Department of Medical Oncology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
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Abstract |
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Introduction |
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Materials and methods |
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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
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.
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Results |
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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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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).
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Discussion |
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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.
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Notes |
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References |
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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, 26375.[ISI]
3
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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
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of Medicine 336, 177680.
4 . Klastersky, J.(1996). Prevention of infection in neutropenic cancer patients. Current Opinion in Oncology 8, 2708.[Medline]
5 . World Health Organization. (1979). Handbook for Reporting Results of Cancer Treatment, pp. 1522. 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, 195760.[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, 61927.[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, 41520.[ISI][Medline]
Received 12 August 1998; returned 9 November 1998; revised 8 December 1998; accepted 30 December 1998