TECHNOLOGY OVERVIEW: PHARMACEUTICALS

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1 TECHNOLOGY OVERVIEW: PHARMACEUTICALS ISSUE 9.0 DECEMBER 1997 THE USE OF G-CSF IN THE PREVENTION OF FEBRILE NEUTROPENIA based primarily on the Technical Report : The Cost-Effectiveness of G-CSF for Prophylaxis of Febrile Neutropenia After Standard Dose Chemotherapy Andrew Lane Ilersich Overview prepared by Christine Perras, B.Sc. Phm, Pharmaceutical Associate, CCOHTA Nicolaas Otten, Pharm D., Director, Pharmaceuticals and Extramural Research, CCOHTA

2 Cite as: Canadian Coordinating Office for Health Technology Assessment. The Use of G-CSF in the Prevention of Febrile Neutropenia. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit National Library of Canada ISSN The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit

3 organization, funded by the federal, provincial and territorial governments. It was established to encourage the appropriate use of health technology by influencing decision-makers through the scientific evaluation of medical procedures, devices and drugs. The effectiveness and cost of technology and its impact on health are examined. This overview has been prepared by staff at CCOHTA and is based primarily on a technical report: The Cost-Effectiveness of G-CSF for Prophylaxis of Febrile Neutropenia After Standard Dose Chemotherapy 1 conducted by Mr. Lane Ilersich, Pharmaceutical Associate, CCOHTA and some analysis by Jacobs et al. 6 This overview attempts to put the original study into a clinical perspective. This overview does not necessarily reflect the opinions of the original investigators. To obtain copies of publications please contact: CCOHTA Publications Green Valley Crescent Ottawa, Ontario, Canada, K2C 3V4 Telephone: (613) Facsimile: (613) pubs@ccohta.ca or download full-text from Vous pouvez aussi vous procurer la version française Emploi des facteurs de stimulation des colonies granulocytaires (G-CSF) pour la prévention de la neutropénie fébrile à l OCCETS.

4 Reviewers for overview are: Dr. Christopher Bredeson Dr. Cynthia Toze Dr. Andreas Laupacis Amgen Canada Inc. REVIEWERS Division of Hematology Ottawa General Hospital Ottawa, Ontario Leukemia/BMT Program Vancouver General Hospital Vancouver, British Columbia Division of Clinical Epidemiology Ottawa Civic Hospital Ottawa, Ontario Mississauga, Ontario Reviewers for technical report were: Dr. Christopher Bredeson Dr. Cynthia Toze Dr. Andreas Laupacis Dr. David Feeny Dr. Lawrence Joseph Amgen Canada Inc. Division of Hematology Ottawa General Hospital Ottawa, Ontario Leukemia/BMT Program Vancouver General Hospital Vancouver, British Columbia Division of Clinical Epidemiology Ottawa Civic Hospital Ottawa, Ontario Centre for Health Economics and Policy Analysis McMaster University Hamilton, Ontario Division of Clinical Epidemiology Montreal General Hospital Montreal, Quebec Mississauga, Ontario This report was reviewed by external reviewers and by members of CCOHTA s Scientific Advisory Panel. These individuals kindly provided comments on drafts of this report. This final document incorporates most of the Reviewers' comments, however, CCOHTA takes sole responsibility for its form and content.

5 BACKGROUND SUMMARY REMARKS Febrile neutropenia is a life-threatening complication of cancer drugs. Granulocyte colony-stimulating factor (G-CSF), reproduced by recombinant DNA technology, stimulates the proliferation of neutrophils. Clinically, G-CSF is used in many indications, one of which is to prevent febrile neutropenia following myelosuppressive chemotherapy. It has been shown to reduce the incidence and duration of febrile neutropenia. This overview is based on a study conducted by CCOHTA and entitled: The Cost-Effectiveness of G-CSF for Prophylaxis of Febrile Neutropenia After Standard Dose Chemotherapy 1. The study was conducted to identify the instances when the prophylactic use of G-CSF is justified by the reduced cost of treating febrile neutropenia. CONCLUSIONS 1. There is currently no evidence demonstrating that G-CSF improves the response to chemotherapy or affects overall survival. 2. G-CSF reduces the probability of febrile neutropenia by 50% (95%CI: 40.9%-59.3%). 3. The use of G-CSF is cost-neutral when the risk of febrile neutropenia is 50.9%. 4. Since the probability of developing febrile neutropenia is only 12.3% in the general population receiving cancer chemotherapy, the use of G-CSF would incur a cost of $19,567 per case of febrile neutropenia avoided. Where the risk of developing febrile neutropenia is high (above 50.9%), as in some of the regimens used in the clinical trials (e.g., cyclophosphamide, doxorubicin and etoposide) 2, using G-CSF would result in cost savings. 5. If different parameters are varied, the probability of febrile neutropenia for G-CSF to be costneutral changes as shown in the table below: Parameter Base case Variation Probability of FNE for G-CSF to be cost-neutral Length of treatment 10 days 8 days 43.7% Drug wastage 0% 30% 66.2% In-patient vs outpatient hospitalized 31% treated in ambulatory setting 71.0% 6. The evaluation was limited by the fact that the efficacy of G-CSF was obtained from a metaanalysis of three clinical trials only. Hospitalization costs were determined from a study done in Canadian Coordinating Office for Health Technology Assessment 1

6 Quebec and physician service fees from the Ontario Schedule of Benefits. The evaluation did not consider indirect costs and quality of life issues. INTRODUCTION Granulocyte colony-stimulating factors are proteins which stimulate the growth and release of neutrophils into the blood circulation. Neutrophils are white blood cells, important in the fight against bacterial and fungal infections. Neutropenia occurs when neutrophil counts fall below the normal range. It is a common complication in cancer patients receiving cytotoxic chemotherapy drugs. Its incidence depends on the chemotherapy regimen used, the patient's previous exposure to myelosuppressive chemotherapy or a previous episode of neutropenia, and the physical well-being of the patient. If a patient develops neutropenia, cancer treatment may need to be delayed or the chemotherapy drug dosage may need to be decreased during the following course of therapy. Neutropenia with fever (febrile neutropenia) is usually indicative of infection and the patient may require hospitalization and empiric antibiotic therapy. The mortality rate of neutropenic cancer patients with a documented infection is 10% despite treatment with antibiotics and hospitalization. 3 G-CSF has been reproduced by recombinant DNA technology and is believed to have similar activity to that of endogenous G-CSF. Clinically, it has been shown to reduce the incidence 2,4,5 and duration 2 of febrile neutropenia. It has been used for many indications, but most frequently in the prevention of febrile neutropenia following myelosuppressive chemotherapy, including both primary and secondary prophylaxis*. However, there are no studies available to date demonstrating that G-CSF improves the response to chemotherapy or affects overall survival. CCOHTA conducted an evaluation of the prophylactic use of G-CSF in febrile neutropenia entitled The Cost-Effectiveness of G-CSF for Prophylaxis of Febrile Neutropenia After Standard Dose Chemotherapy 1 whose findings are summarized in this overview. Also considered is a study conducted by Jacobs et al. entitled Economic Assessment of the Use of Granulocyte Colony- Stimulating Factor (G-CSF) in Lung Cancer - Application to Canada. 6 * The American Society of Clinical Oncology (ASCO) guidelines have defined primary and secondary prophylaxis as follows 7 : Colony-stimulating factor (CSF) primary administration: use of a CSF before any occurence of neutropenia or febrile neutropenia that may result from chemotherapy (i.e. beginning in the first cycle of treatment). 2 Canadian Coordinating Office for Health Technology Assessment

7 CSF secondary administration: use of a CSF to protect against new episodes of febrile neutropenia or chemotherapy dose-modifications in subsequent cycles of treatment in a patient who has experienced one of these complications in an earlier course of that chemotherapy (i.e. beginning in a second or later cycle of treatment). Canadian Coordinating Office for Health Technology Assessment 3

8 PARAMETERS OF THE EVALUATION Product Description G-CSF is an endogenous protein. It has been reproduced for clinical use by recombinant DNA technology and marketed under the generic name of filgrastim and trade name of Neupogen by Amgen. Lenograstim is another recombinant G-CSF currently being investigated and is not yet available in Canada. The manufacturer reports the following usage for filgrastim for 1994: Indication % Patients Adjunct to chemotherapy 82% Transplant/ Peripheral blood stem cell transplant 10% Severe congenital neutropenia 3% Treatment of febrile neutropenia 3% Other 2% Perspective and Target Audience The perspective that was adopted reflected the main target audiences, which were the provincial/ territorial drug benefit plans as well as other third party payers. As well, clinicians and patients may find the analysis relevant. Type of Analysis The study was a cost-effectiveness analysis based on data obtained from phase III clinical trials 2,4,5 and on a Canadian survey 8. Using a decision analytic model, the analysis determined the incremental cost of avoiding one episode of febrile neutropenia and the thresholds at which the use of G-CSF would be cost-neutral. Treatment Comparators G-CSF administered with all courses of chemotherapy for prophylaxis was compared to no G-CSF. Outcomes of Interest The outcome measured was the incidence of febrile neutropenia requiring hospitalization. Time Horizon The time horizon was less than one year. No discounting was applied. Cost Elements of Interest Direct costs accruing to the health care system were used. 4 Canadian Coordinating Office for Health Technology Assessment

9 EFFICACY Primary Prophylaxis Two randomized controlled trials were conducted in patients with small-cell lung cancer and one trial in patients with non-hodgkin's lymphoma, evaluating the use of G-CSF in the prevention of febrile neutropenia. The three trials used a G-CSF dosage of 230 mcg/m 2 /day. Crawford et al. conducted a double-blind placebo-controlled study on 199 patients randomized to receive either G-CSF or placebo one day post-chemotherapy and continued for up to 12 days, for six cycles of treatment 2. This study showed that the incidence of febrile neutropenia (defined as absolute neutrophil count (ANC)<1.0 x 10 9 /L and temperature 38.2 o C) was reduced by 50% in the treatment group (28% event rate) compared to the control group (57% event rate) in the first cycle of chemotherapy. It also showed that the median duration of a febrile neutropenia episode (FNE) for all cycles was five days for the placebo group compared to four days for the G-CSF group, this finding being statistically non-significant. In the first cycle of therapy, the rate of hospitalization and length of stay were 26% and 2.2 days respectively, in the treatment group, compared to 55% and 4.1 days in the placebo group. In a double-blind study conducted by Trillet-Lenoir et al., 130 patients were randomized to receive placebo or G-CSF after the fourth day of chemotherapy for up to 14 days and repeated for each of the six cycles of treatment 4. In the first cycle of therapy, 41% of placebo-treated patients and 20% of G-CSF-treated patients had at least one episode of febrile neutropenia (ANC<1.0 x 10 9 /L and temperature 38.2 o C). Over all cycles, 53% of patients in the placebo group compared to 26% in the G-CSF group developed FNE. The median total days of neutropenia (not to be confused with neutropenia with fever) over all six cycles was 15 days in the placebo group compared to 6 days in the treatment group. The incidence of hospitalization was 39% for the treatment group compared to 58% for the placebo group. In both these studies, patients received highly myelosuppressive chemotherapy. Patients developing febrile neutropenia were removed from the double-blind study. In the study by Crawford et al., patients on placebo who developed FNE in any cycle were switched to G-CSF in subsequent cycles for the duration of their treatment. In the study by Trillet-Lenoir et al., when FNE occurred, the study drug was revealed and patients on G-CSF were allowed to continue receiving the drug on an open basis. A third study by Pettengell et al. compared G-CSF against placebo in 80 patients with non-hodgkin's lymphoma in an open-labelled, randomized trial 5. Twenty-two percent of patients receiving G-CSF and 44% of patients in the control group developed neutropenia with fever (ANC<1.0 x 10 9 /L and temperature 37.5 o C for one hour). The incidence of hospitalization was not significantly different between groups and twenty patients from each group required hospitalization for longer than three days. Table 1 summarizes the key findings of the three phase III trials. Secondary Prophylaxis As mentioned above, in the Crawford study, patients who had been randomized to the placebo group Canadian Coordinating Office for Health Technology Assessment 5

10 initially and had developed FNE in chemotherapy cycle 1, received G-CSF treatment in cycle 2. Of these, only 23% experienced a FNE in cycle 2. This study is often quoted as evidence of efficacy of G-CSF in secondary prevention. TABLE 1: Comparison of Phase III Trials Study Crawford et al Trillet-Lenoir et al Pettengell et al Group Placebo G-CSF Placebo G-CSF Placebo G-CSF Type of cancer SCLC SCLC NHL # patients G-CSF dose 230 mcg/m 2 /day 230 mcg/m 2 /day 230 mcg/m 2 /day Dosing schedule 1 day post-chemo x 12 days for 6 cycles 1 day post-chemo x 14 days for 6 cycles 13 weeks Definition of neutropenia Definition of fever Incidence of FNE Duration of FNE <1.0 x 10 9 /L <1.0 x 10 9 /L <1.0 x 10 9 /L 38.2 o C 38.2 o C 37.5 o C x 1 hr 57% a 28% a 41% a 20% a 44% b 22% b 53% b 26% b 5 days 4 days FNE SCLC NHL a b febrile neutropenia episode small cell lung cancer non-hodgkin s lymphoma incidence of FNE for cycle one incidence of FNE over all cycles 6 Canadian Coordinating Office for Health Technology Assessment

11 EFFECTIVENESS Incidence of Febrile Neutropenia Clinical trials have only evaluated G-CSF in high risk patients in which the incidence of febrile neutropenia was greater than 40%. However, most patients receiving chemotherapy have a lower risk of developing febrile neutropenia. To account for this, the model used two different rates of febrile neutropenia. i) High risk patients: The three phase III clinical trials were conducted with patients receiving high dose chemotherapy regimens and thus patients were at high risk of developing febrile neutropenia. A meta-analysis of the three clinical trials was conducted. It was determined that the baseline risk of febrile neutropenia without G-CSF was 53.2% (95%CI: 46.3%-60.0%). ii) Low risk patients: A Canadian survey determined that 12.3% of new chemotherapy patients developed febrile neutropenia 8. Reduction of Febrile Neutropenia with G-CSF The clinical effectiveness of G-CSF was estimated to be the pooled efficacy rates of the three clinical trials. It was determined that G-CSF reduced the incidence of febrile neutropenia by 50% (95%CI: 40.9%-59.3%). It is unknown if the same reduction can be obtained for other chemotherapy regimens which carry different risks of febrile neutropenia. COSTS Cost of Treating Febrile Neutropenia The cost of hospitalization, the cost of antibiotic therapy, and the cost of laboratory tests and diagnostic imaging were derived from a Quebec study 9 which reported costs of treating patients specifically admitted to hospital for febrile neutropenia. From this study, the cost of treating an episode of febrile neutropenia was calculated to be $5,523 (1992). This cost was adjusted by 4.1% to reflect 1995 dollars. The physician service fees, obtained from the Ontario Schedule of Physician Benefits (1992) were $ The overall cost of treating an episode of febrile neutropenia was calculated to be $6,069.40for 10 days. {(Cost of treating FNE x inflation factor) + physician fees)} Cost G-CSF Prophylaxis The cost of G-CSF was $1, per cycle (assuming a 70 kg patient receiving a dose of 5mcg/kg/day for 10 days). It included a drug acquisition cost of $0.44/mcg, a dispensing fee of $4.24 and no mark-up. Canadian Coordinating Office for Health Technology Assessment 7

12 RESULTS Cost-effectiveness Analysis i) Efficacy Patients in the three clinical trials 2,4,5 (called high risk patients in the evaluation), had a 53.2% probability of developing FNE. From the survey 8, the general chemotherapy population (called low risk patients in the evaluation) only had a 12.3% probability. By using G-CSF, the probability of FNE was determined to be decreased by 50%. ii) Cost The expected cost of not using G-CSF ($3,229) was greater than using G-CSF ($3,159) in patients for which the risk of developing FNE was 53.2%. For patients with a 12.3% probability of developing FNE, not using G-CSF was the least expensive alternative ($747) compared to using G-CSF ($1,921) (Table 2). TABLE 2: Expected Cost and Efficacy Group Strategy Treatment Rate Cost Expected cost High risk patients (baseline risk of FNE is 53.2%) Low risk patients (baseline risk of FNE is 12.3%) no G-CSF hospitalization 53.2% $6, per hospitalization $3, G-CSF hospitalization 26.6% $6, per drug 100% hospitalization $1, $1, $1, =$3, no G-CSF hospitalization 12.3% $6, per hospitalization $ G-CSF hospitalization 6.2% $6, per drug 100% hospitalization $1, $ $1, =$1, iii) Cost-Effectiveness For high risk patients, G-CSF was a dominant strategy (D), incurring less cost for a higher effect compared to no G-CSF. For low risk patients, using G-CSF was more expensive ($1,174) for a small effect (6% more cases of FNE avoided), which equalled $19,567 per case of FNE avoided (Table 3). 8 Canadian Coordinating Office for Health Technology Assessment

13 TABLE 3: Cost-Effectiveness of G-CSF Group Strategy Expected cost (C) (from table 2 above) Rate of FNE Cases of FNE avoided (E) C ($) E C/E (cost per case avoided) High risk patients Low risk patients no G-CSF $3, % 46.8% G-CSF $3, % 73.4% % D no G-CSF $ % 87.7% G-CSF $1, % 93.8% % $19,567 Sensitivity Analyses i) Break-Even Analyses Break-even analyses were conducted to determine the point at which the expected cost of using G-CSF was equal to the expected cost of not using G-CSF. The use of G-CSF was cost-neutral when the risk of febrile neutropenia was 50.9% (95%CI: 42.9%-62.2%). In other words, it would be less expensive to use G-CSF when the baseline risk of developing FNE is 51% or more. In the low risk group, the cost of G-CSF would need to decrease to $ (from $1,544) per cycle of therapy, or the cost per hospital stay would need to be $25,109 (instead of $6,069) for the use of G-CSF to be cost-neutral. ii) One-Way Sensitivity Analyses The rate of febrile neutropenia, at which the use of G-CSF would be cost-neutral, was determined for the following parameters (Table 4): Decreasing the efficacy of G-CSF to 25% If the effectiveness of G-CSF was in fact half of that obtained from the clinical trials, the use of G-CSF would never be cost-neutral. Decreasing the length of G-CSF treatment or dosage Decreasing the length of G-CSF treatment or dosage decreased the point at which the expected cost of using G-CSF equalled the expected cost of the no G-CSF strategy. Considering a 10% or 30% drug wastage The base case analysis did not consider drug wastage. However, this may be an issue, especially in pediatrics, since dosing is based on weight (ie., 5 mcg/kg) and the product is marketed as single dose vials. If there is wastage, the probability of FNE will need to be higher than 50.9% for G-CSF to be cost-neutral. Canadian Coordinating Office for Health Technology Assessment 9

14 TABLE 4: One-Way Sensitivity Analysis Parameter Base case Variation Probability of FNE for G-CSF to be cost-neutral Efficacy of G-CSF 50% to 25% >100% Length of G-CSF treatment 10 days to 8 days 43.7% to 5 days 25.4% Dose of G-CSF 5mcg/kg/day to 2mcg/kg/day 20.4% Drug wastage 0% to 10% 56.0% to 30% 66.2% iii) Two-Way Sensitivity Analyses Two way sensitivity analyses were also conducted (Figures 1 and 2). Frequency of Hospitalization According to one study 10, 31% of patients who develop FNE are at low risk of medical complications. It may be that this group of patients would be eligible for out-patient treatment. If 31% of patients with FNE were treated as out-patients, the risk of febrile neutropenia would have to be 71% for G-CSF to be cost-neutral. If the number of patients treated as out-patients increased above 57%, G-CSF would never be cost-neutral (Figure 1). Length of Stay The length of stay was varied over a range of 0 to 20 days and the risk of FNE from 0 to 100% for four per diem rates: $300, $500, $700 and $1,100. For example, if the per diem rate was $500 and the risk of febrile neutropenia was 100%, a length of stay greater than 6 days favours the use of G-CSF over no G-CSF (Figure 2). Secondary Prophylaxis The analysis is based on clinical trials that have evaluated G-CSF in primary prophylaxis (single cycle) 2,4,5. Yet, according to the manufacturer of Neupogen, the major use of G-CSF is in secondary prophylaxis. (Marcaros, D, Amgen Canada Inc., personal communication, June 27, 1997). Randomized controlled trials have not been conducted to determine the efficacy of G- CSF when used for this indication. In the Crawford study 2, all patients in the placebo arm who developed FNE in cycle 1 of their chemotherapy were administered G-CSF in cycle 2. It was shown that 23% of these patients developed FNE in cycle 2, for an efficacy rate of 77%, which is higher than that demonstrated in primary prophylaxis. This is based on the assumption that the probability of recurrence in subsequent cycles is 100%. However, no data exists to support or refute this assumption. Thus, it remains to be determined what the efficacy of G-CSF is in subsequent cycles and whether or not the probability of a FNE in subsequent cycles is above the break-even point of 50.9%, as that obtained in the evaluation. 10 Canadian Coordinating Office for Health Technology Assessment

15 STUDY LIMITATIONS The study evaluated the use of G-CSF in preventing febrile neutropenia. It did not look at the use of G-CSF for other indications such as its use in bone marrow transplant or in the treatment of febrile neutropenia. The meta-analysis was based on evidence obtained from three clinical trials evaluating the use of G- CSF in two different malignancies (small cell lung cancer and non-hodgkin`s lymphoma) and using different definitions of febrile neutropenia. The evaluation assumed that the efficacy of G-CSF would remain the same regardless of the chemotherapy regimen administered or the type of cancer treated. Hospitalization costs were determined from a study done in Quebec and physician service fees from the Ontario Schedule of Benefits. The evaluation did not consider indirect costs and quality of life issues. Canadian Coordinating Office for Health Technology Assessment 11

16 REFERENCES 1. Ilersich, AL. The cost-effectiveness of G-CSF for prophylaxis of febrile neutropenia after standard dose chemotherapy. Ottawa: Canadian Coordinating Office for Health Technology Assessment; Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. New England Journal of Medicine 1991;325(3): Faulds D, Lewis NJ, Milne R J. Recombinant granulocyte colony-stimulating factor (rg-csf): pharmacoeconomic considerations in chemotherapy-induced neutropenia. Pharmacoeconomics 1992;1(4): Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. European Journal of Cancer 1993;29A(3): Pettengell R, Gurney H, Radford JA, Deakin DP, James R, Wilkinson PM, et al. Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-hodgkin's lymphoma: a randomized controlled trial. Blood 1992;80(6): Jacobs P, Turner AR, Bachynsky J, Hall E. Economic assessment of the use of granulocyte colony-stimulating factor (G-CSF) in lung cancer - application to Canada [unpublished data]. Edmonton, AB: University of Alberta. Department of Public Health Sciences; American Society of Clinical Oncology. Recommendations for the use of hematopoietic colonystimulating factors: evidence-based, clinical practice guidelines. Journal of Clinical Oncology 1994;12(11): Skillings J, Gwadry-Sridhar F. Febrile neutropenia in chemotherapy patients: risk factors and outcome [abstract]. Clinical & Investigative Medicine 1993;16(Suppl B):B Masson E, Grégoire JP, Dupont N, Claveau S, Marceau D. Cost analysis of febrile neutropenic episodes following cancer chemotherapy - a descriptive study in Canada. Canadian Journal of Clinical Oncology 1995;2(2): Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. Journal of Clinical Oncology 1992;10(2): Canadian Coordinating Office for Health Technology Assessment

17 Canadian Coordinating Office for Health Technology Assessment Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4