Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer

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1 Support Care Cancer(1999) 7: DOI /s ORIGINAL ARTICLE Q Springer-Verlag 1999 George Dranitsaris Tom Hsu Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer Published online: 21 May 1999 G. Dranitsaris, M.Pharm. (Y) 7 T. Hsu, B.Pharm Department of Pharmaceutical Services, Ontario Cancer Institute/Princess Margaret Hospital and Centenary Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada georgedranitsaris6pmh.toronto.on.ca Tel.: c Fax: c Abstract Metastatic bone disease is a common complication of advanced breast cancer. Recently, the results of a large randomized placebo-controlled trial demonstrated that monthly pamidronate infusions reduce the incidence of skeletal related events in these patients. In the current study, a cost utility analysis was performed from a Canadian health care system perspective to estimate the incremental cost-effectiveness of pamidronate in patients with advanced breast cancer. Twenty-five advanced breast cancer patients who were bisphosphonate naïve and had developed skeletal related complications were identified. Total hospital resource consumption was then collected for all patients. This included direct costs for hospitalization and costs for radiation treatment to bone, surgery, analgesics, blood products, diagnostic imaging, paramedical services and all related physician fees. Treatment preferences were estimated from a random sample of 25 women selected from the general population and 25 female health care professionals, using the Time Trade-Off technique. The outcomes were then generated through a decision-analytic model. Over a 12-month period, total costs in the pamidronate arm were approximately 44% higher than those in the no-treatment alternative (Can$ 9,180 vs Can$ 6,380). When treatment preferences were incorporated into the analysis, the results of the decision model revealed an incremental pamidronate cost of $18,700 per quality-adjusted life year gained. The results of the sensitivity analysis suggested that this estimate was dependent on the cost of treating skeletal related events, particularly bone surgery. Even though pamidronate has a high drug acquisition cost, the results of the cost utility analysis suggest that this agent does provide patients with a substantial quality-adjusted survival benefit at a reasonable cost to the Canadian health care system. Key words Pamidronate 7 Breast cancer 7 Economic analysis Introduction Despite the advances in chemotherapeutic agents, approximately 70% of breast cancer patients with advanced disease will develop symptomatic bone metastases [5]. In recent years, it has been demonstrated through randomized comparative trials that agents in the bisphosphonate class have an ability to reduce bone pain, promote bone healing and decrease the incidence of skeletal related events [1, 13]. Of the agents available

2 272 in clinical practice, pamidronate is considered to be the most active, this high activity being secondary to its increased ability to inhibit osteoclast bone resorption [6]. The efficacy of this agent in preventing skeletal related complications and improving bone pain has been demonstrated in a wide variety of tumour sites, including breast cancer, through several well-designed clinical trials [2, 11, 17]. However, one area that has received limited attention is the cost-effectiveness of this agent. In the face of rising health care costs, medical oncologists are increasingly required to justify the use of such high-cost drugs as pamidronate. Hence, it would be of value to the medical oncology community and hospital formulary decision makers if economic data on the use of pamidronate in cancer patients were to become available. This is especially relevant in advanced breast cancer, given the high incidence of this disease. In this study, total pamidronate costs, resource requirements for the management of skeletal related events, and health state preferences were incorporated into a cost utility analysis to estimate the incremental cost of prophylactic pamidronate in patients with advanced breast cancer. Methods Clinical trial A comprehensive literature search was conducted to identify high-level randomized pamidronate trials that had bone fractures as primary end-points. Therefore, the economic analysis utilized the clinical data from the only available randomized, doubleblind, placebo controlled trial of pamidronate in patients with metastatic breast cancer receiving chemotherapy [8]. Threehundred and eighty-two patients were stratified according to ECOG performance status scores (0 or 1 vs 1 or 2), then randomized in a 1:1 ratio to receive either a 90-mg i.v. infusion of pamidronate or a placebo infusion. Treatment was repeated every 4 weeks as an adjunct to chemotherapy for up to 12 cycles. The objectives of the trial were to determine whether pamidronate reduced the incidence of pathologic fractures, radiation treatment to bone, hypercalcaemia, and surgery to bone. Alternative endpoints included changes in pain scores, analgesic use, performance status and quality of life as measured by the Spitzer index [8]. After a mean treatment duration of approximately 10 months, 59 of 195 patients (30%) in the placebo group developed at least one nonvertebral pathologic fracture, as against only 37 of 185 subjects (20%) in the pamidronate group (Pp0.02). Similarly, the incidence of radiation treatment to the bone in the control and experimental arms was 19% and 33%, respectively (Pp0.002). Statistically significant rate reductions in hypercalcaemia (12% vs 6%; Pp0.03) and surgery to bone (10% vs 4%; Pp0.02) were also identified between placebo and pamidronate patients. When all the skeletal related complications were combined, the proportions of patients in the pamidronate and placebo group that developed at least one event were 46% [95% confidence interval (CI)p39 53%] and 62% (95% CIp55 69%) respectively. When hypercalcaemia was excluded from the analysis, the corresponding skeletal related event (SRE) rates were 43% (95% CIp36 50%) and 56% (95% CIp49 63%) [8]. The investigators also reported that patients receiving pamidronate had superior scores for pain control, performance status and quality of life. Economic model Prophylactic pamidronate was modelled using the principles of decision analysis [18]. A decision-based analytic-model for a cost utility analysis was developed using the DATA software program, vers (Fig. 1). The model was simple and directly based on the randomized trial [8]. The primary clinical outcomes for measuring success in the analysis was the prevention of SREs as reported in the trial and the quality adjusted life years (QALY) gained. Prior to the pivotal randomized trial [8], most advanced breast cancer patients would typically not receive pamidronate for the prevention of an SRE. Pamidronate would usually be reserved for the management of bone pain. Therefore, the decision model began at the decision node (square) where the treatment choice for patients with advanced breast cancer would be between pamidronate or no treatment (placebo). Following a median of ten monthly doses (as reported in the trial), the development of an SRE would be assessed at 12 months (Fig. 1). The four types of SREs included in the analysis were pathologic fractures, radiation treatment to bone, hypercalcaemia and surgery to bone. In branches one and three of the model, where an SRE occurred, the cost of each event was determined from a chart audit and was weighted by the probability of occurrence for an average patient. The weighting factors were obtained from the clinical trial [8]. Hence, the sum of the weighted SRE costs represented the total Choice Pamidronate Placebo SRE Node # 1 No SRE SRE Node # 2 No SRE Hospitalize Health state # 1 Monitor Health state # 2 Hospitalize Analytic time frame = 12 months Perspective: Canadian Health care system SREs = bone fractures, palliative radiation, hypercalcemia and bone surgery Health state # 3 Monitor Health state # 4 Fig. 1 Decision analytic model of prophylactic pamidronate in patients with advanced breast cancer. The analytic time-frame was 12 months, and a Canadian health care perspective was adopted. Skeletal related events (SRE) considered were bone fractures, palliative radiation, hypercalcaemia and bone surgery

3 273 expenditure in branches one and three of the model. In branches two and four, where no SRE occurred, the economic parameters consisted only of the cost of pamidronate and no treatment (Fig. 1). Estimate of cost The current study was a cost utility analysis (CUA). The analytic time period for the investigation was 12 months, and a Canadian health care system perspective was taken. The drug cost was calculated assuming a 90-mg pamidronate dose administered every 4 weeks for a median of ten treatments (as reported in the trial). The cost estimate also included expenditures for patient admission to the ambulatory care unit, drug preparation, administration, supplies and patient monitoring during the infusion. Hospital resource consumption data secondary to pathologic fractures, radiation treatment and hypercalcaemia were obtained from a retrospective chart audit of metastatic breast cancer patients who presented at the Princess Margaret Hospital (PMH) from 1990 to Such an approach to economic data collection has the advantage of representing real-life hospital resource utilization as opposed to the artificial situation created by a randomized trial. Eligible patients were selected via a random number table. To be eligible, patients had to have a histological diagnosis of breast cancer, be receiving either first- or second-line chemotherapy for their disease, have at least one osteolytic bone lesion and develop a nonvertebral pathologic fracture within 12 months of starting chemotherapy. Patients were ineligible if they had received bisphosphonates for their disease during the 12-month analytic period. After the initial screening process was completed, a final sample of 25 breast cancer patients was selected. With a sample of 25 subjects, the hospital cost of a nonvertebral pathologic fracture was measured with a precision that extended to $3,000, with a 95% probability. Orthopaedic surgeries are not performed at the PMH. Therefore, costs for surgery to bone were obtained from a chart audit of breast cancer patients with metastatic bone disease who required a surgical intervention and were referred to the Centenary Hospital, a 400 bed community health centre located in Scarborough, Ontario. Using costs statistics from the PMH and the Centenary Hospital, the average cost of a nonvertebral pathologic fracture, radiation treatment to the bone, hypercalcaemia and bone surgery was determined. This included direct costs for daily hospitalization secondary to pain control, radiation treatment to bone or postsurgical recovery, analgesic prescriptions (including the pharmacy dispensing fee), blood products, diagnostic imaging, fractionated radiation therapy, laboratory tests, paramedical services (e.g. physiotherapist, occupational therapist) and all related physician fees. These estimates and the SRE rates reported in the randomized trial were then applied to the decision analytic model. The acquisition cost of pamidronate was obtained from Novartis Pharma Canada. The cost of daily hospitalization at the PMH ($644/day) was estimated by Doyle et al. [3]. The cost of daily hospitalization (average operating cost) for the Centenary Hospital ($521/day) was obtained from the Ontario Hospital Association (OHA). The cost of an ambulatory care admission for a pamidronate infusion was obtained from the Department of Financial Services, PMH. Costs for dose preparation, administration, and analgesic prescriptions were obtained from the Nursing and Pharmacy Departments, PMH. Costs for laboratory tests, diagnostic imaging and radiation services were obtained from the Departments of Biochemistry, Oncologic Imaging, and Radiation Oncology, PMH. The physician fees for service were obtained from the Schedule of Benefits, Ontario Ministry of Health, October 1 version, The costs quoted in this study are in Canadian dollars ($Can 1p$U.S. 0.65, as of January, 1999). Preferences for alternative health states The health-related quality of life values measured in the analysis were patient preferences for alternative health outcomes, as depicted in the decision-analytic model. In the current study, QALY periods were measured as healthy months equivalent for the time spent in each outcome of the decision model (Fig. 1). These parameters were determined using the Time Trade-Off (TTO) technique as described by Torrance et al. [14]. It has been recommended in the Canadian Guidelines for economic evaluations [15] and by the Panel on Cost-Effectiveness in Health and Medicine of the United States [12] that treatment preferences be measured from members of the general public who are potential candidates for the new medical intervention. Therefore, the sample population consisted of 25 Canadian women living in Ontario. With a sample of 25 subjects, health state preferences were measured with a precision that extended to 1.5 months, with a 95% probability. Potential subjects were initially screened via a random telephone dialling strategy. To be eligible for the survey, participants had to be 18 years of age or older, have permanent residence status in Ontario, indirectly support the Canadian health care system through tax contributions and give informed consent to participate in the interview. Once subjects were identified by telephone, they were interviewed face to face by a trained field surveyor. After informed consent was obtained, each participant was interviewed for min. Briefly, participants were presented with information describing each health state (e.g. a skeletal complication while on placebo) and the length of time within that state. Information on the benefits, method of administration and toxicity profile of the new drug in the scenarios where it was offered (branches one and two) was also provided to each participant. Subjects were then asked how many months of perfect health they considered to be equivalent to the time spent in each health state. In order to facilitate respondent understanding of each health scenario, visual aids were also used. An identical process was administered for each outcome of the decision tree (Fig. 1). Demographic data were also collected from each participant and consisted of age, marital status, household income, number of children, previous experience with a bone fracture and history of chemotherapy administration. Lastly, to determine whether healthy women were able to understand the clinical scenarios sufficiently, a nonrandom sample of 25 female health care professionals (e.g. pharmacists, nurses) with experience in oncology were also interviewed. Cost utility analysis The clinical, economic and respondent preference data were then combined into a cost utility analysis comparing pamidronate with no treatment (placebo) for the prevention of skeletal related complications in patients with advanced breast cancer. The primary outcome determined in the study was the incremental cost per QALY gained. Future costs and benefits were not discounted because of the short time periods involved. However, the stability of the baseline results were tested by a comprehensive sensitivity analysis. This procedure was characterized by substituting preferences derived from healthy women in the general public with those measured in female health care professionals. In addition, the data were reanalysed using the upper and lower 95% confidence limits for SRE rates (with and without the inclusion of hypercalcaemia), costs for treating SREs and health state preferences.

4 274 Statistical analysis Demographic data and utility estimates were presented as descriptive statistics as means, medians, or proportions. Costs for bone fractures, radiation therapy, hypercalcaemia and surgery to bone were presented as means with 95% CI. Results Estimation of cost In the comparative trial [8], breast cancer patients randomized to the pamidronate group received a 90-mg dose of the study drug every 4 weeks for a median of ten treatments. With this regimen, the cost of pamidronate would be $597 per 4-week cycle. This includes costs for drug preparation, administration, supplies and ambulatory care admission. Therefore, the total cost for ten treatments would be approximately $5,970. A random sampling procedure was used to identify 25 breast cancer patients who developed nonvertebral bone fractures while receiving chemotherapy. Patient and clinical characteristics are presented in Table 1. The majority of patients had multiple metastatic sites in addition to the bone. All patients had received at least one type of hormonal therapy. Furthermore, the entire group was treated with multiple chemotherapy regimens for their disease (Table 1). In the sample, all patients developed at least one nonvertebral pathologic fracture during the 12-month evaluation period. The total number of hospital days was 249, with a mean of 10 days (Table 2). Combining expenditures for hospitalization, drug therapy (including outpatient prescriptions), medical consultations, diagnostic imaging and laboratory tests generated an average cost of $8,040 per patient (Table 2). From the original sample, 20 of 25 patients were referred for radiation therapy to the bone. A total of 57 radiation oncologist consultations were required, with a median of three per patient (Table 3). The total number of radiation fractions delivered was 154, which translated to a cumulative dose of 3,200 cgy administered over a median of 7.5 fractions. Transforming these medical resources into costs, the average health care expenditure for radiation treatment to the bone was approximately $1,299 per patient (Table 3). The additional benefits of pamidronate reported by Hortobagyi et al. [8] were statistically significant risk reductions in hypercalcaemia and surgery to bone. However, there were no cases of hypercalcaemia or bone surgery in the original 25 breast cancer patients. In order to estimate treatment costs for hypercalcaemia, a computerized search from 1994 until 1996 was performed to identify bisphosphonate-naive breast cancer patients who developed hypercalcaemia and were Table 1 Clinical and demographic data of breast cancer patients with nonvertebral pathologic fractures (C cyclophosphamide, F 5- fluorouracil, A doxorubicin, E epirubicin, M methotrexate) Characteristic Patient data a (np25) Age (years) 52 (27 70) Weight (kg) 74.5 (52 157) Height (cm) 163 ( ) Serum creatinine (mol/l) 83 (46 124) Serum calcium (mmol/l) 2.4 ( ) Metastatic sites (%) Bone 25 (100) Brain 6 (24) Liver 10 (40) Lung/Pleura 7 (28) Soft tissue 5 (20) Eye 1 (4) Hormonal therapy (%) Tamoxifen 24 (96) Medroxyprogesterone 12 (48) Aminoglutethamide 7 (28) Progesterone 1 (4) Fluoxymesterone 2 (8) Chemotherapy (%) b CAF 13 (52) CEF 11 (44) CMF 6 (24) Mitomycin/vinblastine 5 (20) Mitoxanthrone 3 (12) Paclitaxel 1 (4) a Median (range) b Primary and subsequent antineoplastic regimens. All patients received at least one regimen Table 2 Cost of treating a nonvertebral pathologic fracture in breast cancer Resource item Mean cost (np25) Total hospital days 249 Length of hospitalization 10 (0 86) [days (range)] Cost of hospitalization a 6414 Drug therapy b 1074 Medical consultations c 66 Diagnostic imaging d 282 Laboratory tests e 205 Total cost per patient (95% CI) $Can 8040 ($2316 $13764) f a Determined as in [3] b Analgesics, stool softeners, antidepressants etc. c Pain, orthopaedic, anaesthesia d Skeletal surveys, CT scans, MRI, X-Rays e Serum creatinine, calcium etc. f Individual mean costs do not necessarily add up to the final sum

5 275 Table 3 Cost of radiation treatment to bone in patients with breast cancer Table 4 Cost of treating hypercalcemia in patients with breast cancer a Resource item Mean cost (np20) a Resource item Mean cost (np10) Total radiation consultations 57 Median (range) 3 (1 8) Consultation costs $382 Total number of fractions 154 Median (range) 7.5 (1 21) Total median dose (cgy) (range) 3200 ( ) Fractionated radiation costs $917 Total cost per patient (95% CI) $Can 1299 ($930 $1668) b a Five patients from the original sample of 25 were not referred for radiation therapy b Individual mean costs do not necessarily add up to the final sum treated at the PMH. Only 10 patients with hypercalcaemia who met the inclusion criteria were identified. The median age of the 10 patients was 48 years (rangep33 63), and all had been receiving chemotherapy for their disease (e.g. CMF, CAF, CEF, paclitaxel) prior to the development of hypercalcaemia. All patients had elevated serum calcium levels (medianp3.4 mmol/l, rangep ) and the majority had an increased serum creatinine (medianp102 mol/l, rangep59 339). In these patients, the total number of hospital days required for hypercalcaemia was 21, with a mean of 2.1 days (Table 4). Combining expenditures for hospitalization, ambulatory care visits, drug therapy, physician visits and laboratory tests generated a mean cost of $2369/case (Table 4). The final economic parameter required to complete the analysis was an estimation of the cost of surgery to bone. Orthopaedic surgeries secondary to pathologic fractures are not performed at the PMH. Therefore, the Centenary Hospital in Scarborough, Ontario, was contacted to provide estimates for surgery costs. A computerized patient search was conducted from 1988 to 1997 for patients who had metastatic breast cancer that had invaded the bone and caused a nonvertebral pathologic fracture requiring a surgical intervention. Twenty-eight patient charts were initially identified. After an initial screening process, 6 charts met the inclusion criteria. The median age of the patients was concerned 68.5 years (rangep38 85), and all had been receiving chemotherapy for their disease prior to the development of the bone fracture. Once the fracture developed, patients were admitted to hospital for the surgical procedure. Four patients recovered from the surgery and were discharged home. However, 2 patients expired during the admission in which they received the orthopaedic surgery. Death in these 2 patients was due to disease progression. Total hospital days 21 Length (days) of hospitalization 2.1 (0 9) (range) Cost of hospitalization b 1352 Ambulatory care visits c 213 Drug therapy d 650 Physician visits 75 Laboratory tests e 79 Total cost per patient (95% CI) $Can 2369 ( ) a Over a 1-year period. Includes recurrent episodes of hypercalcaemia b Determined as in [3] c For hydration, biphosphonate administration etc. d Clodronate, pamidronate etc. e Serum creatinine, calcium etc. Health care resource use was collected from the initial day of hospitalization until the day of postsurgical discharge or death. The data collected included direct surgery related costs such as blood products, anaesthetic drugs, nursing personnel and all related physician fees. The second component of the cost analysis consisted of resource items during postsurgical recovery, such as hospital stay, laboratory tests, diagnostic imaging, antibiotics, blood products, medical consultations and all paramedical services. Therefore, the combination of all these resources translated to an overall cost of approximately $32,347 per patient (Table 5). Estimation of treatment preferences Health state preferences for each of the four treatment outcomes were estimated from a sample of 25 women selected from the general population. The median age of respondents was 45 years (rangep28 66), 68% were married, 17% had a household income below Can$30,000, 20% did not have children, 8% had received some form of chemotherapy for cancer in the past, and 29% had had personal experience of a broken bone. For comparison, preferences were also measured in a cohort of health care professionals. Health care workers were younger (median agep40, rangep26 56) and tended to have higher household incomes (100% had incomes above Can$30,000) than the former group. However, the two groups were comparable in marital status (72% in the latter group were married). Preference values for the four health states from public female volunteers and health care professionals are presented in Table 6. The most interesting observation worth noting was that the healthy months equival-

6 276 Table 5 The cost of bone surgery in breast cancer patients Resource item Mean cost (np6) Surgery related Blood products a 875 Pharmaceuticals 27 Nursing 225 Physician fees b 947 Postanaesthesia care unit 46 Subtotal (SD) $2120 (3174) Postsurgical recovery Mean hospital stay (range) 51 days (13 88) Hospitalization cost Blood products 805 Medical consultations 587 Diagnostic imaging 628 Laboratory tests 83 Pharmaceuticals 155 Paramedical c 673 Primary care physician 311 Other d 66 Subtotal (SD) $30227 (16 030) Total (95% CI) $Can ( ) a From Tretiak et al. [16] b Orthopaedic surgeon, neurosurgeon, anaesthetist, surgical assistant c Physiotherapist, occupational therapist, discharge planning nurse etc. d Ambulance cost, visits to follow-up clinic ent in the case of successful pamidronate treatment (branch two of the model) reported by health care professionals was significantly higher (i.e. better quality of life) than those from public volunteers. Specifically, the latter group considered 12 months of pamidronate treatment and no SRE to be equivalent to a mean of 7.7 months of perfect health. However, with health care workers, the point of equivalence was at a mean of 9.9 months (P~0.05). Cost utility analysis The SRE rates with the inclusion of hypercalcaemia were used (pamidronatep46% vs placebop62%) for the baseline analysis. From the model, the overall annual health care utilization cost per patient was $9,180 and $6,380 for the pamidronate and the no-treatment (placebo) arms, respectively. Using the health state preferences derived from public volunteers for the baseline analysis, the average number of healthy months equivalent gained by patients treated with pamidronate was 1.8 months or 0.15 QALYs. When these estimates were combined, the results of the cost utility study revealed an incremental cost of $18,700 per QALY gained with pamidronate in advanced breast cancer (Table 7). The data were then reanalysed using preferences derived from health care workers in place of the public volunteer estimates. The results were insensitive to the substitution ($16,500 per QALY gained), suggesting that in this particular study, health care professionals were suitable substitutes for public volunteers for calculation of the incremental cost/utility ratios (Table 7). Sensitivity analysis A series of one-way sensitivity analyses were then conducted, using the 95% CI for SRE rates, costs for treating SREs, and the healthy months equivalent estimates from public volunteers (Table 6). In the majority of cases, the incremental cost of pamidronate remained below $30,000 per QALY gained, with a range of $5,700 $32,000 (Table 7). Similarly, when the analysis was repeated with the exclusion of hypercalcaemia from the clinical and economic data, identical results were obtained with incremental costs per QALY ranging from $15,100 to $30,000 (Table 7). Among the four main types of SREs that occur in breast cancer patients, the need for bone surgery was the most resource intensive with an estimated cost from the day of surgery until primary discharge at $32,347 (Table 5). It is likely that this is a conservative estimate since it has been reported that rehabilitation health care resources are required for up to 1 year after surgery [19]. Therefore, to evaluate the impact that surgery had, the data were reanalysed with the exclusion of the cost for bone surgery. The incremental cost per QALY Table 6 Health state preferences derived using the Time Trade-Off technique Health state Time in the health state (months) Healthy months equivalent [mean (95% CI)] Public volunteers (np25) Health care workers (np25) SRE with pamidronate ( ) 4.80 ( ) No SRE with pamidronate a ( ) 9.92 ( ) SRE with placebo ( ) 4.13 ( ) No SRE with placebo ( ) 7.89 ( ) a Difference was statistically significant (P~0.05)

7 277 Table 7 Sensitivity analysis of pamidronate therapy in breast cancer using societal preferences Sensitivity manoeuvre Cost ($Can) per QALY Gained a Baseline (public volunteers) Health care professionals % CI of SRE rate in pamidronate group ( ) 95% CI of SRE rate in placebo group ( ) 95% CI of SRE costs ( ) 95% CI of QALY estimates ( ) Excluding hypercalcaemia (HCM) % CI of SRE rate in pamidronate group (no HCM) ( ) 95% CI of SRE rate in placebo group (no HCM) ( ) Excluding surgical costs Surgery costs estimated as in [19] a Rounded to the nearest hundred increased from $18,700 at baseline to $32,100 (Table 7), suggesting that the resource requirements secondary to orthopaedic surgery had a major impact on the results. Hence, it appears that one of the main economic benefits of pamidronate is its ability reduce the incidence of bone surgery in patients with metastatic breast cancer. The final sensitivity manoeuvre once again focused on the cost of surgery. Turning to the literature for economic evaluations that measured the cost of bone surgery, Zethraeus and Gerdtham [19] collected resource utilization data on 1080 Swedish patients who developed a hip fracture that required a surgical intervention (5 of 6 breast cancer patients in the current study had hip fractures). At 1 year after the hip fracture surgery, the total cost was estimated at $243,870 SEK. Using the current rate of exchange, this is equivalent to approximately $Can 45,140 per patient. Since Sweden and Canada have very similar socialized health care systems, the Swedish cost assessment would be a reasonable estimate for the situation in Canada. Therefore, the data were reanalysed using $45,145 as the estimate for the cost of surgery for the entire year following the fracture. The cost per QALY gained decreased from $18,700 at baseline to $13,300, suggesting that pamidronate provides good economic value because it is able to reduce the incidence of costly bone surgeries (Table 7). All of the above sensitivity analyses were then repeated using the utility estimates derived from health care professionals (Table 6). The results suggested an even greater improvement in the cost-effectiveness profile of the drug (baselinep$16,500 per QALY gained, rangep$5,000 29,000), as illustrated in Table 8. This observation is related to the fact that health care professionals gave a higher preference rating for the clinical benefits of pamidronate in the scenario where an SRE did not develop (Fig. 1). Discussion The unfortunate reality faced by many cancer treatment centres around the world is that drug budgets are shrinking while new and expensive antineoplastic agents are being introduced into the clinical setting. These factors, alone or in combination, can complicate hospital formulary decision making. For rational health policy initiatives to be made, economic data should be available for each new agent before it is introduced into clinical practice. The available methodology of pharma- Table 8 Sensitivity analysis of pamidronate therapy using health care worker preferences (QALY quality-adjusted life year) Sensitivity manoeuvre Cost ($Can) per QALY gained a Baseline (health care professionals) % CI of SRE rate in pamidronate group ( ) 95% CI of SRE rate in placebo group ( ) 95% CI of SRE costs ( ) 95% CI of QALY estimates ( ) Excluding hypercalcaemia (HCM) % CI of SRE rate in pamidronate group (no HCM) ( ) 95% CI of SRE rate in placebo group (no HCM) ( ) Excluding surgical costs Surgical costs estimated as in [19] a Roundes to the nearest hundred

8 278 coeconomics can provide the necessary information for informed decision making. Breast cancer is one disease that falls into this category. Furthermore, the availability of drugs with high acquisition costs, such as pamidronate, can complicate the allocation of limited oncology resources between the many available programmes. In order to quantify the overall impact of pamidronate from both the clinical and economic perspective, a cost utility analysis was performed. The overall finding of the current study was that pamidronate as an adjuvant to chemotherapy resulted in an incremental cost to the Canadian health care system of approximately $18,700 per QALY gained. These results were stable despite the source of utility estimates (Tables 7, 8). Comparing this outcome with those of other medical therapies that have been adopted into clinical practice revealed similar incremental cost-effectiveness ratios. The therapies considered include hydrochlorothiazide treatment for mild to moderate hypertension [4] and adjuvant chemotherapy in women with node-negative breast cancer [7]. In the four health states where patient preferences where assessed (Fig 1), there was a trend for higher scores in the scenarios that included adjuvant pamidronate. These observations are probably related to the drug s ability to reduce bone pain, maintain the patient s performance status and quality of life relative to baseline, and delay the onset of SREs [8]. Furthermore, the benefits of monthly pamidronate are maintained for up to 24 months after randomization, as was recently reported in the long-term follow-up to the original randomized trial [9]. To test for uncertainty, a series of one-way sensitivity analyses were performed. The primary focus of the investigation was to evaluate the 95% CI for SRE rates in both the pamidronate and placebo arms, SRE related costs and QALY estimates. The outcomes of the investigation indicated that the most important factor in a favourable cost-effectiveness profile of pamidronate was the cost of treating SREs (Table 7, 8). Generally speaking, the higher the expected cost of treating an SRE, the greater the value that pamidronate would offer a given cancer treatment centre. Even under the worst case scenario for pamidronate (lower 95%CI for SRE costs), the maximum incremental cost of the drug would be reasonable at $31,600 per QALY gained. Considering the four types of SREs that pamidronate avoids, the cost of surgery to bone had the largest impact on the overall results. When the analysis was repeated with the exclusion of surgical costs, the incremental cost per QALY gained increased almost twofold (Table 7, 8). Even though the absolute risk reduction in bone surgery reported in the trial was only 6% [8], this is a major socioeconomic benefit of pamidronate because bone surgeries can be very costly interventions [10, 19]. In addition, the estimated value in the current study is likely to be conservative, since health care costs were only collected from the day of surgery until patient discharge. However, many patients require health care support services for up to 1 year after surgery [19]. When 1-year surgical cost estimates were used in the sensitivity analysis, the incremental cost was only $13,300 per QALY gained, indicating that pamidronate is an economically attractive treatment for the health care system to adopt. The limitations of the economic evaluation have to be addressed. A major drawback lay in estimating the cost of treating skeletal related events. These estimates were obtained from patients treated at the Princess Margaret Hospital and the Centenary Health Centre only, and may not necessarily represent the resource use of other institutions across the country. Furthermore, only direct hospital- and drug-related expenditures were collected, and additional outpatient costs for physiotherapy, chronic care and time off work were not included in the analysis. The inclusion of these societal costs would improve the economic profile of pamidronate. Cost utility studies are valuable sources of information for the formulary decision making committee. However, they are only one part of a very large and complicated process. Formulary committees also have to consider the incidence of the disease in question and be able to perform cost impact analyses if the agent is accepted for reimbursement. Using the province of Ontario as an example, the National Cancer Institute of Canada reported approximately 7,100 new cases of breast cancer in Of these, approximately 25% will develop metastatic disease with bone metastases. Therefore, it is estimated that 1,775 Ontario patients would be eligible to receive prophylactic pamidronate. Based on the estimated 1-year drug cost, the projected annual Ontario budgetary requirement for this drug would be over $10 million. Therefore, difficult decisions would have to be made about which patients to treat with pamidronate (e.g. multiple myeloma, breast cancer) and where the funding should be allocated from. In conclusion, the results of the cost utility evaluation suggest that prophylactic pamidronate therapy for advanced breast cancer offers patients a substantial quality-adjusted benefit at a reasonable cost to the Canadian health care system. However, given the high incidence of the disease, innovative collaborative strategies have to be developed between the key stakeholders to make the drug available to all eligible patients. Acknowledgements This study was supported by a grant from Novartis Pharma Canada, Inc.

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