Pharmacoeconomics of liposomal anthracycline therapy

Pharmacoeconomics of Liposomal Anthracycline Therapy Charles L. Bennett and Elizabeth A. Calhoun Pharmacoeconomic analyses are being used with greater frequency in clinical oncology trials. These analyses provide guidelines for prioritizing competing interventions and allocating health care resources, particularly when deciding whether to use a drug with a higher acquisition cost. For liposomal anthracyclines, the competing treatments are other liposomal anthracyclines and nonliposomal chemotherapy agents with similar activity. Pharmacoeconomic analyses of data from clinical trials in patients with Kaposi’s sarcoma determined that the overall cost to achieve objective response was substantially lower with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) than with liposomal daunorubicin (DaunoXome [DNX]). Additional economic analyses in patients with ovarian cancer showed that PLD has lower overall treatment costs than topotecan because it is administered less frequently and requires fewer interventions for toxicity. The decision to allocate health care resources to liposomal anthracycline treatment must therefore include consideration of cost-effectiveness and potential cost savings owing to improved tolerability. Semin Oncol 31(Suppl 13):191-195 © 2004 Elsevier Inc. All rights reserved.

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harmacoeconomic analyses compare the costs and outcomes of medical interventions and have become increasingly important to health care decision-making.1-3 Indeed, oncology clinical trial groups are beginning to evaluate economic outcomes in large clinical studies.4 Such analyses provide guidelines for prioritization of competing interventions and subsequent allocation of health care resources.5 The four major types of pharmacoeconomic analyses are cost-minimization analysis, cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis.6 Cost-minimization analysis is used when the outcomes of two regimens are identical but the regimens differ in cost.1 Cost-benefit analysis requires that the benefits of each therapy be expressed in monetary units.7 Cost-effectiveness addresses both cost and outcome,4 and such analyses can be used when two treatments do not produce equivalent outcomes.1 Outcome is measured in natural units, such as number of days of hospitalization or incidence or severity of adverse effects.4 Similar to cost-effectiveness analysis, cost-utility analysis addresses Veterans Affairs Chicago Healthcare System-Lakeside and the Institute of Health Services and Policy Studies, Northwestern University, Chicago, IL. Drs Bennett and Calhoun are consultants to Tibotec Therapeutics, Division of Ortho Biotech Products, L.P. and have received research grant support from Alza Pharmaceuticals and Schering-Plough Inc. Address correspondence to Charles L. Bennett, MD, PhD, Lakeside VA Medical Center, 400 East Ontario St, Chicago, IL 60611. E-mail: cbenne@ northwestern.edu

0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.08.008

both cost and outcome, but the outcomes are measured in patient-weighted utilities or quality of health care outcomes rather than in natural units.4 The utility scores are derived from information obtained from patients, clinicians, and the literature and represent patient preference for a particular outcome.4 A full pharmacoeconomic analysis could include not only the direct costs of drug acquisition, drug waste, inpatient chemotherapy administration (initial hospital visit, subsequent visits, discharge, procedures and tests, computed tomography of abdomen/pelvis, electrocardiograms, and physician fees), and outpatient chemotherapy administration (infusion-room costs, nursing costs, and procedural costs) but also the indirect costs of lost work time, impaired quality of life, and death.8

Liposomal Anthracyclines in Kaposi’s Sarcoma Doxorubicin HCl liposome injection (Doxil [PLD] is distributed in the United States by Tibotec Therapeutics, Division of Ortho Biotech Products, L.P., Bridgewater, NJ; Caelyx is distributed outside the United States by Schering-Plough, Kenilworth, NJ) and daunorubicin citrate liposome injection (DaunoXome [DNX]; Gilead Pharmaceuticals, Inc, San Dimas, CA) are each indicated for the treatment of Kaposi’s sarcoma.9,10 A full pharmacoeconomic analysis based on a 191

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Table 1 Cost-Effectiveness Analysis of PLD (Doxil) or DNX (DaunoXome) for the Management of Kaposi’s Sarcoma11

Drug acquisition Dose No. of cycles, mean Cost/cycle Response rate† Comparator response rate G-CSF treatment Grade III/IV leukopenia Possibility of G-CSF use Cost per G-CSF use Total cost/patient‡ Effectiveness† Cost-effectiveness§

PLD (n ⴝ 121)12

DNX (n ⴝ 116)13

20 mg/m2 every 3 wks 4.8* $1,212 59% 23% (BV)

40 mg/m2 every 2 wks 8.6 $538 25% 28% (ABV)

29% 24% $2,200 $7,066 59% $11,976

38% 32% $2,200 $6,621 25% $26,483

Incremental CostEffectiveness

$445 34% $1,308储

Abbreviations: BV, bleomycin and vincristine; ABV, conventional doxorubicin (Adriamycin), bleomycin, and vincristine; KS, Kaposi’s sarcoma; G-CSF, granulocyte colony-stimulating factor. *Protocol limit was six cycles. †Probability of complete or partial response. ‡Total estimated cost of treatment and chemotherapy-related hematologic toxicities. §Cost-effectiveness ⴝ total cost ⴜ effectiveness. 储Incremental cost-effectiveness is the additional cost to achieve objective response by using PLD instead of DNX, calculated as difference in total cost/patient ⴜ difference in effectiveness.

randomized comparison of these two drugs has not been performed; however, an indirect comparison has been conducted11 based on data from a randomized trial comparing PLD to bleomycin plus vincristine (BV)12 and a randomized trial comparing DNX with conventional doxorubicin plus bleomycin plus vincristine (ABV).13 The analysis assumed that patient characteristics in the two studies were the same; responses were scored in an equivalent manner; cost estimates were for the full course of the specified chemotherapy; no other treatment was administered (except for granulocyte colony-stimulating factor [G-CSF]); further treatment costs were the same in the two studies; the frequency and type of opportunistic infections were the same; and the average duration of G-CSF treatment for neutropenia was 11 days in each study with no patient receiving intravenous antibiotics or hospitalization for infection. Drug acquisition costs were based on average wholesale prices in 1998 plus the cost of intravenous fluids and nursing monitoring. Drug acquisition costs for PLD were more than twice those for DNX (Table 1).10 However, the average cycle length (3 weeks) and the number of treatment cycles were fewer for PLD. The frequency of neutropenia that might require G-CSF therapy was higher for DNX. When these factors were taken together, the total cost of treatment per patient was $445 higher ($US) for PLD than for DNX. The objective response to PLD was much greater than the response to DNX (59% v 25%). As a result, the cost-effectiveness ratio (the cost of achieving one response with treatment) for DNX was more than twice as great as for PLD (Table 1). The incremental cost to achieve one responder was $1,308, using PLD instead of DNX. Using the same clinical trial data and analysis methods, a second study showed that similar pharmacoeconomic results would apply to Swedish patients.14 The cost per objective

response was $18,340 for DNX and $8,871 for PLD. The incremental cost per additional response by using PLD instead of DNX was $1,910. Sensitivity analyses in each of these studies showed that PLD was consistently cost-effective for the treatment of Kaposi’s sarcoma.11,14 Variables included increasing the response rate to DNX while decreasing that to PLD by 10%, decreasing G-CSF use for the former while increasing G-CSF use for the latter, increasing the DNX dose, decreasing the PLD cycle length, and using the same number of cycles in each treatment group.

PLD in Ovarian Cancer Of the liposomal anthracyclines, only PLD was shown to be effective for the treatment of ovarian cancer in comparative phase III clinical trials.15,16 In a noncomparative study of PLD as second- or greater-line therapy for platinum-refractory ovarian cancer, overall treatment costs were calculated from direct medical charges.17 A total of 62 consecutive patients received a median of two cycles of PLD treatment (range, 1 to 8 cycles), with a mean total cost per cycle of $5,763. The major cost drivers were hospitalization and drug acquisition and administration costs. A comparative clinical trial in 474 patients showed that PLD and topotecan had similar effectiveness for ovarian cancer that was refractory or resistant to platinum treatment.15 PLD was associated with 19.7% complete response rate and 60 weeks median survival duration, compared with 17.0% and 56.7 weeks, respectively, in the topotecan group. More patients experienced grade 4 toxicity with topotecan treatment (71.1%) than with PLD treatment (17.2%). Compared with topotecan recipients, patients receiving PLD had fewer episodes of grade 3 or 4 neutropenia (642 v 53, respectively), anemia (130 v 18),

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Table 2 North American Cost-Minimization Analysis of PLD (Doxil) or Topotecan in the Management of Recurrent Ovarian Cancer Mean Cost of PLD per Patient ($US) Drug and administration Drug Administration Subtotal Adverse events Stomatitis/pharyngitis Hand-foot syndrome Nausea/vomiting Diarrhea CSF treatment Office visits/other Neutropenia Sepsis and fever Erythropoietin Transfusions Office visits/other Anemia/thrombocytopenia Hospitalization Total cost (95% CI)

Mean Cost of Topotecan per Patient ($US)

12,962 1,438

Difference ($US) ⴙ2,904 ⴚ6,939

10,058 8,377 14,400

18,435

ⴚ4,035

101 104 49 34

30 0 83 58

ⴙ71 ⴙ104 ⴚ34 ⴚ24

419 78

ⴚ1,517 ⴚ1,742

1,936 1,820 497 56

3,756 111

308 140 18

ⴚ3,185 ⴚ1,206 ⴚ342

3,493 1,346 342

ⴚ3,259 ⴚ55

466 188

5,181 566

ⴚ4,715 ⴚ378

15,877 (14,515 to 17,306)

28,220 (25,750 to 30,974)

ⴚ12,325 (ⴚ9445 to ⴚ15,415)

From Smith et al: A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the USA and the UK. Ann Oncol 13:1590-1597, 2002. By permission of the European Society for Medical Oncology.18

thrombocytopenia (184 v 3), and sepsis (23 v 5). Patients treated with PLD had more episodes of hand-foot syndrome (62 v 0) and stomatitis/pharyngitis (31 v 2) than topotecan-treated patients. A retrospective cost-minimization analysis was performed on the 235 patients from the study who were treated in North America, representing half of the total study population.18 Overall care for the women who received PLD versus those who received topotecan was associated with an estimated $12,325 savings per patient (Table 2). The per-patient drug acquisition cost was $2,904 greater for PLD, but the administration cost was $6,939 greater for topotecan because five outpatient visits were required every 3 weeks instead of one

outpatient visit every 4 weeks. Thus, the net cost increase associated with topotecan acquisition and administration was $4,035. In addition, toxicity management was much more costly for topotecan because of significant differences in erythropoietin use (291,091 v 25,670 units), blood transfusions (1.56 v 0.26), G-CSF use (3,520 v 762 ␮g), and office visits (12.7 v 4.6 visits). A second analysis was performed only among the 239 European patients in the same clinical trial.18 Cost savings for PLD versus topotecan were $92 for drug acquisition and administration and $2,817 for toxicity management, for a net cost savings of $2,909 per patient (Table 3). Significantly greater use of blood transfusions (3.49 v 0.65 units) and

Table 3 Geographic Variation in Retrospective Cost-Minimization Analyses Mean Cost of PLD (Doxil) per Patient Geographic Area North America (n ⴝ Europe* (n ⴝ 239)18 Italy† (n ⴝ 474)19 Spain† (n ⴝ 474)20

235)18

Mean Cost of Topotecan per Patient

Drug ⴙ Administration

Adverse Events

Total

Drug ⴙ Administration

Adverse Events

Total

$14,400 $12,894 €7,617 €8,648

$1,495 $1,103 €1,195 €967

$15,895 $13,997 €8,812 €9,615

$18,435 $12,986 €7,911 €8,520

$9,785 $3,920 €7,877 €3,305

$28,220 $16,906 €15,788 €11,825

NOTE. Each retrospective analysis was based on drug utilization and adverse event data from a prospective, randomized, parallel-group trial comparing PLD and topotecan in the management of ovarian cancer.15 *Comprising 49% in the United Kingdom and less than 10% in each of the other European Union countries. Cost-minimization analyses based on toxicity management strategies and treatment cost estimates in the United Kingdom. †Analysis based on efficacy and safety data from all patients (North American and European) enrolled in the clinical trial, with toxicity management and treatment cost estimates specific to Italy or Spain.18

C.L. Bennett and E.A. Calhoun

194 hospitalization for toxicity management (0.41 v 0.12 stays) contributed to the increased cost of care with topotecan compared with PLD. Subsequent cost-minimization analyses were performed on all 474 patients but used estimated treatment costs and toxicity management strategies specific to Italy19 or Spain.20 These studies confirmed the cost savings of PLD treatment compared with topotecan treatment in ovarian cancer, with net per-patient cost savings of €6,976 in Italy and €2,210 in Spain (Table 3). Each of these cost-minimization analyses was performed based on the assumption that PLD and topotecan did not have significantly different efficacy for second-line treatment ovarian cancer, as was shown in the initial clinical trial.15 A systematic review of PLD treatment in ovarian cancer reanalyzed the results of the trial to assess cost-effectiveness based on the European cost analysis by Smith et al,18 an estimate of mean survival duration, and a Monte Carlo simulation of 10,000 patients.21 All but one of the 10,000 simulated patients in the cost-effectiveness analysis were projected to have greater total treatment costs with topotecan than PLD. In most cases PLD was not only less costly but also more effective, making it the dominant intervention for ovarian cancer.21

PLD in Multiple Myeloma Preliminary findings from one study address the costs and cost-effectiveness of PLD, vincristine, and dexamethasone (DVd) versus vincristine, conventional doxorubicin, and dexamethasone (VAd) in patients with newly diagnosed multiple myeloma.22 In the clinical trial, similar rates were noted with respect to response (44% v 41%) and 2-year progression-free survival (40% v 34%), although the PLD arm had a smaller decrement in left ventricular ejection fraction (-2.3 v -4.5; P ⬍.01) and lower rate of grade 3 or 4 neutropenia (10% v 24%; P ⫽ .01) . With respect to mean per-person costs (including both inpatient and outpatient care), the PLD arm had lower costs per cycle ($4,232 v $6,797) and for the entire treatment ($14,389 v $21,070).

Potential Cost Savings of Reducing Cardiotoxicity Reduced cardiotoxicity is an important toxicity advantage of liposomal anthracyclines compared with conventional doxorubicin.23 The cost savings associated with cardiotoxicity prevention by using a liposomal anthracycline instead of a conventional anthracyclines has not been determined; however, the cost-effectiveness of preventing cardiotoxicity was shown in a pharmacoeconomic study of the cardioprotectant dexrazoxane.24 Patients with stage IIIB or IV metastatic breast cancer treated with intravenous 5-fluorouracil, conventional doxorubicin, and cyclophosphamide (the FAC regimen) were randomly assigned to receive prophylactic dexrazoxane or placebo treatment. The primary endpoint of the analysis was cost per cardiac event avoided. Dexrazoxane therapy cost $5,661.77 per cardiac event prevented; $12,991.53 per congestive heart failure event prevented; and $2,809.31 per ad-

ditional life-year saved. This cost was lower than those associated with other treatments designed to prevent cardiotoxicity. For example, the cost of invasive cardiologic monitoring for patients who receive conventional doxorubicin treatment is $20,308 per case of heart failure prevented and $25,650 per averted death.25

Conclusion The acquisition costs of liposomal anthracyclines tend to be higher than those of other chemotherapeutic agents used for similar indications. Cost-effectiveness analyses in the United States and Sweden have shown that the cost to achieve objective response was more than twice as great for DNX compared with PLD in the treatment of Kaposi’s sarcoma. International cost-minimization analyses concluded that PLD was associated with net cost savings compared with topotecan in the treatment of platinum-refractory ovarian cancer. A costeffectiveness analysis of the same clinical data concluded that PLD was the dominant treatment: lower total cost was associated with greater effectiveness in the majority of patients. Similar pharmacoeconomic analyses of liposomal anthracyclines for the treatment of other tumor types are not yet available. The cost savings of avoiding cardiotoxicity by using a liposomal anthracycline instead of a conventional anthracycline has not been determined. In the meantime, the decision to allocate health care resources to liposomal anthracycline treatment must therefore include consideration of costeffectiveness and potential cost savings because of improved tolerability.

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