Originally published as JCO Early Release 10.1200/JCO.2005.04.3281 on May 8 2006

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Cost-Effectiveness of Adding Granulocyte Colony-Stimulating Factor to Primary Prophylaxis With Antibiotics in Small-Cell Lung Cancer

Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Hans J.M. Smit, Bonne Biesma, Frank A. Wilschut, Gerben P. Bootsma, Theo M. de Boo, Vivianne C.G. Tjan-Heijnen

From the Departments of Medical Oncology, Medical Technology Assessment, Pulmonology, and Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen; Nijmegen Rijnstate Hospital, Arnhem; Jeroen Bosch Hospital, 's-Hertogenbosch; and Hospital Gelderse Vallei, Ede, the Netherlands

Address reprint requests to J.N.H. Timmer-Bonte, MD, 452 Department of Medical Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: J.Timmer{at}onco.umcn.nl

	ABSTRACT

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PURPOSE: Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis.

METHODS: Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented.

RESULTS: For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, –36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, –2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%.

CONCLUSION: Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

	INTRODUCTION

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Febrile neutropenia (FN) is a major complication in patients treated with chemotherapy, leading to morbidity and consequently consuming medical resources, primarily because of hospitalization. Both prophylactic antibiotics and prophylactic granulocyte colony-stimulating factor (GCSF) have been shown to reduce hospitalization for FN by approximately 50%.^1-3

Risk factors of FN (eg, poor performance status, extensive disease, elderly age, or prior chemotherapy treatment) have been identified, making it possible to target prophylactic strategies.^1,3-5 We recently reported the results of a randomized, phase III clinical trial assessing the impact of primary GCSF prophylaxis in small-cell lung cancer (SCLC) patients treated with standard dose chemotherapy and with an estimated 25% baseline risk of FN in the first cycle, despite the use of primary antibiotic prophylaxis.⁶ In this high-risk population, the addition of GCSF reduced the incidence of FN from 24% to 10% in the first chemotherapy cycle (P = .01). In cycles 2 through 5, this reduction was less important: 17% of patients treated with antibiotics alone, compared with 11% of patients treated with GCSF, developed at least one episode of FN. During the entire treatment period, the incidence of FN was 32% with antibiotic prophylaxis alone, compared with 18% with the addition of GCSF, largely because of the different rates found in cycle 1 (Table 1).

Prophylactic antibiotics can be cost saving in some occasions.⁷ However, the use of prophylactic GCSF comes with considerable expense, and restraint of use is therefore recommended.^8,9 An early decision model including economic parameters favored the use of primary prophylactic GCSF in the United States, given a probability of FN of at least 40%.¹⁰ Based on updated costs, more recent publications estimated that GCSF prophylaxis might be cost saving above FN thresholds of 20% to 25%.^11-13

We hypothesized that the addition of prophylactic GCSF to prophylactic antibiotics in patients considered at risk of FN might increase the cost-effective administration of prophylaxis. Further, we argued that a prospective economic evaluation alongside a clinical trial might improve the quality of the economic data and might provide a better understanding of the cost variance in production processes between patients and prices in the Netherlands.

GCSF prophylaxis has not shown any impact on survival. Therefore, our primary focus was a cost-minimization analysis to determine whether the savings associated with the expected decrease in incidence of FN would offset the additional costs of prophylactic G-CSF. A secondary end point was the cost per percent FN prevented.

	METHODS

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Design
Economic analysis was performed prospectively from a health care perspective alongside the clinical trial.^6,14-16Case Report Forms were used to collect resource utilization data during the trial period, providing a patient-based cost data set. Costs were calculated for the time the patient was receiving chemotherapy in the clinical trial.

The incidence of FN in the first cycle was the primary end point of the clinical study, as subsequent episodes may be related. For that reason, economic analysis primarily focused on cost-minimization analysis of the first cycle. Cost-minimization analysis for the entire treatment period and cost-effectiveness were taken into account as secondary analyses. Outcome measures were the difference in mean total costs per patient between both prophylactic treatment arms and cost-effectiveness expressed as costs per percent FN prevented.¹⁷

Cost-Minimization Analysis
Specific costs that were evaluated included actual delivered chemotherapy, prophylactic antibiotics, prophylactic GCSF, delivered transfusions, all costs (including hospitalization) related to a period of FN, and costs of hospitalization for any other reason. The mean cost of an episode of FN was related to the incidence of FN (Table 1) and was based on the resource utilization of hospitalization, visits to general practitioner, emergency room or outpatient-department, therapeutic antibiotics, laboratory investigations, and cultures and radiologic procedures during each FN-related treatment period. The study protocol provided stringent definitions of FN and its management, according to current standards in the Netherlands.⁶

Prices were retrieved from various sources (Table 2). Available guideline prices were used, as defined in 2000 by the Dutch Health Care Insurance Board.¹⁸ Prices for chemotherapy, prophylactic antibiotics, prophylactic GCSF, and therapeutic antibiotics were based on the Dutch reimbursement system for pharmaceuticals. Prices of laboratory investigations, radiologic procedures, microbial cultures, and transfusions were all derived from the national health tariffs authority. All prices were adjusted to the price level of 2002 using price index numbers for health care as reported by the Central Bureau of Statistics in the Netherlands. Prices were given in euro. The monthly euro exchange rate in 2002 fluctuated between 0.9 and 1.1 US dollars, so the euro was almost equivalent to the US dollar.

Cost-effectiveness is graphically represented by an acceptability curve. This curve summarizes the evidence in support of antibiotics plus GCSF being cost effective for all potential values of the decision rule (willingness to pay per percent more effect). Furthermore, it also represents uncertainty in the ICER. Acceptability can be interpreted as the probability of adding GCSF being cost effective (for the given willingness to pay) in a Bayesian sense, using an uninformative prior. For example, if the acceptability is 0.95 for a certain value, W, of the willingness to pay, then for values greater than W, the corresponding ICER is significantly smaller than W (adding GCSF is cost effective). Thus, the net monetary benefit also is significantly greater than zero. We calculated an acceptability curve for the additional probability that FN did not occur, based on the approximate normal distributions of costs and effects in cycle 1.

Threshold and Sensitivity Analysis Based on the First Cycle
Threshold analysis was performed per variable to determine at what point both strategies would break even. Sensitivity analyses enable generalization and transferability to other countries, other chemotherapy regimens, and other patient groups.

In most publications dealing with the economic analysis of prophylactic GCSF, only the FN-related costs are incorporated in threshold and sensitivity analyses.⁸ To weigh our results against previous publications, we also incorporated only FN-related costs into threshold and sensitivity analyses, based on a formula that is well accepted in the clinical field^7,10,19,20:

Threshold points were calculated by adjusting one variable at a time while keeping all other variables constant. The relative risk reduction as seen in the first cycle was used (58%; Table 1). Threshold lines were generated by varying the risk of FN from 10% to 80% and the FN-related costs from 1,000 euro to 35,000 euro at given prices of GCSF administration of 250, 500, 1,000, 1,500 and 2,500 euro per cycle. Results of the threshold and sensitivity analyses refer to the incidence and cost of the first cycle only.

	RESULTS

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Clinical Trial
The key results of the clinical trial are summarized in Table 1.

Cost-Minimization Analysis
In the first cycle, the mean total costs were 2,103 euro (95% CI, 1,512 to 2,694 euro) per patient in the antibiotics group compared with 2,783 euro (95% CI, 2,359 to 3,208 euro) in the antibiotics plus GCSF group (Table 3). The mean difference in total cost amounted to 681 euro (95% CI, –36 to 1,397) per patient in cycle 1.

Cost-Effectiveness Analysis
In the first chemotherapy cycle, the difference in the incidence of FN was 24% with antibiotics compared with 10% with antibiotics plus GCSF, and the mean incremental cost of adding GCSF was 681 euro per patient (95% CI, –36 to 1,397 euro). This implies an ICER of 50 euro (681 euro/14% risk reduction) per percent decrease of the probability of FN (95% CI, –2 to 433 euro).

During the entire treatment period, an ICER of 366 euro per absolute decrease percent of the probability of FN per patient in any cycle (95% CI, 165 to 4,815 euro) was calculated.

If effect is defined as the probability to remain FN-free, then an acceptability curve can be computed to show the acceptability of adding GCSF to antibiotics, given the willingness to pay per percent extra effect. In our study, we found an ICER of 50 euro per percent extra effect. Figure 1 shows that the acceptability for this willingness to pay is approximately 0.5 (50%) and that the willingness to pay should be at least 240 euro to be cost effective. For these values, the net monetary benefit is significantly greater than zero (P < .05), and the corresponding ICER is significantly smaller than the willingness to pay concerned.

View larger version (8K): [in this window] [in a new window]   Fig 1. Acceptability curve based on the probability to remain febrile neutropenia (FN)-free in cycle 1. This figure summarizes the evidence supporting the cost-effectiveness of antibiotics plus granulocyte colony-stimulating factor (GCSF) for all potential values of the willingness to pay per percent decrease of the probability of FN. The willingness to pay should be at least 240 euro to be considered cost effective.

View larger version (22K): [in this window] [in a new window]   Fig 2. Sensitivity analysis based on cycle 1. Each curve represents a threshold line for a given cost of granulocyte colony-stimulating factor (G-CSF) prophylaxis per cycle. The reduction of the probability of febrile neutropenia (FN) is 0.58 in all cases. The area above the curve favors the addition of G-CSF to antibiotic prophylaxis at given FN-related costs (vertical axis) and probabilities (horizontal axis).

	DISCUSSION

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How likely is it that the addition of GCSF to antibiotics is cost-effective? The answer depends on the willingness to exchange money and effectiveness. No reference values exist for the outcome of percent more effect. However, if health care policy makers are willing to pay at least 240 euro for a percent decrease of the probability of FN (or 3,360 euro for the 14% reduction of FN seen in our trial), then Figure 1 shows an acceptability of at least 95%; thus, prophylactic antibiotics plus GCSF is cost effective. When making such a decision, economic analysis and clinical effect should be the focus.

In prior studies, prophylactic administration of GCSF was not routinely advised because cost savings were unproven.^21,22 When survival was the same in arms with and without GCSF, the less expensive arm optimally was chosen. However, good clinical practice may require examining more than survival. Although cost per percent-FN-prevented may seem artificial, it has been used by Messori et al and in other fields of medicine: cost-effectiveness is expressed as cost per headache-day-prevented in menstrual-associated migraine, cost per exacerbation-chronic obstructive pulmonary disease [COPD]-prevented, and cost per gastrointestinal-ulcer-prevented when using different NSAIDs.^17,23-25 In economic analyses, the preferred approach may be to use multiple analyses, because strategies may differ in their clinical effects but not in survival.¹⁶ In our opinion, some money may be spent for supportive care matters, even without an impact on survival. Policy makers should decide on the acceptable amount of money to spend.

Threshold analysis showed that, for the Netherlands, the addition of GCSF to antibiotics is only cost saving if the probability of FN is greater than 84%, the price of prophylactic GCSF is less than 469 euro per patient, or the cost of an episode of FN is greater than 11,552 euro.

Although the mean non–FN-related costs did not differ significantly in cycle 1 (mean difference, 351 euro; 95% CI, –150 to 853; Table 3), they actually did impact the cost analysis. When including non–FN-related hospitalization costs in the threshold formula, the addition of GCSF in the first cycle was cost saving when the probability of FN was greater than 65%, the price of prophylactic GCSF was less than 806 euro per cycle, or the cost of an episode of FN was greater than 9,000 euro. Threshold values differed considerably when including non–FN-related costs. Our findings stress the importance of prospectively collecting cost and resource-utilization data.

Although the 2000 guidelines on the use of hematopoietic growth factors published by ASCO refer to an FN threshold of 40%, above which primary prophylaxis with GCSF is cost saving in the United States, more recent publications estimate a threshold of 20% to 25%.^9,11-13 Sensitivity analysis of our data cannot identify thresholds for the United States, as economic implications can vary between countries. Smith et al²⁶ demonstrated the differences in health care systems and practical management of cancer care by comparing treatment of ovarian cancer in Europe and the United States.

The mean cost of an episode of FN in our trial was 3,300 euro, or approximately 3,135 US dollars, based on the 2002 annual exchange rate of 0.95 US dollar per euro. This cost is less than the cost of an episode of FN in the United States ($12,302 in patients with solid tumors in 1995-2000 as reported by institutions to the University Health System Consortium).²⁷ The difference in our study may be related to several factors, including the strict definition of FN-related costs (eliminating costs of possible comorbid conditions), no required admission to the intensive care unit, and a fairly low cost of therapeutic antibiotics in the Netherlands.²⁸ Nevertheless, the difference in FN-related cost seems mainly caused by differing hospitalization costs in the Netherlands and the United States.

In the near future, outpatient treatment for FN will gain importance and interest, especially in patients with a predicted low risk of complications of FN. The Multinational Association of Supportive Care of Cancer (MASCC) risk-index score is based on seven independent factors present at the onset of FN. Although comorbidity data was not collected systematically in our trial, a substantial number of patients in our trial may have suffered COPD. In addition, the majority of patients with FN were older than 60 years and had extensive disease. This results in a MASCC risk index score of 18, which is associated with a high risk of complicated FN.^29,30 Therefore, cost savings by outpatient treatment of FN is unlikely to be relevant in the studied population.

The control arm was based on a placebo-controlled trial in SCLC patients conducted by the European Organisation for Research and Treatment of Cancer, in which prophylactic ciprofloxacin plus roxithromycin reduced both the incidence of FN and FN-related hospitalizations by approximately 50% and proved cost effective.^3,7 The efficacy of antibiotic prophylaxis has been confirmed in patients with hematologic and solid cancers.^31,32 Different antibiotic regimens have a similar relative risk reduction for FN, so it is unlikely that GCSF has a different impact on the risk of FN when combined with quinolones other than those used in our study.

At the time of the study design, pegylated filgrastim was not yet available. Because of the advantage to the patient (only one injection per cycle) and equal or greater efficacy compared with daily filgrastim, pegylated filgrastim will increasingly be used.^33,34 In the Netherlands, the price of one injection of pegylated filgrastim is comparable to the cost of GCSF used per cycle in our study. Therefore, pegylated filgrastim is economically exchangeable with daily GCSF.

A high incidence of FN in the first cycle with a lower incidence of FN in later cycles has been reported before in SCLC and in other malignancies without proper explanation.^3,35-37 Possible explanations are patient selection, reduced median chemotherapy dose, and declining occurrence or duration of severe neutropenia in later cycles; these did not occur in our study. In our study, continuing GCSF prophylaxis in all cycles led to substantial additional costs of 5,123 euro per patient (95% CI, 3,908 to 6,337 euro) and 360 euro per decreased percent of the probability of FN per patient in any cycle (95% CI, 174 to 2,116 euro). Analysis of the first cycle may thus underestimate the additional costs. Our results suggest administering primary GCSF prophylaxis in the first cycle only.

We performed a prospective economic analysis alongside a multicenter, phase III clinical trial of primary GCSF and antibiotic prophylaxis in SCLC patients at risk of chemotherapy-induced FN. Despite the selection of patients with a 24% baseline risk of FN, and despite the significant reduction of FN, the addition of GCSF did not result in cost savings. Only if one is willing to pay 3,360 euro to achieve a 14% reduction of FN, or 240 euro for each percent gain in effect, can the addition of GCSF to primary prophylaxis with antibiotics be considered cost effective. However, the continued use of GCSF beyond the first chemotherapy cycle does not appear cost effective, even at these rates of FN.

	Appendix

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Participating hospitals and responsible investigators. Rijnstate Ziekenhuis- Arnhem (H.J.M. Smit); Jeroen Bosch Ziekenhuis, GZG- 's-Hertogenbosch (B. Biesma); Ziekenhuis Gelderse Vallei- Ede (F.A. Wilschut); Radboud Universiteit Nijmegen Medisch Centrum -Nijmegen (J. Timmer-Bonte, V. Tjan-Heijnen, J. Festen, G. Bootsma); Streekziekenhuis Koningin Beatrix- Winterswijk (S. Cheragwandi); Canisius Wilhelmina Ziekenhuis- Nijmegen (A. Termeer); Diaconessenhuis- Meppel (C. Hensing); Medisch Centrum Rijnmond-Zuid, Zuiderziekenhuis Rotterdam (R. Slingerland); St. Franciscus Gasthuis- Rotterdam (K. Tan); St Anna Ziekenhuis- Geldrop (C. vd Moosdijk); Slingeland Ziekenhuis- Doetinchem (G. Bosman); Isala klinieken, Weezenlanden- Zwolle (J. vd Berg); Maasziekenhuis- Boxmeer (R. Bunnik), the Netherlands.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Gerben P. Bootsma, Theo M. deBoo, Vivianne C.G. Tjan-Heijnen Provision of study materials or patients: Johanna N.H. Timmer-Bonte, Hans J.M. Smit, Bonne Biesma, Frank A. Wilschut, Gerben P. Bootsma, Vivianne C.G. Tjan-Heijnen Collection and assembly of data: Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Theo M. deBoo, Vivianne C.G. Tjan-Heijnen Data analysis and interpretation: Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Theo M. deBoo, Vivianne C.G. Tjan-Heijnen Manuscript writing: Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Theo M. deBoo, Vivianne C.G. Tjan-Heijnen Final approval of manuscript: Johanna N.H. Timmer-Bonte, Eddy M.M. Adang, Hans J.M. Smit, Bonne Biesma, Frank A. Wilschut, Gerben P. Bootsma, Theo M. deBoo, Vivianne C.G. Tjan-Heijnen

 

	ACKNOWLEDGMENTS

 
We wish to thank Hans Severens, Department of Health Organisation, Policy and Economics, Maastricht University; Evelien Termeer, Department of Medical Technology Assessment, Radboud University, Nijmegen; Linda Mol and Frank van Leeuwen, Trial Office, Comprehensive Cancer Centre East, Nijmegen, the Netherlands; responsible investigators from participating hospitals.

	NOTES

 
Supported by a research grant from the Dutch Healthcare Insurance Board (OG-99053).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted September 22, 2005; accepted January 13, 2006.

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