Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923)

V. C. G. Tjan-Heijnen1,+, S. Caleo2, P. E. Postmus3, A. Ardizzoni4, J. T. M. Burghouts5, E. Buccholz6, B. Biesma5, T. Gorlia2, R. Crott2, G. Giaccone3, C. Debruyne2 and C. Manegold On behalf of the European Organisation for Research Treatment of Cancer (EORTC)—Lung Cancer Group and Health Economics Unit6

1 University Medical Centre Nijmegen, Nijmegen, The Netherlands; 2 EORTC Data Center, Brussels, Belgium; 3 Vrije Universiteit Medical Center, Amsterdam, The Netherlands; 4 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; 5 Bosch Medicentrum Groot Ziekengasthuis, ’s-Hertogenbosch, The Netherlands; 6 Thoraxklinik Rohrbach, Heidelberg, Germany

Received 24 June 2002; revised 16 September 2002; accepted 22 October 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL).

Patients and methods:

Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed.

Results:

In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (–)1.713–2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810–5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10–20% for FL per cycle.

Conclusions:

Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.

Key words: antibiotic prophylaxis, chemotherapy, economic evaluation, small-cell lung cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The most frequent dose-limiting toxicity of chemotherapy is febrile leukopenia (FL). Cyclophosphamide, doxorubicin and etoposide (CDE), one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), is associated with an incidence of FL varying from 43% to 77% [13]. The mainstay of treatment for FL is hospitalisation and intravenous (i.v.) antibiotics. The administration of oral prophylactic antibiotics may have clinical benefits for patients by reducing the incidence of FL and at the same time produce cost savings. Economic evaluation is a useful tool to help determine whether it is worthwhile to give prophylactic antibiotics in terms of cost, and benefits to patients and to the health care system.

We have previously reported the results of a randomised trial in patients with SCLC treated with CDE chemotherapy in which the role of prophylactic antibiotics was evaluated [1]. We demonstrated that with prophylactic antibiotics the incidence of FL, number of documented infections, use of therapeutic antibiotics and hospitalisations were reduced by approximately 50%, with a reduced number of infectious deaths. We report here the results of the economic evaluation of this prospectively randomised trial. Importantly, we also performed sensitivity analyses to place the outcome in a broader perspective.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A more detailed report of the clinical trial has been reported elsewhere [1, 4]. In brief, patients with chemo-naïve SCLC with a European Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomised to standard-dose CDE (cyclophosphamide 1000 mg/m2, day 1; doxorubicin 45 mg/m2, day 1; etoposide 100 mg/m2, days 1–3, i.v., q 3 weeks, five times) or to intensified CDE chemotherapy (125% dose, q 2 weeks, four times; with filgrastim 5 µg/kg/day, days 4–13) to assess the impact on survival (n = 244). Patients were also randomised to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, b.i.d., days 4–13) or to placebo in a 2 x 2 factorial design (n = 161) with as primary end point the incidence of FL during the first cycle. In cases of FL, prophylaxis was interrupted and replaced by i.v. broad-spectrum antibiotics. After inclusion of 161 eligible patients, the antibiotic/placebo part of the trial was prematurely terminated on advice from an independent data monitoring committee. Randomisation was done using the minimisation technique stratifying patients according to their institution, age (>60 versus <=60 years) and stage of disease [limited disease (LD) versus extensive disease].

Economic evaluation
Prospective economic evaluation was conducted alongside the trial. This evaluation concerned only the randomisation of prophylactic antibiotics versus placebo. All prices were adjusted to 1998 prices. No discounting of costs was necessary because treatments were given over a period of 4–6 months. Although the clinical trial was conducted in 13 centres throughout Europe, Heidelberg in Germany (GE) and ’s-Hertogenbosch in The Netherlands (NL) were both expected to recruit the highest number of patients and thus were chosen for the cost assessments (n = 82, 51% of total).

The objective of the analysis was to determine whether the costs of prophylactic antibiotics were offset by cost savings associated with the expected decrease in incidence of FL, fever, documented infections, days of i.v. antibiotics and days of hospitalisation. Protocol-driven costs were not included in the analysis.

The average clinical effect and costs were determined for each arm. The economic evaluation was primarily based on the incidence of FL per patient. In addition, we looked at the incidence of FL per cycle of delivered chemotherapy.

Uncertainty analysis. The skewness of cost data means that producing confidence intervals by parametric methods is inappropriate. Therefore, the cost data were analysed using the non-parametric bootstrap, specifically employing the bias corrected and accelerated bootstrapping method [5]. The number of bootstrap replications for each sample was 5000. These calculations yielded an average cost per patient and cycle for both arms with their corresponding 95% confidence interval (CI). The difference in average cost between the antibiotic and placebo arms for both sites was also calculated in this manner.

Resource utilisation. Resource use included those items that were associated with direct medical treatment costs and did not include patient out-of-pocket costs, non-medical costs, indirect costs or quality-of-life issues.

Unit cost data. It was assumed that patients were treated as public patients. Unit costs were applied from the health insurance and hospital perspectives (Table 1). Where it was not possible to obtain the pertinent hospital prices for some items, such as pharmaceuticals, which are subject to negotiated prices and considered commercially sensitive information, the listed tariff prices had to be used. The costs were expressed in Euros (1 Euro = 1.96 DM = 2.20 f = 0.86 US $ as of 28 June 2001).


View this table:
[in this window]
[in a new window]
 
Table 1. Sources of unit costs
 
Hospitalisations. The per diem rates in both countries are hospital specific and based on their annual budgets. Hospital budgets are influenced by their relative size, whether it is a university hospital and also whether the hospital is specialised in certain diagnostic areas (e.g. thoracic clinic). In Heidelberg (GE), the rate for 1 day (no overnight stay) and also per diem (including overnight stay) was 280 Euros, while the per diem rate of intensive care was 765 Euros. The figures in ’s-Hertogenbosch (NL) were 170, 625 and 1416 Euros, respectively. Hospitalisation for chemotherapy administration was not taken into account, as this was considered to be comparable for both arms.

Pharmaceuticals. The unit costs of the prophylactic antibiotics were applied as if the patient had bought the full box of antibiotics from their local pharmacy. A course of prophylactic antibiotics costs 180 Euros in GE and 110 Euros in NL. National public tariff prices were applied to all medications.

Transfusions. In GE, the cost of transfusion with either one unit of red blood cells or one unit of platelets (six donors) was 50 Euros, while in NL this was 86 and 273 Euros, respectively.

Diagnostic tests. For GE, we used the tariffs from ‘DKG-NT Band 1, Tarif der Deutschen Krankenhausgesellschaft’. For NL, we used the listed ‘Centraal Orgaan Tarieven Gezondheidszorg’ (COTG) tariffs, with an additional physician’s fee when these tests were carried out in the outpatient setting.

Microbial cultures. In GE, the cost of a single culture depends upon the number of tests that need to be carried out (ranging from 20 Euros to 42 Euros). In NL, the costs of the tests depend upon whether the sample test was positive (52 Euros) or negative (31 Euros), regardless of the source of the culture.

Sensitivity analyses
Threshold and three-way sensitivity analyses were performed.

Threshold analysis. The following formula was used to calculate cost neutrality [68]:

(FL risk x relative reduction) x (unit cost x days hospitalisation) = (unit cost x days prophylaxis)

On the left-hand side of the equation, the cost savings of prophylactic antibiotics are determined by taking ‘the avoided number of FL episodes’ times ‘the average cost of hospitalisation per FL episode’. On the right-hand side of the equation, the costs of prophylaxis are calculated. There is cost neutrality in cases where the cost savings are equal to the cost of prophylaxis itself. In a threshold analysis, all parameters but one are kept unchanged. The threshold of this parameter is the value at which point there is cost neutrality. Prophylactic antibiotics will produce cost savings, in cases where the parameters on the left-hand side of the equation do in reality have values above their threshold value, or in cases where the values on the right-hand side of the equation have values below their threshold value.

The numbers in the threshold and sensitivity analyses refer to costs and incidences per cycle, in contrast to the efficacy and economic evaluation in which primarily incidences per patient were used as was specified in the prospective trial.

The baseline assumptions for the threshold and sensitivity analyses were based on the incidence of FL, the efficacy of prophylaxis (relative reduction in FL) and the duration of hospitalisation due to FL as seen in the main trial, and not those of only one or two subgroups (GE and/or NL), as such subgroups may not be representative of the whole patient population [6].

Thresholds were calculated for both GE and NL separately, as the unit costs were not the same for both countries. The costs used were those that determined the outcome from a health insurance perspective. Cost variations in cultures and diagnostic tests were not included for NL, as these accounted for <5% of total costs.

Three-way sensitivity analysis. A three-way sensitivity analysis was conducted by varying the average baseline risk for hospitalisation due to FL per cycle, the average cost of a hospitalisation due to FL and the cost of antibiotic prophylaxis per cycle. The baseline risk for hospitalisation due to FL was varied from 10% to 50%, by step increments of 10%. The average cost of hospitalisation due to FL was varied from 2000 to 20 000 Euros, with step increments of 2000 Euros. The cost of prophylaxis per cycle was varied from 100, 250, 500 to 1000 Euros.

The hospitalisation cost for which there is cost neutrality can be calculated per cost of prophylaxis for one baseline risk for hospitalisation due to FL (threshold point), but also over a range of baseline risks for FL (threshold line). Several threshold lines can be calculated for different unit costs of prophylaxis. Any combination in the area above a given threshold line favours prophylaxis on a cost basis.

Such three-way sensitivity analysis enables extrapolation of results to different countries and to different chemotherapy regimens with different risks for FL.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Efficacy
The baseline patient characteristics were comparable for both sites, except for more LD in patients from GE (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics at baseline
 
In almost all instances, each of the subgroups, when compared separately to the main trial results, had a similar rate of outcome, although there were some differences, especially in GE (Tables 3 and 4).


View this table:
[in this window]
[in a new window]
 
Table 3. Clinical outcome comparisons for the whole trial minus Heidelberg (All-GE) and Heidelberg (GE)
 

View this table:
[in this window]
[in a new window]
 
Table 4. Clinical outcome comparisons for the whole trial minus ’s-Hertogenbosch (All-NL) and ’s-Hertogenbosch (NL)
 
In the main clinical trial (n = 161), 48 episodes of FL in total occurred in the placebo arm (15% of 320 chemotherapy cycles) versus 23 in the antibiotics arm (7% of 335 cycles). This reflects a 55% relative decrease in risk for FL (taking all cycles into account). In NL, the average incidence of FL per cycle was 16% versus 5% in the antibiotics arm, which is comparable with the main trial. However, in GE the outcome was quite different with incidences of 8% and 9%.

For GE, there was a prolonged duration of hospitalisation due to FL and longer i.v. antibiotic treatment in the prophylactic arm (Table 5). In NL, the average duration of i.v. antibiotics in the placebo arm was higher than in the main trial.


View this table:
[in this window]
[in a new window]
 
Table 5. Comparison of duration of FL and of the main resource utilisations for the whole trial minus Heidelberg (All-GE) and Heidelberg (GE) and for the whole trial minus ’s-Hertogenbosch (All-NL) and ’s-Hertogenbosch (NL)
 
Finally, the average number of chemotherapy cycles for patients treated in GE (regardless of treatment arm) was 3.71 [standard deviation (SD) = 1.32], whilst in NL it was 4.33 (SD = 0.69); P <0.01.

Costs
In NL, there were no patients who required intensive care, whereas two patients in GE had spent time in intensive care. One of these patients (in the placebo arm) spent 30 days in intensive care at a cost of 22 959 Euros.

The cost of treating an episode of FL in either GE or NL with i.v. antibiotics was about the same on a daily basis (44 and 45 Euros, respectively), although different antibiotics were used. Gentamicin and cefotiam were often used to treat FL in Heidelberg. In contrast, at ’s-Hertogenbosch, cefuroxime and tobramycin were most often given.

Relatively more patients underwent cultures and diagnostic tests in the placebo and antibiotics arms in NL compared with the placebo and antibiotics arms in GE (Table 6).


View this table:
[in this window]
[in a new window]
 
Table 6. Total resource use in Heidelberg (GE) and ’s-Hertogenbosch (NL)
 
From a health insurance perspective, there was an average cost saving of 35 Euros [95% CI (–)1713–2263] per patient in favour of giving prophylactic antibiotics in GE (not significant) (Table 7). The cost difference in NL was 2706 Euros (95% CI 810–5948) per patient, demonstrating savings in favour of prophylactic antibiotics of nearly 45% (Table 7). This correlated with cost savings in NL of 605 Euros per cycle.


View this table:
[in this window]
[in a new window]
 
Table 7. Average costs (Euro) of all patients included for Heidelberg (GE) and ’s-Hertogenbosch (NL), from both a health insurance perspective and the hospital perspective
 
From a hospital perspective, there is a similar overall picture with again a cost reduction of approximately 45% per patient in NL (Table 7), and cost neutrality for GE.

In GE, the average cost of treating an episode of FL was higher in patients in the antibiotics arm compared with the placebo arm (Table 8), largely due an unexpected longer duration of FL and hospitalisation due to FL in the antibiotics arm (Table 5). In contrast, in NL the cost difference incurred per patient who experienced FL was 37% [1 – (2485/3970)] in favour of the antibiotics arm (Table 8).


View this table:
[in this window]
[in a new window]
 
Table 8. Cost of treating FL for Heidelberg (GE) and ’s-Hertogenbosch (NL), health insurance perspective
 
Cost-effectiveness
For the first cycle in GE, prophylactic antibiotics reduced the absolute risk of FL by 6% (down from 15%). It also saved 274 Euros per patient. In NL, prophylactic antibiotics reduced the absolute risk of FL by 7% (down from 19%) in the first cycle. It also saved 676 Euros per patient.

In subsequent cycles in GE, prophylactic antibiotics did not reduce the risk of FL. With effectiveness the same, a cost minimisation analysis yields a saving of 28 Euros per patient. In NL, prophylactic antibiotics reduced the absolute risk of FL by 21% (down from 38%). It also saved 892 Euros per patient.

In both cases treatment with prophylactic antibiotics was the dominant strategy as it results, at the same time, in a risk reduction and lower costs.

Threshold and sensitivity analysis
In the sensitivity and threshold analyses the numbers refer to incidences per cycle.

In GE, prophylaxis produces cost savings in the following situations: (i) a baseline risk for FL of >20% per cycle; (ii) a relative reduction in risk of FL of >71%; (iii) costs of hospitalisation due to FL of >377 Euros per day; (iv) a hospital stay >8 days; (v) a reduced cost of prophylaxis due to a unit cost price of <13 Euros per day or (vi) a shorter need for prophylaxis of <7 days (Table 9). The figures for NL are 6%, 20%, 231 Euros, 2 days, 30 Euros and 27 days, respectively (Table 9), with better threshold levels.


View this table:
[in this window]
[in a new window]
 
Table 9. Threshold analysis for The Netherlands (NL) and Germany (GE) based on rates from main clinical trial
 
In addition, a three-way sensitivity analysis was conducted (Figure 1). Any combination in the area above a given threshold line favours prophylaxis on a cost basis. For example, with an average hospitalisation cost for FL of 4000 Euros, prophylaxis at the cost of 100 Euros would be cost saving for all baseline risks, whereas with prophylaxis at a cost of 1000 Euros cost savings occur only at a baseline risk for FL of >47%.



View larger version (22K):
[in this window]
[in a new window]
 
Figure 1. Three-way sensitivity analysis based on rates of the main clinical trial. The effectiveness of prophylaxis in reducing FL is assumed to be 53% per cycle. Threshold lines are displayed for different costs of prophylaxis (100–1000 Euros).

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To our knowledge, this is the first economic evaluation of the cost savings of prophylactic antibiotics. This prospective evaluation was performed at two centres, in GE and NL, which accrued together 51% of the patients of a randomised trial evaluating prophylactic antibiotics during CDE chemotherapy in SCLC. Determination of resource utilisation and the associated unit costs required site visits; thus, it was not feasible both from a practical and funding perspective to visit all the centres included in the trial. It was demonstrated that with prophylactic antibiotics the incidence of FL, number of documented infections, use of therapeutic antibiotics and hospitalisations due to FL were decreased by approximately 50%, along with a reduced number of infectious deaths (6% versus 0%) [1]. In GE, the use of prophylactic antibiotics was cost neutral, while in NL prophylaxis incurred cost savings of 2706 Euros (95% CI 810–5948) per patient, i.e. 605 Euros per cycle, demonstrating savings in favour of prophylactic antibiotics of nearly 45% of average costs in the placebo arm.

The different outcome according to centre indicates that differences in clinical parameters (more LD in GE), change due to the relatively small sample size per centre, patient management and financing mechanisms of health care systems influence cost results. In NL, the clinical outcome was similar to that of the main trial. However, in GE the incidence of FL was more or less the same for both treatment arms. Consequently, no difference in costs was observed in GE.

For straightforward economic evaluations, it is not uncommon to evaluate only one or two subgroups of patients because it is not feasible from a practical viewpoint to evaluate all patients, especially not in a multicentre international trial. Of note, the most important reason for performing an economic evaluation is to obtain the costs of relevant variables (in this case, of prophylaxis and of treating FL). These cost data are essential in order to perform sensitivity analyses, of which the outcome is more important than the outcome of the economic evaluation, performed in a subgroup of patients. To estimate the variations in costs between various countries, one should preferably consider the costs of more than one subgroup. For that reason, we evaluated the costs in two different countries.

It should be noted that the clinical parameters of the main trial were used for the sensitivity analyses. The numbers from the main trial were considered to be more accurate and representative of the real efficacy of prophylactic antibiotics. The same method was used for the pivotal ‘granulocyte colony-stimulating factor (G-CSF) versus placebo’ trial [2], with an economic evaluation in a subgroup of patients [7], but with (frequently quoted) sensitivity analyses based on the results of the main clinical trial [6, 7].

For the sake of simplicity, in the sensitivity analyses only hospitalisations for FL were included [5]. We accept that the threshold values are hereby underestimated, which is also stressed by others [9].

Recently, it was reported that (out-patient) treatment of FL by oral broad-spectrum antibiotics may be feasible [10, 11]. However, for patients already receiving prophylactic antibiotics the optimal choice of antibiotic treatment in the case of FL has not yet been clarified. Therefore, we did not implement this variable in our sensitivity analyses.

From a health insurance perspective, cost savings largely depend on the costs of hospitalisation versus those of prophylaxis. In the threshold analysis it was demonstrated that for the two countries, with the same baseline assumptions, the thresholds reflecting cost neutrality are quite different. In GE, the unit cost price of prophylaxis was higher, while the unit cost price of hospitalisation was lower compared with NL, making prophylaxis for NL more cost saving.

Three-way sensitivity analysis clearly demonstrates that for antibiotic prophylaxis costs of <=500 Euros, cost savings will incur over a broad range of baseline risks for FL, i.e. a risk above 10–20% for FL per cycle. Costs of antibiotic prophylaxis and hospitalisations will fall in this range in most countries.

Importantly, these sensitivity analyses indicate that the strategy of antibiotic prophylaxis may be useful, both from a clinical and a cost–benefit viewpoint, to other regimens and other tumour types with an increased risk for FL.

Prophylactic G-CSF is an alternative way of preventing FL or febrile neutropenia (FN). The efficacy of G-CSF and antibiotic prophylaxis appears to be comparable [13, 12, 13], although for G-CSF a reduction in infectious mortality has never been reported [2, 3]. The American Society of Clinical Oncology (ASCO) recommended that primary administration of CSFs should be reserved for patients with an expected incidence of FN >=40% [14]. In our trial the overall incidence of FL in the placebo arm was not that high (25% in the first cycle and 15% over all cycles). This lower incidence is in line with what was reported by others [15, 16], implying that for the majority of (SCLC) patients treated by standard-dose chemotherapy primary G-CSF prophylaxis may not be indicated.

In fact, this 40% threshold remains somewhat confusing, as it was not based on clinical grounds [17]. This threshold was based on a sensitivity analysis, which used as its parameters a 50% efficacy of G-CSF in preventing FN in the first cycle, an average cost of $10 000 (11 628 Euros) per hospitalisation for FN and an average cost of $2000 (2326 Euros) per cycle for G-CSF prophylaxis [6].

This threshold of 40% only holds true for the cost prices used above. However, the actual cost prices may vary enormously. The Canadian Coordinating Office for Health Technology Assessment estimated the costs of treating an episode of FN at US $6000 (6980 Euros) [18]. With this lower hospitalisation price, the use of G-CSF would be cost neutral when the risk of FN is 50.9%. Other studies reported hospitalisation costs of $4000 (3440 Euros) [16] and $7464 (8680 Euros) for 6 days of hospitalisation due to FL [15]. In our study, we demonstrated also that applying the cost of one country (1680 Euros for 6 days hospitalisation in GE) to another (3750 Euros for NL) underestimates the complexity of what determines such thresholds.

In the reported economic analyses of G-CSF [68, 13, 15, 16], the cost of G-CSF was >1000 Euros per cycle. In general, with cost of prophylaxis of >1000 Euros, cost savings will not occur in the range of baseline risks for FL as seen during standard-dose chemotherapy (Figure 1).

Another important issue is that the economic and sensitivity analyses concerning G-CSF are based on the risk of FN in the first cycle only, while prophylaxis will generally be continued to the end of chemotherapy. In SCLC, the incidence of FN/FL during the first cycle is in fact much higher than in subsequent cycles [13]. In our trial, the risk for FL in the placebo arm was 25% for the first cycle, but only 15% over all cycles [1]. This declining risk through later cycles may be due to improved performance status, patient selection and tumour response with less risk for post-obstructive pneumonia. This may indicate that primary G-CSF or antibiotic prophylaxis in certain circumstances and with certain unit cost prices may be cost-effective for the first cycle but not necessarily for subsequent cycles. One may also hypothesise that for lung carcinoma with an increased risk for pneumonia in the first cycle, the use of prophylaxis may be indicated for the first cycle only, while in other tumours treated by other chemotherapy regimens, prophylaxis may only be cost-effective during later cycles due to cumulative myelotoxicity.

In conclusion, this is the first economic evaluation concerning prophylactic antibiotics versus placebo during chemotherapy, prospectively conducted alongside a multi-national phase III trial. We demonstrated that prophylactic antibiotics during chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost savings and superior efficacy. Moreover, we showed that pooling of resource use in multi-centre multinational clinical trials cannot be recommended. We demonstrated that a sensitivity analysis is a valuable tool to place results in a broader perspective, enabling extrapolation to other institutions or other reimbursement systems. Sensitivity analysis may also prevent the misinterpretation of the results of economic evaluations based on the results of a subgroup analysis. In this trial, the sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL—a risk range relevant to routine clinical practice. Therefore, we recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.


    Acknowledgements
 
We would like to thank Bayer B.V. for sponsoring this study. The following institutions participated in the main trial: University Medical Centre Nijmegen, Nijmegen, The Netherlands; Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Thoraxklinik Rohrbach, Heidelberg, Germany; Bosch Medicentrum Groot Ziekengasthuis, ’s-Hertogenbosch, The Netherlands; University Hospital Antwerp, Edegem, Belgium; Ziekenhuis St Jansdal, Harderwijk, The Netherlands; Lukas Ziekenhuis, Apeldoorn, The Netherlands; Academic Medical Center, Amsterdam, The Netherlands; CHU de Marseille, Hopital Sainte-Marguerite, Marseille, France; Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli, Italy; Spaarne Ziekenhuis, Haarlem, The Netherlands; Ospedale Civile di Asti, Asti, Italy; EORTC Data Center, Brussels, Belgium.


    Footnotes
 
+ Correspondence to: Dr V. C. G.Tjan-Heijnen, University Medical Centre Nijmegen, Department of Medical Oncology (550), PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3615215; Fax: +31-24-3540788; E-mail: v.tjan{at}onco.umcn.nl Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Tjan-Heijnen VCG, Postmus PE, Ardizzoni A et al. Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small cell lung cancer patients: an EORTC double-blind placebo controlled phase III study. Ann Oncol 2001; 12: 1359–1368.[Abstract]

2. Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325: 164–170.[Abstract]

3. Trillet-Lenoir V, Green J, Manegold C et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993; 29A: 319–324.

4. Tjan-Heijnen VCG, Ardizzoni A, Postmus PE et al. Dose-intensification of cyclophosphamide, doxorubicin and etoposide (CDE) chemotherapy does not improve survival in small cell lung cancer (SCLC): final results of a randomized phase III EORTC study. Proc Am Soc Clin Oncol 2001; 20: 346 (Abstr 1379).

5. Efron B. Better bootstrap confidence intervals (with discussion). J Am Stat Assoc 1987; 82: 171–200.[ISI]

6. Lyman GH, Lyman CG, Sanderson RA et al. Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 1993; 85: 488–493.[Abstract]

7. Glaspy JA, Bleecker G, Crawford J et al. The impact of therapy with filgrastim (recombination granulocyte colony-stimulating factor) on health care costs associated with cancer chemotherapy. Eur J Cancer 1993; 29 (Suppl 7): 23–30.

8. Uyl-de Groot CA, Vellenga E, Rutten FFH. An economic model to assess the savings from a clinical application of haematopoietic growth factors. Eur J Cancer 1996; 32A: 57–62.

9. Lyman GH, Kudere N, Green J et al. The economics of febrile neutropenia: implications for the use of the colony-stimulating factors. Eur J Cancer 1998; 34: 1857–1864.[CrossRef][ISI][Medline]

10. Freifeld A, Marchigiani D, Walsh Th et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999; 341: 305–311.[Abstract/Free Full Text]

11. Del Prete SA, Ryan SP, Jacobson JS et al. Safety and costs of treating neutropenic fever in an outpatient setting. Conn Med 1999; 63: 713–716.[Medline]

12. Carlson JW, Fowler JM, Saltzman AK et al. Chemoprophylaxis with oral ciprofloxacin in ovarian cancer patients receiving taxol. Gynecol Oncol 1994; 55: 415–420.[CrossRef][ISI][Medline]

13. Schröder CP, de Vries EGE, Mulder NH et al. 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. J Antimicrob Chemother 1999; 43: 741–743.[Abstract/Free Full Text]

14. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 1994; 12: 2471–2508.[Abstract]

15. Nichols CR, Fox EP, Roth BJ et al. Incidence of neutropenic fever in patients treated with standard-dose combination chemotherapy for small-cell lung cancer and the cost impact of treatment with granulocyte colony-stimulating factor. J Clin Oncol 1994; 12: 1245–1250.[Abstract]

16. Chouiaid C, Bassinet L, Fuhrman C et al. Routine use of granulocyte colony-stimulating factor is not cost-effective and does not increase patients comfort in the treatment of small-cell lung cancer: an analysis using a Markov model. J Clin Oncol 1998; 16: 2700–2707.[Abstract]

17. Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000; 18: 3558–3585.[Free Full Text]

18. Canadian Coordinating Office for Health Technology Assessment: the use of G-CSF in the prevention of febrile neutropenia. Ottawa, Canada: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 1997; 1203–9012.