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
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Abstract |
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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) ()1.7132.263] 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 8105948], 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 >1020% 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
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Introduction |
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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.
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Patients and methods |
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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 46 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).
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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 physicians 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.
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Results |
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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.
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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).
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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).
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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.
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Discussion |
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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 1020% 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 costbenefit 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 FLa risk range relevant to routine clinical practice. Therefore, we recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.
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Acknowledgements |
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Footnotes |
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References |
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