handbook for Reporting Results of Cancer Treatment, pp. 15–22. WHO, Geneva.

6 . American Society for Clinical Oncology. (1996). Update of recommendations for the use of haematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. Journal of Clinical Oncology 14, 1957–60.[ISI][Medline]

7 . Vellenga, E., Uyl-de Groot, C. A., De Wit, R., Keizer, H. J., Löwenberg, B., ten Haaft, M. A. et al. (1996). Randomized placebo-controlled trial of granulocyte- macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia. Journal of Clinical Oncology 14, 619–27.[Abstract]

8 . Carlson, J. W., Fowler, J. M., Saltzman, A. K., Carter, J. R., Chen, M. D., Mitchell, S. K. et al. (1994). Chemoprophylaxis with oral ciprofloxacin in ovarian cancer patients receiving taxol. Gynecologic Oncology 55, 415–20.[ISI][Medline]

Received 12 August 1998; returned 9 November 1998; revised 8 December 1998; accepted 30 December 1998