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Keywords:

  • cancer;
  • anemia;
  • cost-effectiveness;
  • erythropoietin analogs

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

Erythropoiesis-stimulating agents (ESA) administered to cancer patients with anemia reduce the need for blood transfusions and improve quality-of-life (QOL). Concerns about toxicity have led to more restrictive recommendations for ESA use; however, the incremental costs and benefits of such a strategy are unknown.

METHODS:

The authors created a decision model to examine the costs and consequences of ESA use in patients with anemia and cancer from the perspective of the Canadian public healthcare system. Model inputs were informed by a recent systematic review. Extensive sensitivity analyses and scenario analysis rigorously assessed QOL benefits and more conservative ESA administration practices (initial hemoglobin [Hb] <10 g/dL, target Hb ≤12 g/dL, and chemotherapy induced anemia only).

RESULTS:

Compared with supportive transfusions only, conventional ESA treatment was associated with an incremental cost per quality-adjusted life year (QALY) gained of $267,000 during a 15-week time frame. During a 1.3-year time horizon, ESA was associated with higher costs and worse clinical outcomes. In scenarios where multiple assumptions regarding QOL all favored ESA, the lowest incremental cost per QALY gained was $126,000. Analyses simulating the use of ESA in accordance with recently issued guidelines resulted in incremental cost per QALY gained of >$100,000 or ESA being dominated (greater costs with lower benefit) in the majority of the scenarios, although greater variability in the cost-utility ratio was present.

CONCLUSIONS:

Use of ESA for anemia related to cancer is associated with incremental cost-effectiveness ratios that are not economically attractive, even when used in a conservative fashion recommended by current guidelines. Cancer 2010. © 2010 American Cancer Society.

Anemia is common in patients with cancer and is associated with negative clinical outcomes. Treatment with erythropoiesis-stimulating agents (ESA) effectively increases hemoglobin and reduces the need for blood transfusions, improves short-term disease-specific quality of life (QOL),1 and is preferred over transfusions by patients,2, 3 but is costly. In addition, recent evidence indicates that traditional administration of ESA in patients with anemia related to cancer (ARC) is associated with increased risk of mortality and adverse events.4-6

The conclusions of previous economic evaluations of ESA for the treatment of ARC have varied, although many have concluded that it is generally not cost-effective.1, 7, 8 However, all previous analyses have evaluated use of this agent as commonly used before recent guidelines from the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH), which recommend initiation of ESA when hemoglobin is <10 g/dL, a target hemoglobin of ≤12 g/dL, and use in chemotherapy-induced anemia only.9 Guideline adherence is likely to result in lower cumulative ESA dose, the major driver of costs. Furthermore, although increased risk of thromboembolic events and death have been reported with traditional ESA use in this population,4-6 the risk of these events is less clear with more conservative ESA use. As such uncertainty exists concerning the balance of costs, adverse events, and clinical benefit of ESA in this patient population. Many patients and clinicians seek to use ESA because of its convenience, effectiveness in reducing transfusions, and improvements in QOL. We sought to determine the cost-effectiveness of ESA when used in a conventional fashion and in accordance with ASCO/ASH guidelines.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Base case — conventional ESA use

A decision analytic model was constructed incorporating healthcare resource utilization and health outcomes in adult patients with ARC in adherence to published guidelines.10, 11 Treatment strategies evaluated included treatment with conventional use of ESA compared with no ESA, with supportive blood transfusion as required in either strategy. The population was based on characteristics of subjects in randomized controlled trials of ESA for the treatment of ARC identified in our systematic review,4 and summary measures from this review informed all model inputs where data was available. The base-case analysis considered subjects from all included studies, and subsequent analyses focused on subjects enrolled in studies that met components of the ASCO/ASH guidelines. The perspective was that of the Canadian publicly funded healthcare system.

A short-term decision model was created incorporating events that may influence incremental costs and quality-adjusted life years (QALY) in this patient population during the typical duration of treatment with ESA (Fig. 1). Long-term outcomes occurring during an additional 1-year time frame were evaluated in a secondary analysis that considered mortality only (as no other differences in long-term outcomes was found in the clinical review). The risk of mortality during the short-term, probability of blood transfusion, and starting and ending hemoglobin values were based on weighted summary characteristics of the control arms of studies included in the systematic review (Table 1). Long-term annual mortality was estimated from 16 studies that assessed mortality beyond the short-term treatment period (average follow-up duration 90 weeks).12-26 The weekly starting dose and duration of treatment was based on the intervention arm of included studies to define traditional ESA use. The cumulative dose of ESA was inconsistently reported, but as the mean weekly dose did not appear to differ from the weekly starting dose when both were reported,13, 16, 17, 26-31 the weekly dose was assumed to be constant over the duration of administration.

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Figure 1. Model structure and outcomes are shown. Quality of life, survival, and costs are determined for an average patient in each treatment strategy. ESA indicates erythropoiesis-stimulating agent; TE, thromboembolic.

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Table 1. Model Variables
VariableEstimateRangeSource/Comments, No. of Studies
Baseline Clinical Event Rates for No ESA Strategy
  • RBC indicates red blood cells; SD, standard deviation; RCT, randomized controlled trial; SR, systematic review; RR, relative risk; CI, confidence interval; AHW DBL, Alberta Health and Wellness Drug Benefit List; IQR, interquartile range.

  • a

    Based on 30,000 U syringe of epoetin alpha.

  • b

    When only weight-based dosing was reported, we converted to fixed units using information available from each study.

 Short term mortality risk, 15 wk0.131SD=0.122Control arm from RCTs in clinical SR, n=29
 Long term mortality risk, annual0.332SD=0.203Control arm from RCTs in clinical SR, n=17
 Probability of RBC transfusion0.391SD=0.143Control arm from RCTs in clinical SR, n=29
 Initial hemoglobin10.3 g/dLSD=1.03Treatment & control arms from RCTs in clinical SR, n=84 arms
 No. of RBC units if transfused3.63SD=3.46Expert opinion
 Risk of thromboembolic event0.044Control arm from RCTs in clinical SR
Effectiveness Model Variables for Conventional ESA vs No ESA
 RR of short-term mortality1.1595% CI, 1.03-1.29Meta-analysis, n=31
 RR of long-term mortality1.3395% CI, 0.79-1.88Meta-analysis, n=6
 RR of transfusion0.6495% CI, 0.56-0.73Meta-analysis, n=31
 RR of thromboembolic event1.6995% CI, 1.27-2.24Meta-analysis, n=23
 Difference in final hemoglobin1.50 g/dL95% CI, 1.27-1.72Meta-analysis, n=44
 Difference in units of RBCs transfused−0.80 units95% CI, −0.61 to −0.99Meta-analysis, n=20
Cost Model Variables
 Cost per 1000 U epoetina$14.40±25%AHW DBL38
 Cost per 1 mcg darbepoetin$2.88±25%AHW DBL38
 Cost of 1 RBC unit transfusion$576-$418±25%Cremieux33 Amin,37 includes costs of transfusion reactions
 Epoetin (Units)b42,111 Units30,000-40,000 (IQR)From 48 treatment arms, 42 studies, from clinical SR
 Darbepoetin μgb187 μg114-284 (IQR)From 16 treatment arms, 10 studies, from clinical SR
 Cost of thromboembolic event$8394MacDougall32
Utility Score Model Variable
 Utility score for each day of hospitalization, transfusion or transfusion reaction0Estimate

The relative risk of mortality for all ESA during the ESA treatment period was determined from the clinical systematic review; 6 studies reported mortality in patients who survived the short-term treatment period during an additional 63 weeks,12-17 from which the relative risk of mortality during the subsequent year was calculated (Table 1). The difference in the number of units (U) that were transfused per subject between treatment arms was determined from a meta-analysis of studies in the clinical review. As the relative risk of transfusions was more commonly reported, this was incorporated in a secondary analysis using expert opinion to estimate the total number of units transfused for those who needed a transfusion.

The impact of thrombotic events was considered by determining the baseline risk of thrombotic events in the control arms of included studies, applying the relative risk from the systematic review, and incorporating annual costs of thromboembolic from literature sources.32 As the true costs and consequences of thrombotic events in a cancer patient population are not well described, these were included in sensitivity analysis only (favoring ESA in the base case). The long-term infectious complications of erythrocyte transfusion were not incorporated as previous work suggests that the risk of blood-borne illness does not have a meaningful impact,1, 33, 34 and the risks are estimated to be very small given the current safety of the Canadian blood supply.35-37

ESA use in ARC results in improvements in disease-specific quality-of-life (QOL) measures (Functional Assessment of Cancer Therapy, Linear Analogue Self-Assessment) compared with no ESA,1, 4 although no randomized clinical trials (RCTs) have used a preference-based measure of QOL required for cost-utility analyses. As such, we used the relation between achieved hemoglobin and utility score reported by Ossa2 that uses time trade-off analysis to elicit utilities for anemia-related health states in patients with cancer (Table 2). Various health states were described based on a typical cancer patient undergoing chemotherapy without anemia (hemoglobin >11.0g/L) as the reference health state, and additional health states were described for various degrees of anemia. All health-state descriptions were based on the Functional Assessment of Cancer Therapy-Anemia subscale and clinical literature, and health-state descriptions were validated by 3 specialists in oncology and 6 cancer patients who experienced anemia. Laypersons (n = 110) from the United Kingdom underwent face-to-face interviews where health states were described in detail, and time trade-off methodology was used to derive utilities for each of the anemia states. As the health status related to cancer and its treatment was constant in all scenarios, we assumed that incremental differences between the health states were due to treatment of anemia only. This approach values the health state of anemia related to cancer only, and it does not incorporate preferences as to how anemia is treated.

This association between hemoglobin and QOL was transformed into a linear relation to capture the potential difference in QOL that would occur with small differences in hemoglobin (Fig. 2). Alternative associations of hemoglobin values and QOL using untransformed data2 and utility estimates from ESA-manufacturer studies1 were considered in secondary analyses.

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Figure 2. Linear transformation of hemoglobin and QOL is displayed.

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Initial hemoglobin was calculated from the control and intervention arms in the included studies, and the final achieved hemoglobin was calculated using the incremental change in hemoglobin achieved using ESA from the systematic review (1.50 g/dL; 95% CI, 1.27-1.72; Table 1). Hemoglobin (g/dL) in the ESA arm tends to gradually increase after administration until the end of the study period and may persist after this.1 As a result, the incremental differences in hemoglobin at the end of ESA use are likely near their greatest. For simplicity, and because we did not have access to primary data to calculate the area under the curve, we assumed that incremental differences in hemoglobin and associated QOL would occur immediately after the initiation of ESA and persist throughout the treatment period (15 weeks). This approach to estimating the utility scores is favorable to the ESA strategy. We also tested the impact of the duration of hemoglobin (and QOL) benefits persisting for 26 weeks (15 weeks of treatment with 11 weeks after treatment1).

The cost of ESA was based on the cost of a 30,000 U syringe of epoetin alpha from Alberta Blue Cross,38 and the cost of 1 unit of erythrocytes for transfusion was taken from literature sources.3, 33, 37 All costs were converted to 2008 Canadian dollars by using the consumer price index for healthcare goods in Canada.39 No discounting was performed given the short time horizon.

A 1-way sensitivity analysis was performed on model parameters by using the 95% confidence interval, standard deviation, or interquartile range as appropriate. The costs of ESA varied by ±25%, and a range of estimates of costs per unit of blood transfusion was considered (Table 1). An alternative approach to modeling reduction in blood transfusion (applying a relative risk to the baseline rate of transfusion) was also performed. In some circumstances, timely blood transfusion for outpatients may be difficult to provide. This may result in an emergency room visit or admission to hospital. Although this issue is best addressed through assessment and modification of healthcare service capacity, we assessed a scenario in which all those who received a blood transfusion would be admitted for 1 day (with per diem costs of $934 to $1330 based on local data, and utility of 0 [equivalent to death] during hospitalization) in the model incorporating relative risk of transfusion. Finally, whereas mortality and cost differences due to clinically significant transfusion reactions are incorporated in the base case,37, 40 we assessed the impact of change in QOL, assuming an average of 3 days hospitalization (based on expert opinion) for management with utility score of 0.

ESA use in accordance with ASCO/ASH guidelines

The recently published ASCO/ASH guidelines recommend that ESA be used in patients with chemotherapy-induced anemia, started only when Hb is <10 g/dL and the dose adjusted to achieve hemoglobin of 12 g/dL or less.9 To estimate the cost-utility of this strategy, we performed scenario analyses by identifying study populations approximating these elements. Subgroups were considered by using data from studies with 1) target Hb of ≤12 g/dL; 2) baseline Hb of <10 g/dL; and 3) target Hb of ≤12 g/dL, starting Hb of <10 g/dL, and chemotherapy-induced anemia only. We determined the relative risk (RR) of mortality and transfusion, initial hemoglobin, and the starting and actual ESA weekly dose from these studies (Table 3). Input from the base model were used when data were not available from the included studies.

Table 2. Relation Between Hemoglobin and Utility by TTO From Ossa2
Health StatusNo. of ParticipantsAverage Hb Level, g/dLaUtility Scores Mean (SD;SE)Utility Scores Minimum, MaximumRatio Compared With Typical Cancer Patient Without Anemia
  • TTO indicates time trade-off; Hb, hemoglobin; SD, standard deviation; SE, standard error.

  • a

    Average hemoglobin level represents the median hemoglobin level within each anemia level as classified by the World Health Organization.

No anemia10611.00.86 (0.14;0.014)0.3, 1.01.0
Mild anemia10610.20.78 (0.17;0.016)0.3, 1.00.91
Moderate anemia1068.70.61 (0.21;0.020)0.1,1.00.72
Severe anemia1067.20.48 (0.21;0.020)0.0, 1.00.56
Table 3. Scenario Analyses Considering Results of RCTs That Were Conducted in Accordance With 1, 2 or All of the Components of the ASCO/ASH Guidelines for Use of ESAs in ARC
ASCO/ASH ScenariosRR Death Short-Term (95% CI)RR Transfusion (95% CI)ESA Dose U/wkRR Death Long-Term (95% CI)Initial Hb, g/dLIncremental $/QALY Gained Short-Term ModelIncremental $/QALY Gained Long-Term Model
  • RCT indicates randomized controlled trial; ASCO/ASH, American Society of Clinical Oncology/American Society of Hematology; ESA, erythropoiesis-stimulating agents; ARC, anemia related to cancer; Hb, hemoglobin; CIA, chemotherapy-induced anemia; RR, relative risk; CI, confidence interval; NR, not reported; QALY, quality-adjusted life year.

  • a

    All studies reported initial weekly starting dose of ESA (initial dose), and few reported actual weekly dose administered. When available, both are reported, and results for both are calculated.

  • b

    When results were not available, base-case model inputs were used.

ASCO Scenario A
 Considering RCTs with a target Hb≤12 g/dL1.15 (0.94-1.40) 8 Studiesb0.56 (0.42-0.73) 5 Studies 1.77 (0.22-3.32) 2 Studies9.8  
 Initial dosea  22,191 8 Studies  $101,679ESA dominated
 Actual dosea  17,673 3 Studies  $71,859ESA dominated
ASCO Scenario B
 Considering RCTs with an initial Hb≥10 g/dL1.04 (0.81-1.32) 13 Studies0.72 (0.62-0.84) 9 Studies 0.97 (0.94-1.01) 3 Studies9.6  
 Initial dosea  29,502 13 Studies  $149,346$180,712
 Actual dosea  16,596 1 Study  $72,810$88,102
ASCO Scenario C
 Considering RCTs with a target Hb≤12 g/dL, initial Hb≤10 g/dL, and CIA only0.77 (0.36-1.66) 2 Studies0.50 (0.29-0.87) 2 Studies     
 Initial dosea  37,069 2 StudiesNRbNR$139,691ESA dominated
 Actual dosea  NR

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

In the base case, we modeled a cohort of patients similar to those identified in a recent systematic review.4 The average age of the cohort was 62 years, their mean initial hemoglobin was 10.4 g/dL, and 80% were treated with chemotherapy. The type of cancer among patients in this cohort was 21% hematological, 63% solid, and 17% mixed malignancy. Compared with no ESA and supportive transfusion, treatment with epoetin resulted in incremental costs of $8643 and incremental benefits of 0.03 QALYs over 15 weeks, resulting in an incremental cost per QALY gained of $267,000. During a 17-month time frame, the ESA strategy was dominated with incremental costs of $8643 and lower QALYs (−0.086) compared with the no ESA strategy.

The base-case results were robust in sensitivity analysis (Tables 4 and 5). By using the extremes of 95% confidence intervals for short-term and long-term mortality, both favoring ESA, resulted in an incremental cost per QALY gained of $101,000. A best-case quality-of-life scenario in which all assumptions favored the ESA arm over the short-term led to an incremental cost effectiveness of $125,000/QALY (Table 6). Making the assumption that there is no increased risk of mortality or adverse events with ESA did not significantly alter the results of the QOL scenarios. Incremental cost per QALY gained remained >$180,000 under the assumption that transfusion required 1 day of hospitalization, disutility for transfusion reaction, weekly dose and dose duration of epoetin, and cost per unit of ESA (Table 5). Varying the cumulative dose and cost per unit of ESA had a larger quantitative impact on results. Use of the most up-to-date Canadian estimates of the cost of transfusing 1 unit of erythrocytes (including collection, production, distribution, administration, and transfusion reactions)37 resulted in an incremental cost per QALY gained of $271,000/QALY.

Table 4. Sensitivity Analyses Parameters and Results for Relative Risk of Mortality at 15 Weeks and at 1 Year (Base-Case ESA Compared With No ESA)
Model Time HorizonRR Short-Term Mortality, 15 WkRR Long-Term Mortality, AnnualIncremental $/QALY Gained
  1. Sensitivity analyses parameters and results are indented.

  2. RR indicates relative risk; ESA, erythropoiesis-stimulating agent; CI, confidence interval; na, not applicable; QALY, quality-adjusted life year.

Short-Term, 15 wk1.15 (Point estimate)na$267,346 (Base Case)
 Sensitivity analysis1.29 (Upper 95% CI)na$315,336
 Sensitivity analysis1.03 (Lower 95% CI)na$236,497
Long-Term, 1.3 y1.15 (Point estimate)1.33 (Point estimate)Dominated
 Sensitivity analysis1.29 (Upper 95% CI)1.88 (Upper 95% CI)Dominated
 Sensitivity analysis1.03 (Lower 95% CI)0.79 (Lower 95% CI)$100,984
Table 5. Base-Case Model of Additional 1-Way Sensitivity Analyses
VariablePoint EstimateRangeIncremental CostIncremental Effectiveness QALYIncremental $/QALY Gained
  1. QALY indicates quality-adjusted life years.

Base case  $86340.03$267,000
Cost per 1000 U epoetin$14.40−25% to +25%$6367-$10,9190.0323-0.0323$196,946-$337,746
Unit of epoetin per wk42,14830,000$60190.0323$186,183
Baseline risk of mortality0.1310.087 to 0.175$8643-$86430.0360-0.0287$240,062-$301,628
Incremental units of blood transfused−0.80−0.99 to −0.61$8534-$87530.0323-0.0323$263,961-$270,732
Cost of transfusion$576−25% to +25%$8758-$85280.0323-0.0323$270,910-$263,783
Inclusion of thrombotic event costs$88980.0323$275,230
Admission to hospital for transfusion, cost per day$934-$1330 $7905-$84660.0323-0.0323$244,076-$256,255
Table 6. Sensitivity Analyses and the Impact of Alternate Methods of Estimating QOL and Other Assumptions on Incremental Costs and QALYs of ESA Compared With Standard Treatment
Source of QOL EstimateDuration of BenefitIncremental Hemoglobin ESA vs Standard, g/dLQOL Standard TreatmentQOL ESAIncremental CostIncremental Effectiveness QALYIncremental $/QALY Gained
  • QOL indicates quality of life; QALY, quality-adjusted life year; ESA, erythropoiesis stimulating agent; TTO, time trade-off.

  • a

    Parameters changed for sensitivity analyses.

Ossa prediction15 wk1.500.780.93$8643.20.0323$267,346
Ossa originala15 wk1.500.780.86$8643.20.0152$569,411
TTOa15 wk1.500.73650.785$8643.20.00771$1,121,317
EQ-5Da15 wk1.500.6820.75$8643.20.0128$675,534
Ossa prediction15 wk1.72a0.780.96$8643.20.0397$217,824
Ossa prediction26 wka1.72a0.780.96$8643.20.0688$125,668

To estimate the cost effectiveness of ESA use concordant with ASH/ASCO guidelines,9 model inputs from studies that met components of these guidelines were summarized where available (Table 3). The initial and actual dose of ESA was substantially lower than the base-case analysis, although infrequently reported. The results were quantitatively lower than the base case, but all exceeded $70,000/QALY, and ESA was dominated (more costly with less benefit) in 3 of 10 models. It should be noted that because of the poor quality of studies, inconsistent reporting, and wide confidence intervals of the model inputs, there is considerable uncertainty in these estimates.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Recent evidence clearly demonstrates that increased risk of mortality and adverse events are associated with conventional ESA use in patients with anemia related to cancer.4-6 A currently unanswered question facing clinicians and policy makers is whether the benefits in quality of life, on balance, outweigh risks and costs where the risk of adverse consequences of ESA are attenuated or eliminated, which is possible under more conservative ESA administration practices. Several Canadian provinces currently fund ESA for the treatment of ARC when used according to the ASCO/ASH guidelines, despite the lack of evidence to support this practice.4 Our results suggest that treatment with ESA remains economically unattractive even when used according to the ASCO/ASH guidelines41, 42 —similar to the conclusions reached by previous economic evaluations evaluating more liberal use of ESA.1, 7, 8

To our knowledge, no RCTs used a preference-based measure of overall quality of life, which is required to perform cost-utility analyses. This is especially important when considering strategies to treat anemia, as the major benefit is in QOL. Disease-specific measures, which are commonly used in clinical studies of cancer patients with anemia, may have an increased sensitivity to detect small differences in certain aspects of quality of life. Although changes in disease-specific measures do not necessarily lead to clinically important changes in utility-based measures, the magnitude of the changes found4, 40 meet thresholds for minimal clinically important differences (MCID).43, 44 In addition, the sole study that reported a generic (not disease-specific) measure of overall quality of life28 found greater improvements among ESA recipients in the physical components summary of the Short Form 36 (SF-36) (3.4 vs −0.7 for ESA and no ESA, respectively) and in a global measure of QOL that was assessed by using a visual analog scale (11.0 vs −0.4 for ESA and no ESA, respectively). Although this trial was not eligible for inclusion in the systematic review, the magnitude of this improvement also met the MCID threshold.45 Therefore, it appears reasonable to assume that ESA may improve quality of life among cancer patients, at least in the short term.

We used assumptions that may exaggerate the QOL gains associated with differences in hemoglobin, favoring the ESA strategy. In the base-case method of estimating QOL, the difference in the utility score between the ESA and the no ESA arm in surviving patients was 0.15. This large difference in utility is far greater than the minimal clinically important difference of 0.03 for the EQ-5D46 and is similar to the change in QOL that is associated with a patient with end-stage kidney disease on dialysis who receives a kidney transplant.47 Despite this possible overestimation of QOL in the ESA arm, the incremental cost-utility ratio (ICUR) remained >$100,000/QALY, even in multiway sensitivity analysis.

We did not incorporate patient preferences with respect to avoiding blood transfusion (travel, time requirement, intravenous administration, aversion to receipt of blood products) and avoiding the potential cyclic nature of this treatment (gradually dropping hemoglobin followed by a rapid rise with blood transfusion). However, 2 published studies used willingness-to-pay (WTP) and discrete-choice experiment (DCE) methods to estimate the value that participants place on these considerations. Ortega3 reported the willingness-to-pay for ESA therapy (compared with no ESA therapy) of $587 and $613 (1997 US dollars), respectively, from patients who were receiving cisplatin or noncisplatin therapy. By using DCE methods, Ossa2 elicited WTP from laypersons in the United Kingdom of £368 (2004 British pounds). These results indicated the preference of patients and laypersons for ESA over transfusion only, although these studies did not inform respondents of the increased risk of adverse outcomes that have recently come to light. Regardless, incorporation of the monetary value of these preferences would not result in meaningful changes in the conclusions, suggesting that in private-payor systems, this treatment strategy would be unattractive.

We performed additional scenario analyses to simulate the use of ESA in accordance with the ASCO/ASH criteria.9 However, very few studies met even individual components of these guidelines, and the selective reporting of outcomes might have introduced bias. In light of these inherent uncertainties, we performed 10 analyses simulating the use of ESA in accordance with components of ASCO/ASH criteria. In 3 of these analyses, ESA therapy was dominated (more costly with less benefit than the no ESA strategy); in 4 the incremental cost per QALY gained was >$100,000/QALY; and none were <$70,000/QALY. These analyses included scenarios where the mortality risk was similar or lower than the no ESA strategy (and the cost of thrombotic events were not considered). Overall, these findings suggest that even with more conservative administration and dosing, ESA therapy for patients with cancer is unlikely to be economically attractive when using a commonly accepted threshold of economic attractiveness.41, 42

As in most economic evaluations, our models and results are limited by the availability and quality of existing evidence. Our evaluation has been strengthened by its rigorous methods and our state-of-the-art systematic review. The lack of strong evidence on the incremental changes in utility-based QOL was addressed by modeling approaches and sensitivity analyses as described above. The model did not incorporate other considerations that may affect QOL, including cyclical hemoglobin values, aversion to intravenous administration, and receipt of human-blood products, but this was informally assessed by using willingness-to-pay estimates from other sources.

This is the first economic evaluation to determine the ICUR of ESA use in accordance with recently published ASCO/ASH guidelines. Although considerable uncertainty concerning the precise incremental costs and benefits of ESA therapy in this subgroup remains, there is no evidence to suggest that ESA is more economically attractive in this subgroup than in any other. Finally, this economic evaluation considered subjects that were candidates for blood transfusion. Specific subpopulations, such as those in whom blood transfusions are difficult or unacceptable (ie, iron overload, Jehovah's Witnesses) and patients with poor access to transfusion support, were not examined.

In summary, ESA use in patients with ARC does not appear to be economically attractive, even when used in the more conservative fashion recommended by current guidelines. Available evidence suggests that using ESA to treat ARC does not represent a good value for the money.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
  • 1
    Wilson J, Yao GL, Raftery J, et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. Health Technol Assess. 2007; 11: 1-202, iii-iv.
  • 2
    Ossa DF, Briggs A, McIntosh E, Cowell W, Littlewood T, Sculpher M. Recombinant erythropoietin for chemotherapy-related anaemia: economic value and health-related quality-of-life assessment using direct utility elicitation and discrete choice experiment methods. Pharmacoeconomics. 2007; 25: 223-237.
  • 3
    Ortega A, Dranitsaris G, Puodziunas AL. What are cancer patients willing to pay for prophylactic epoetin alfa? A cost-benefit analysis. Cancer. 1998; 83: 2588-2596.
  • 4
    Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ. 2009; 180: E62-E71.
  • 5
    Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009; 373: 1532-1542.
  • 6
    Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008; 299: 914-924.
  • 7
    Sheffield R, Sullivan SD, Saltiel E, Nishimura L. Cost comparison of recombinant human erythropoietin and blood transfusion in cancer chemotherapy-induced anemia. Ann Pharmacother. 1997; 31: 15-22.
  • 8
    Fagnoni P, Limat S, Chaigneau L, et al. Clinical and economic impact of epoetin in adjuvant-chemotherapy for breast cancer. Support Care Cancer. 2006; 14: 1030-1037.
  • 9
    Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008; 26: 132-149.
  • 10
    Guidelines for the economic evaluation of health technologies. 3rd ed. Ottawa, Canada: Canadian Agency for Drugs and Technology in Health. 2006.
  • 11
    Weinstein MC, O'Brien B, Hornberger J, et al. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices–Modeling Studies. Value Health. 2003; 6: 9-17.
  • 12
    Witzig TE, Silberstein PT, Loprinzi CL, et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol. 2005; 23: 2606-2617.
  • 13
    Kettelhack C, Hones C, Messinger D, Schlag PM. Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma. Br J Surg. 1998; 85: 63-67.
  • 14
    Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B; Epoetin Alfa Study G. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2001; 19: 2865-2874.
  • 15
    Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002; 94: 1211-1220.
  • 16
    Smith RE, Jr, Aapro MS, Ludwig H, et al. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2008; 26: 1040-1050.
  • 17
    Gordon D, Nichols G, Ben-Jacob A, Tomita D, Lillie T, Miller C. Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study. Oncologist. 2008; 13: 715-724.
  • 18
    Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer. 1993; 29A( suppl 2): S2-S8.
  • 19
    Kosmadakis N, Messaris E, Maris A, et al. Perioperative erythropoietin administration in patients with gastrointestinal tract cancer: prospective randomized double-blind study. Ann Surg. 2003; 237: 417-421.
  • 20
    Chang J, Couture F, Young S, McWatters KL, Lau CY. Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol. 2005; 23: 2597-2605.
  • 21
    Savonije JH, van Groeningen CJ, van Bochove A, et al. Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: Results of a multicenter randomised controlled trial. Eur J Cancer. 2005; 41: 1560-1569.
  • 22
    Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007; 25: 1027-1032.
  • 23
    Aapro M, Leonard RC, Barnadas A, et al. Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study. J Clin Oncol. 2008; 26: 592-598.
  • 24
    Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol. 2008; 108: 317-325.
  • 25
    Overgaard J, Hoff C, Sand Hansen H, et al. Randomized study of the importance on novel erythropoiesis stimulating protein (Aransep) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC) - the Danish Head and Neck Cancer Group DAHANCA 10 rand [abstract]. Eur J Cancer. 2007; 5S: 7.
  • 26
    Results from a phase 3, randomized, double-blind, placebo-controlled study of darbepoetin alfa in subjects with previously untreated extensive-stage small-cell lung cancer (SCLC) treated with platinum plus etoposide chemotherapy. Study: 20010145. Thousand Oaks, CA: Amgen. 2007.
  • 27
    O'Shaughnessy JA, Vukelja SJ, Holmes FA, et al. Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer. 2005; 5: 439-446.
  • 28
    Boogaerts M, Coiffier B, Kainz C; Epoetin beta QOL Working Group. Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer. 2003; 88: 988-995.
  • 29
    Strauss HG, Haensgen G, Dunst J, et al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer. 2008; 18: 515-524.
  • 30
    ten Bokkel Huinink WW, de Swart CA, van Toorn DW, et al. Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy. Med Oncol. 1998; 15: 174-182.
  • 31
    Charu V, Belani CP, Gill AN, et al. Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial. Oncologist. 2007; 12: 727-737.
  • 32
    MacDougall DA, Feliu AL, Boccuzzi SJ, Lin J. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm. 2006; 63( 20 suppl 6): S5-S15.
  • 33
    Cremieux PY, Finkelstein SN, Berndt ER, Crawford J, Slavin MB. Cost effectiveness, quality-adjusted life-years and supportive care. Recombinant human erythropoietin as a treatment of cancer-associated anaemia. Pharmacoeconomics. 1999; 16( 5 pt 1): 459-472.
  • 34
    Barosi G, Marchetti M, Liberato NL. Cost-effectiveness of recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia. Br J Cancer. 1998; 78: 781-787.
  • 35
    Transfusion Transmitted Injuries Section: About Risks of Blood Transfusion. Public Health Agency of Canada. Available at: http://www.ab.bluecross.ca/hcai-iamss/tti-it/risks-eng.php. Accessed March 2009.
  • 36
    Kleinman S, Chan P, Robillard P. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev. 2003; 17: 120-162.
  • 37
    Amin M, Fergusson D, Wilson K, et al. The societal unit cost of allogenic red blood cells and red blood cell transfusion in Canada. Transfusion. 2004; 44: 1479-1486.
  • 38
    Alberta Blue Cross. Alberta Health and Wellness Drug Benefit List Criteria for Special Authorization of Select Drug Products. 2008. Edmonton, Canada: Alberta Health and Wellness. Available at: http://www.ab.bluecross.ca/dbl/pdfs/ahwdbl_sec3.pdf. Accessed March 2009.
  • 39
    Statistics Canada. Consumer Price Index for Canada [health care (not seasonally adjusted) 1972-1996]. 1997; Cat no 62-553. Ottawa, Canada: Statistics Canada.
  • 40
    Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ. 2009; 180: E62-71.
  • 41
    Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ. 1992; 146: 473-481.
  • 42
    Rawlins MD, Culyer AJ. National Institute for Clinical Excellence and its value judgments. BMJ. 2004; 329: 224-227.
  • 43
    Patrick DL, Gagnon DD, Zagari MJ, Mathijs R, Sweetenham J. Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer. 2003; 39: 335-345.
  • 44
    Cella D, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage. 2002; 24: 547-561.
  • 45
    Samsa G, Edelman D, Rothman ML, Williams GR, Lipscomb J, Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics. 1999; 15: 141-155.
  • 46
    Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997; 35: 1095-1108.
  • 47
    Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996; 50: 235-242.