Docetaxel in Combination With Doxorubicin and ...

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JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

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Docetaxel in Combination With Doxorubicin and Cyclophosphamide As Adjuvant Treatment for Early Node-Positive Breast Cancer: A Cost-Effectiveness and Cost-Utility Analysis Sorrel E. Wolowacz, David A. Cameron, Helen C. Tate, and Adrian Bagust From RTI-Health Solutions, Manchester; Department of Oncology, Western General Hospital, Edinburgh; New House Farm, Purton End, Debden, Saffron Walden Essex, UK; and Prescribing Research Group, The University of Liverpool Management School, Liverpool, United Kingdom. Submitted January 3, 2007; accepted October 24, 2007. Supported by a grant from Sanofi-aventis to Western General Hospital, Edinburgh, United Kingdom, to cover costs of data retrieval. RTI-HS was commissioned by Sanofi-aventis Inc to perform the modeling work. Contractual arrangements between RTI-HS and Sanofi-aventis did not prevent RTI-HS from independently publishing this work. This manuscript was reviewed by Sanofi-aventis.

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Purpose To estimate the cost effectiveness of TAC (docetaxel, doxorubicin, and cyclophosphamide) compared with FAC (fluorouracil, doxorubicin, and cyclophosphamide) when administered as adjuvant therapy to women with node-positive early breast cancer in the United Kingdom (UK), both with and without primary prophylaxis with granulocyte colony-stimulating factor (G-CSF). Methods A standard health economic Markov model estimated the cost and outcome for node-positive early breast cancer patients, from initiation of adjuvant chemotherapy to death. Patient-level data were used from the Breast Cancer International Research Group (BCIRG) 001 trial for estimates of the effect of chemotherapy on toxicity and outcome, and an observational data set collected from a UK university hospital provided estimates of resource use and outcome for patients with relapsed disease.

The model reported herein was used to support submissions to the UK National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC).

Results Over a 10-year analysis timeframe, the incremental cost per life-year saved associated with the use of TAC rather than FAC was estimated as £15,418 (95% CI, £13,734 to £17,997) and the incremental cost per quality-adjusted life-year gained (IC/QALY) was £18,188 (95% CI, £14,161 to £32,422). The addition of primary G-CSF (lenograstim or filgrastim) to the TAC regimen resulted in an IC/QALY of £20,432. The results were most sensitive to the quality-of-life (QOL) score for patients in remission postchemotherapy. However, even if QOL was assumed to be as poor as for patients with metastatic disease, the IC/QALY estimate rose only to £32,430.

Presented in part at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 8th Annual European Congress, November 6-8, 2005, Florence, Italy.

Conclusion The use of adjuvant TAC rather than FAC for node-positive early breast cancer patients is cost effective, despite the increased drug and toxicity treatment costs, and when primary G-CSF prophylaxis is given to all patients.

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

J Clin Oncol 26:925-933. © 2008 by American Society of Clinical Oncology

Corresponding author: Sorrel E. Wolowacz, PhD, RTI-Health Solutions, Williams House, University of Manchester Science Park, Manchester M15 6SE, United Kingdom; e-mail: [email protected]. © 2008 by American Society of Clinical Oncology 0732-183X/08/2606-925/$20.00 DOI: 10.1200/JCO.2006.10.4190

INTRODUCTION

Docetaxel is an antineoplastic agent that binds beta tubulin, resulting in stabilization of microtubules, cell-cycle arrest, and cell death.1 Docetaxel has an extensive history of use since its approval in the mid-1990s in the treatment of locally advanced or metastatic breast cancer, non–small-cell lung cancer, and hormone-refractory prostate cancer. Recently, docetaxel has been investigated as an adjuvant treatment for early breast cancer (EBC) in combination with anthracycline-containing regimens. Two phase III trials have demonstrated significant relative reductions in the risk of relapse and death of between 17% and 30% in comparison to robust anthracycline-containing regimens. In

trial BCIRG001,2 six cycles of docetaxel in combination with doxorubicin and cyclophosphamide (TAC) was significantly more effective than six cycles of fluorouracil in combination with doxorubicin and cyclophosphamide (FAC; hazard ratio [HR] for relapse ⫽ 0.72, P ⫽ .001; HR for death ⫽ 0.70, P ⫽ .008; median follow-up, 55 months). In trial PACS 01,3 three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel (FEC3 T) was significantly more effective than six cycles of FEC (HR for relapse ⫽ 0.82, P ⫽ .0434; HR for death ⫽ 0.73; median follow-up, 60 months). Because the number of cycles was equal in both treatment arms, improved outcomes in these trials may be directly 925

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Wolowacz et al

attributed to the substitution of docetaxel into these regimens. The superior survival outcome expected from docetaxelcontaining regimens is, however, acquired at an additional cost. At 2005 values, the drug acquisition cost for TAC in the United Kingdom (UK) is £1,196 per cycle (€1,783 using an exchange rate of £1.00 ⫽ €1.49046) compared with £186 (€277) for FAC (assuming a body surface area of 1.7 m2 and unused drug in opened vials is discarded; for docetaxel, one 2-mL vial [at £534.75 per vial]and three 0.5-mL vials [at £162.75 per vial] are assumed per cycle). In addition, there is concern about the higher rate of febrile neutropenia reported for the TAC regimen in trial BCIRG001 (in which primary prophylactic granulocyte colony-stimulating factor [G-CSF] was not permitted), and the resultant impact on health-related quality of life (HRQoL) and medical costs. We present an economic analysis that estimates the cost effectiveness of TAC versus FAC as adjuvant therapy for node-positive EBC. The analysis takes the perspective of the UK National Health Service (NHS) for the cost year 2005 and estimates the incremental cost per life-year saved (IC/LYS) and the incremental cost per quality-adjusted life-year gained (IC/QALY) for TAC versus FAC. The implications of adverse events in terms of cost and HRQoL, and the impact of providing all patients with primary G-CSF prophylaxis to prevent neutropenia, are explored.

METHODS Model A cohort of 1,000 women with node-positive EBC (median age, 49 years; 55% premenopausal; 76% estrogen or progesterone receptor positive), who were disease free after locoregional surgery, were entered into a Markov model (Fig 1). Patients remained in the remission health state unless they had a relapse (locoregional or distant) or died as a result of other causes. The number of patients exiting the remission state at the end of each monthly cycle was governed by time-dependent transition probabilities of relapse or death resulting from other causes. Patients remaining in the remission state were attributed the survival and quality-adjusted survival for that month, and the cost of any monitoring in that month. Because there are no data suggesting that outcomes after first relapse are affected by the adjuvant chemotherapy received (confirmed for survival outcome in patients receiving TAC or FAC in BCIRG001 [treatment group did not have a significant effect on survival from locoregional recurrence (log-rank P ⫽ .48) or distant recurrence (log-rank P ⫽ .83), Sanofi-aventis data on file]), the analysis of events postrelapse was simplified to a series of three pay-offs: the total expected survival, QALYs, and cost postrelapse. These represented the average experience of relapsing patients, including those achieving long-term remission after first locoregional recurrence and those developing further locoregional and/or metastatic disease. A decision tree was used to estimate the costs of adjuvant chemotherapy, and the impact of adverse events on costs and HRQoL, which allowed the proportion of patients receiving primary G-CSF prophylaxis, experiencing adverse events, and discontinuing therapy as a result of adverse events to be

A Costs and outcomes during remission: • Cost of monitoring • QALYs per month in remission

Locoregional recurrence

First recurrence TAC

Average costs and outcomes from the point of first recurrence: • Mean cost • Mean life-expectancy • Mean QALYs

Distant recurrence

Remission

Death from other causes

Average costs and outcomes from the point of first recurrence: • Mean cost • Mean life-expectancy • Mean QALYs

Dead

As for TAC

FAC

B Cost of adjuvant chemotherapy

Cost of G-CSF

Cost of managing adverse event

Cost adjustment for less adjuvant chemotherapy

Impact of adverse event on quality of life

Cost of supplementary adjuvant chemotherapy and AEs Impact of AEs from supplementary chemotherapy on quality of life

Supplementary adjuvant chemotherapy Discontinue due to adverse event* No supplementary adjuvant chemotherapy

Adverse event Don't discontinue due to adverse event

No primary G-CSF No adverse event

TAC Primary G-CSF FAC

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Fig 1. Schematic representation of the model structure. Patients who are disease free after locoregional surgery enter the model and receive adjuvant chemotherapy (chemo) with either TAC (docetaxel, doxorubicin, cyclophosphamide) or FAC (fluorouracil, doxorubicin, cyclophosphamide). (B) A decision tree calculates costs during the adjuvant chemotherapy period, and qualityadjusted life years (QALYs) lost as a result of adverse events. Costs included adjuvant chemotherapy, granulocyte colonystimulating factor (G-CSF), management of adverse events (AEs,) and supplementary adjuvant chemotherapy for patients discontinuing prematurely due to AEs. In (A) the Markov model, patients remain in the remission health state until they experience a recurrence (locoregional or distant) or die as a result of other causes. Patients in remission are attributed monitoring costs and QALYs for the remission state. Patients experiencing a recurrence are attributed average costs, life years, and QALYs expected for patients whose first recurrence is locoregional, or whose first recurrence is distant. The cycle length was 1 month.

As for No Primary G-CSF

As for TAC



TAC As Adjuvant Treatment for Early Node-Positive Breast Cancer

varied. Patients discontinuing as a result of adverse events received fewer cycles of the planned regimen and appropriate supplementary adjuvant chemotherapy (FAC or CMF [cyclophosphamide, methotrexate and fluorouracil]). The time horizon of the analysis was varied from 5 years to 40 years. The primary data source was trial BCIRG001,2 in which women with node-positive EBC were randomly assigned to TAC (n ⫽ 745) or FAC (n ⫽ 746) and followed up for a median of 55 months. The primary end point was disease-free survival (DFS). Patient-level data were analyzed to derive estimates of DFS and overall survival, chemotherapy usage, and adverse event probabilities. An observational data set provided by the Western General Hospital (WGH; Edinburgh, UK), consisting of women with node-positive EBC who had received adjuvant chemotherapy and subsequently relapsed, was analyzed to estimate health care resource use and outcomes postrelapse. Key model parameters are summarized in Tables 1 and 2. Probabilistic and univariate sensitivity analyses were performed (described in the Appendix, online only). Details of probabilistic parameter estimation are presented in Tables 1 and 2. Costs and outcomes were discounted at 3.5% per annum. Cost of Adjuvant Chemotherapy and Support Drug costs assumed an average body surface area4 of 1.7 m2, an average weight of 70 kg and that unused drug in opened vials is discarded (Table 1). Administration costs were adapted from a NHS report.5 The number of cycles was estimated by treatment group from drug use in trial BCIRG001. Although primary prophylaxis with G-CSF was not permitted in BCIRG001, a small proportion of patients received it (7.0% and 7.7% in the TAC and FAC arms, respectively). Because the adverse events recorded reflect this use of primary prophylaxis, the cost was included. The impact of assuming that all TAC patients received primary prophylaxis was investigated in sensitivity analysis. The cost of adjuvant hormone and radiotherapy was excluded because they were used equally in the TAC and FAC arms of BCIRG001 (68.4% and 68.9% of TAC and FAC patients received hormone, respectively; 68.8% and 71.9% received radiotherapy, respectively). Adverse Events Grade 3/4 or severe to life-threatening events that occurred in more than 1% of patients in either trial arm and at a difference of greater than 2% between arms were included. Probabilities were derived from trial BCIRG001. Febrile neutropenia and neutropenic infection were combined because the impact on costs and HRQoL are similar. For analyses in which TAC patients received primary prophylaxis with G-CSF, the probability of febrile neutropenia was assumed to be 7.5% for lenograstim or filgrastim (from GEICAM98056) and 1% for pegfilgrastim (from Vogel et al7). Cost estimates (Table 2) were derived from the published literature8-10 with the exception of stomatitis, which was based on clinical opinion (from five UK consultant oncologists). Utility decrements were derived from the published literature.11-13 The duration of HRQoL impairment was estimated from published data and clinical opinion (five UK consultant oncologists). G-CSF use was estimated from trial BCIRG001. Costs assumed 50% of patients receive lenograstim, and 50% receive filgrastim. Survival Estimates DFS. Survival modeling of the patient-level data from trial BCIRG001 was performed to estimate probabilities of relapse and predict events beyond trial follow-up. Simple survival functions (Weibull and loglogistic) incorporating age, node status, estrogen-receptor status, and grade as covariates were unable to achieve an acceptable fit to the data. We therefore fitted a partitioned function composed of superimposed loglogistic and exponential functions, after an event-free lag-period (Appendix). The partitioned function closely predicted the Kaplan-Meier DFS curve (Fig 2A). Long-term DFS was dominated by an exponential function common to both treatment arms, thereby making the conservative assumption that the treatment effect does not continue in the long term. This resulted in a gradual convergence of the DFS curves after trial end (Fig 2B). The uncertainty in the extrapolation of DFS beyond trial end was explored using three additional methods: a survival model fitted to pooled data from both treatment arms (ie, assuming a common long-term risk and that no differential treatment effect is continued beyond trial follow-up); a model

fitted with treatment as a factor (ie, assuming continuation of the proportional odds predicted by the trial data); and natural history data for a population of EBC patients treated with CMF and followed-up for a period of 20 years.14 Survival postrelapse. Mean overall survival postrelapse was estimated from the BCIRG001 patient-level data pooled for both treatment arms using Kaplan-Meier survival analysis (Table 1). The uncertainty in these estimates was explored in sensitivity analysis. All-cause mortality. The probability of death resulting from other causes was estimated from age-specific mortality rates for women.15 Probabilities were calculated for the age distribution of the BCIRG001 population, and adjusted as patients aged in subsequent model cycles. QoL The utility weight for remission was derived from European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire QLQ-C30 data collected in trial BCIRG001. Assessments of patients who had completed chemotherapy and had not experienced a relapse (n ⫽ 929) were converted into utilities using a published algorithm.16 Utility weights for health states postrelapse were obtained from the literature.17 QALYs postrelapse were estimated by combining these utility weights with the probability of experiencing each health state and the mean time spent in each health state, estimated from the WGH data set. Costs of Monitoring and Care Postrelapse Monitoring for patients in remission consisted of 6-monthly outpatient visits for the first 2 years and then a final visit at 3 years with annual mammograms, in line with current UK National Institute for Health and Clinical Excellence (NICE) guidelines.18,19 Because follow-up practices vary, prolonged follow-up was investigated in sensitivity analysis. The NICE Final Appraisal Determination was issued on July 24, 2006, and the Scottish Medicines Consortium advice was issued on September 9, 2005. In both cases, docetaxel was recommended for use in the NHS in combination with doxorubicin and cyclophosphamide as an option for the adjuvant treatment of early (operable), node-positive breast cancer. The mean cost of hospital care postrelapse was estimated from patient-level resource use data provided by the WGH (Appendix),20 including diagnostics, out-patient visits, day case procedures, in-patient stay, surgery, chemotherapy, radiotherapy, and hormonal treatments. Unit costs from national sources22,23 were applied to the patient-level data to calculate total costs for individual patients, and mean costs were estimated by bootstrapping (1,000 simulations with replacement). The cost of palliative care in the community was estimated from published data.21 The cost of hospice care was excluded because it is not funded by the NHS. Unit costs were obtained from national sources22,23 and inflated to 2005 values where necessary.23

RESULTS

Base-Case Analysis The base-case results are presented in Table 3. Over a timeframe of 10 years, patients receiving TAC benefited from an average additional 0.37 years of life, and 0.32 QALYs compared with those receiving FAC. The impact of grade 3 or 4 adverse events on HRQoL was estimated as an average loss per patient of 2.8 quality-adjusted life days in the TAC arm compared with 1.4 in the FAC arm. The mean number of cycles of chemotherapy received was 5.75 for TAC and 5.91 for FAC. The estimated mean cost of chemotherapy and administration was £7,190 in the TAC arm and £1,263 in the FAC arm; a difference between arms of £5,927. The average additional cost of managing adverse events and supportive G-CSF in the TAC arm were £514 and £609 respectively. The average cost of treatments for disease relapse was £1,322 less in the TAC arm than in the FAC arm. 927

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Wolowacz et al

Table 1. Summary of Key Model Parameters Central Estimate

Estimate of Uncertaintyⴱ

2.49

0.16#

Gamma

1.59

0.08#

Gamma

0.79 0.70 0.79

0.016†† 0.60-0.80‡‡ 0.016††

Gamma for decrement Gamma for decrement Gamma for decrement

Second locoregional recurrence Third locoregional recurrence Distant disease Terminal Illness Cost of monitoring for patients in remission§ Hospital care costs postrelapse First relapse is locoregional

0.50 0.50 0.50 0.30 £732

0.40-0.60‡‡ 0.40-0.60‡‡ 0.40-0.60‡‡ 0.20-0.40‡‡ None

Gamma Gamma Gamma Gamma None

£14,137

£1621#

Normal

Bootstrap estimate using patientlevel resource use data (WGH data set)

First relapse is distant Primary care costs postrelapse (cost per month) Stable distant disease Early progressive disease Late progressive disease Terminal illness

£13,576 None None None None

None None None None

Brown Brown Brown Brown

Parameter Chemotherapy specific Cost per cycle of chemotherapy and administration† Docetaxel Doxorubicin Cyclophosphamide Fluorouracil Administration Ciprofloxacin Total cost per cycle (including administration) Mean No. of cycles‡ Patients discontinuing because of adverse events Patients not discontinuing because of adverse events Probability of receiving primary G-CSF prophylaxis§ Adverse event probabilities (Grade 3/4)㛳 Anemia Asthenia Diarrhea Febrile neutropenia (or neutropenic infection) Pain (body as a whole) Stomatitis Vomiting Probability of discontinuing chemotherapy because of AEs㛳 General Survival postrelapse estimates (years) First relapse is locoregional¶ First relapse is distantⴱⴱ Health state utility weights Remission First locoregional recurrence, under treatment First locoregional recurrence, after treatment

TAC

FAC

£1023 £168 £5 Not applicable £48 £2.90 £1247

Not applicable £168 £5 £13 £27 £0 £214

3.13 5.92 0.070

3.25 5.94 0.077

0.043 0.112 0.038 0.367 0.038 0.071 0.043 0.060

0.016 0.056 0.018 0.087 0.018 0.020 0.073 0.011

£310 £310 £487 £692

Distributional Form

Source

Kaplan-Meier BCIRG001 Kaplan-Meier BCIRG001

for for for for

decrement decrement decrement decrement

analysis of data analysis of data

BCIRG001 QLQ-C30 data Hillner and Smith, 199117 Assumed to be equivalent to remission Hillner and Smith, 199117 Hillner and Smith, 199117 Hillner and Smith, 199117 Hillner and Smith, 199117 Guidelines10,11

et et et et

al, al, al, al,

200113 200113 200113 200113

NOTE. The cost year was 2005. Abbreviations: TAC, docetaxel, doxorubicin, cyclophosphamide; FAC, fluorouracil, doxorubicin, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; AEs, adverse events; WGH, Western General Hospital patient-level resource utilization data set (collected over 5 years postrelapse for 180 relapsed early breast cancer patients); BCIRG, Breast Cancer International Research Group. ⴱ Where no estimate of uncertainty is reported, the cost in the model was dependent on the time spent in each health state. †Assumes a body surface area4 of 1.7 m2 and a weight of 70 kg. Drug doses were per protocol and prices were from the British National Formulary.24 Cost estimates for drug administration were based on a United Kingdom National Health Service Cancer Drug Policy Forum report.5 These parameters were fixed in the probabilistic analysis. ‡Estimates of drug usage in trial BCIRG001. The uncertainty around the mean number of cycles of TAC and FAC was reflected in the probabilistic sensitivity analysis using the number of patients receiving 1, 2, 3, 4, 5, and 6 cycles. §Although primary G-CSF prophylaxis was not permitted in trial BCIRG001, a small proportion of patients actually received it. Since adverse event rates reflect this level of usage, the cost of primary G-CSF usage to this extent was included in the base-case analysis (source, trial BCIRG001). 㛳Derived from trial BCIRG001. The uncertainty around the probabilities was reflected in the probabilistic sensitivity analysis by random sampling from a beta distribution defined by the total number in the treatment arm (n ⫽ 744 for TAC and 736 for FAC) and the number experiencing each event. ¶Survival after locoregional relapse was partitioned into postrelapse health states using estimates of the probability of experiencing the health state and the mean time spent in each health state derived from the WGH data set. Estimates were (in weeks): First locoregional recurrence, undertreatment (n ⫽ 9); first locoregional recurrence, after treatment (n ⫽ 82); second locoregional recurrence (n ⫽ 0); third locoregional recurrence (n ⫽ 2); distant disease (n ⫽ 35); terminal illness (n ⫽ 2). #Standard error was used in the probabilistic analysis. ⴱⴱ Survival after distant relapse was partitioned into postrelapse health states as described in the table. Estimates were (in weeks): distant disease (80) and terminal illness (3). ††Variance was used in the probabilistic analysis. ‡‡Range was used in the probabilistic analysis. §§Per patient remaining in remission for the full follow-up period. Costs were incurred at 12 months (£127), 18 months (£159), 24 months (£127), 30 months (£159), and 42 months (£159).

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Table 2. Consequences of Adverse Events: Costs, Utility Decrements and G-CSF Usage Days of Treatment

Duration of impact on HRQoL (days)ⴱ

Utility Decrement† Event

Cost per Episodeⴱ

Source

Mean Variance

Anemia

£1,965 Smith et al, 20028

Asthenia

£0 Clinical opinion

0.38

Diarrhea

£2,527 Twelves et al, 20019 and Smith et al, 20028 £1,412# Aristides et al, 200310 £0ⴱⴱ Clinical opinion

0.38

Febrile neutropenia Pain (body as a whole)

Stomatitis

£390 Clinical opinion £2,209 Twelves et al, 20019 and Smith et al, 20028

Vomiting

Source‡

Average Range Mean

0§

0.34 0.38

0.38 0.38

Clinical opinion 0.0006 Ossa et al, 200411 0.0006 Launois et al, 199612

0.0006 Brown et al, 199813 0.0006 Assumed to be equal to diarrhea 0.0006 Launois et al, 199612 0.0006 Launois et al, 199612

G-CSF usage†† Primary prophylaxis

Secondary prophylaxis and treatment for patients experiencing febrile neutropenia Cost per day of G-CSF††

Patients Patients Not Discontinuing Discontinuing Chemotherapy Chemotherapy Because of Because of AEs AEs Standard Standard Error Mean Error

Source

NA§ 21㛳

NA

8¶

2-8

5

3-7

7

5-14

3

2-7

5

2-7

15.29

14.14

22.39

5.67

14.42

2.58

26.16

1.17

£89

De novo analysis of trial BCIRG001 patient-level data

BNF5022

Abbreviations: NA, not applicable; HRQoL, health related quality of life; AEs, adverse events; G-CSF, granulocyte colony stimulating factor; BNF, British National Formulary; UK, United Kingdom; BCIRG, Breast Cancer International Research Group. ⴱ Fixed in the probabilistic analysis. †Sampled in the probabilistic analysis from a gamma distribution defined by the mean and variance. ‡Derivation of utility decrements: Anemia—It is assumed that anemia has no impact on quality of life in itself, but that its impact is reflected in other recorded adverse events, including asthenia nausea and constipation (clinical opinion and Ossa et al11). Asthenia: Derived from Ossa et al11 for fatigue associated with chemotherapy-related anemia, 106 members of the UK general public, time trade-off. Mean utility value for “no anemia” (0.86) 关minus兴 “severe anemia” (WHO grade 3 anemia; 0.48) ⫽ decrement (0.38). Diarrhea, vomiting, and stomatitis—Derived from Launois et al12 for GI toxicity associated with chemotherapy for metastatic breast cancer (docetaxel 关100 mg/m2兴, paclitaxel, and vinorelbine), 20 oncology nurses in France, Standard Gamble. Mean utility value for “before starting chemotherapy” (0.86) ⫺ “GI toxicity with hospitalization” (0.48) ⫽ decrement (0.38). Febrile neutropenia and neutropenic infection— Brown et al.21 For febrile neutropenia with hospitalization (associated with second-line chemotherapy for advanced breast cancer, including docetaxel, and paclitaxel), ⬎ 154 oncology nurses (United States and Europe), 25-30 in the UK, Standard Gamble. Mean utility value for “at start of second-line chemotherapy” (0.64) ⫺ “febrile neutropenia with hospitalization” (0.30) ⫽ decrement (0.34). Severe pain—A utility decrement equivalent to that of diarrhea is assumed based on the opinion of the Clinical Advisory Panel. §The primary impact of anemia on patients’ quality of life is fatigue, which is captured in the asthenia event. 㛳The impact of asthenia on HRQoL was assumed to be continuous and therefore last for the full duration of any cycle in which it was recorded. ¶Twelves et al (2001) reported a mean length of stay of 8 days (hospitalization days for diarrhea, 596 patients receiving chemotherapy for advanced or metastatic colorectal cancer); a clinical survey of five UK oncologists yielded a range of 2-3 days for the impact of diarrhea on HRQoL. #Excluding the cost of G-CSF. ⴱⴱ The cost of treating pain was assumed to be negligible based on the opinion of five UK oncologists. No patients in trial BCIRG001 had pain severe enough to result in hospitalization. Patients would receive analgesics, at negligible cost. ††Assumes 50% of patients receive lenograstim and 50% receive filgrastim, (the two agents specified in the protocol of trial BCIRG001) and that unused drug in opened vials is discarded.

The cost effectiveness of TAC versus FAC was estimated as £15,418/ LYS and £18,188/QALY. Sensitivity and Subgroup Analysis In the probabilistic sensitivity analysis, 1,000 model simulations in which key model parameters were sampled from their statistical distributions were performed. Parameters varied included mean cycles of chemotherapy, adverse event probabilities, relapse probabilities, utility weights and estimates of mean survival and cost postrelapse

(Tables 1 and 2). The mean IC/LYS estimated from the probabilistic simulations was £15,400 (95% CI, £13,734 to £17,997) and the mean IC/QALY was £18,274 (95% CI, £14,161 to £32,422; Appendix contains detailed results). The results of other sensitivity analyses are summarized in Table 4. The timeframe of the analysis had the greatest impact on the results. A timeframe of 5 years yielded an estimate of £58,201/ QALY, whereas the lifetime analysis longer than 40 years (on completion of which all patients had died) yielded an estimate of 929

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Wolowacz et al

B 100

TAC FAC KM TAC KM FAC

95 90

Surviving and Disease Free (%)

Surviving and Disease Free (%)

A

85 80 75 70 65

100

TAC FAC

90 80 70 60 50 40 30 20 10

60 0

1

2

3

4

5

8

0

Time (years)

16

24

32

40

Time (years)

Fig 2. Model prediction for disease-free survival (A) compared with Kaplan-Meier (KM) analysis of the Breast Cancer International Research Group (BCIRG) 001 trial data and (B) over the analysis timeframe of 40 years. Lines represent the model prediction; points represent the KM analysis data. The model prediction for overall survival (OS) was also close to that estimated directly from trial BCIRG001: mean life years predicted by the model within the 5-year trial follow-up was 4.676 and 4.573 for the TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (fluorouracil, doxorubicin, cyclophosphamide) arms, respectively, compared with 4.683 and 4.567 estimated from the published OS curve. The incremental gain in life years predicted by the model was 0.104 compared with 0.116 estimated from the OS curve; thus the model underestimated the survival benefit for TAC versus FAC within 5 years by approximately 10%.

£9,865 (95% CI, £7,864 to £15,891). The various methods of extrapolation of outcomes beyond the end of trial follow-up resulted in estimates varying from £15,588 to £28,782/QALY. The lowest estimates were generated by the treatment-specific loglogistic model, which assumed continuation of treatment effect beyond

trial follow-up, and the highest by the pooled loglogistic model which assumed no continuation of treatment effect. The sensitivity analysis also explored the costs applied for the management of adverse events as well as their impact on HRQoL (Table 4). Increasing the cost of all events occurring at a higher rate in

Table 3. Base Case Results Outcome % of patients Discontinued therapy because of AEs Disease recurrence over 10 years Locoregional disease Distant disease Patient status at 10 years Surviving With no disease recurrence With disease recurrence Dead After disease recurrence* Died as a result of other causes Estimated life years, QALYs, and costs Mean life years Mean QALYs Mean costs Chemotherapy and administration Supportive G-CSF Treatment of adverse events Monitoring for patients in remission Treatment of recurrent disease Mean total cost Estimated incremental cost-effectiveness ratios Incremental cost/life year saved Incremental cost/QALY

TAC Cohort

FAC Cohort

6.04 36.0 6.6 29.3

1.07 42.6 8.0 34.6

61.2 56.2 4.9 38.8 30.8 8.1

54.7 50.3 4.4 45.3 37.9 7.4

Incremental

7.194 5.517

6.821 5.201

0.374 0.317

£7190 £963 £1014 £620 £5801 £15,587

£1263 £353 £499 £590 £7123 £9828

£5927 £609 £514 £30 -£1322 £5759

Deterministic Estimate

Probabilistic Estimates

95% CI

£15,418 £18,188

£15,400 £18,274

£13,734 to £17,997 £14,161 to £32,422

NOTE. Model timeframe: 40 years; discount rate for costs and outcomes: 3.5%; method of extrapolation beyond trial end: 2-part parametric model; percentage of patients planned to receive primary G-CSF prophylaxis: 0%; and actually receiving primary G-CSF prophylaxis: TAC arm, 7.0%; FAC arm, 7.7%. Abbreviations: TAC, docetaxel, doxorubicin, cyclophosphamide; FAC, fluorouracil, doxorubicin, cyclophosphamide; AE, adverse events; QALY, quality-adjusted life year; G-CSF, granulocyte colony stimulating factor. * These data are provided for information only and are not used to estimate cost-effectiveness ratios.

930




Table 4. Sensitivity and Subgroup Analysis Results

Measure Base case results Analysis timeframe, years 20 10 5 Method of extrapolation beyond trial follow-upⴱ Pooled loglogistic (common long-term risk) Loglogistic (treatment-specific long-term risk) Natural history data (common long-term risk) All TAC patients receive primary prophylaxis with lenograstim/filgrastim All TAC patients receive primary prophylaxis with pegfilgrastim Variation of individual parameters Cost of febrile neutropenia† Cost of vomiting† Cost of all adverse events with higher rate in TAC arm† Duration of all AEs set to maximum of reported range Utility decrement for febrile neutropenia increased

Deterministic Estimate (IC/QALY)

95% CI

£18,188

£14,161 to £32,422

£9,865 £11,155 £58,201

£7864 to £15,891 £8868 to £20,550 £39,114 to £176,483

£28,782 £15,588 £20,483 £20,432

£10,338 to £71,113 £7869 to £40,672 £10,780 to £70,509 £15,226 to £37,269

£57,320

£34,806 to £113,676

Parameter Value Sensitivity

Rationale Analysis

£19,889 £18,471 £20,754

£1,412 £2,209 Various‡

£3,000 £500 £3,000

£18,241

Various‡

Various§

£18,231

0.34

0.5

Mean number of cycles of TAC Cost of monitoring for patients in remission㛳

£19,114 £18,196

5.75 £846

6.00 £1,197

Survival postrelapse

£25,254

2.49

7.67

£19,726

1.59 Various‡

5.00 Various¶ Minimum estimate of improved HRQoL because of reduced risk of relapse

First relapse is locoregional First relapse is distant All postrelapse utility weights set to upper limit of range Subgroup analysis# Age ⬍ 50 years Age ⱖ 50 years 1-3 positive nodes 4⫹ positive nodes ER positive ER negative Grade 1 and 2 Grade 3

£13,718 £25,826 £14,308 £26,582 £26,770 £11,214 £21,263 £17,111

Most common TAC adverse event Less common in TAC arm than FAC arm Maximum estimate of impact of AEs on cost Maximum estimate of impact of AEs on HRQoL Base case value based on published data is lower than other AEs, possibly counterintuitive Maximum estimate of the cost of TAC Maximum additional cost of monitoring in TAC arm Both estimates triples to investigate impact of underestimation by KaplanMeier analysis

£13,586 to £29,430 £14,884 to £33,271 £14,202 to £34,878 £14,175 to £33,931 £14,421 to £38,803 £14,080 to £34,595 £14,314 to £36,517 £14,152 to £30,893

NOTE. Base case result data taken from Table 3. Abbreviations: IC, incremental cost; QALY, quality-adjusted life year; G-CSF, granulocyte colony-stimulating factor; TAC, docetaxel, doxorubicin, cyclophosphamide; FAC, fluorouracil, doxorubicin, cyclophosphamide; AEs, adverse events; HRQoL, health-related quality of life; BCIRG, Breast Cancer International Research Group. ⴱ Analysis timeframe set to 20 years to allow comparison with natural history data. †Cost per episode excluding G-CSF. ‡Reported in Table 2. §Diarrhea, 8 days; febrile neutropenia, 7 days; pain, 14 days; stomatitis, 7 days; vomiting, 7 days. 㛳The monitoring regimen for patients in remission was based on clinical practice as described by the Clinical Advisory Panel (6-monthly outpatient visits for 2 years and then at 36, 48, and 64 months with a mammogram annually) rather than on guidelines. ¶First locoregional relapse: 0.730.8. After first locoregional relapse: 0.7930.87; second locoregional relapse: 0.530.75; third locoregional relapse: 0.530.75; distant relapse 0.530.75. Terminal illness remains at 0.3. Mean QALYs postrelapse increased from 0.82 to 1.22. #In trial BCIRG001, no treatment-by-subgroup interaction was detected that suggested differences in treatment effect for any covariate analyzed.2 However, the underlying risk of relapse in early breast cancer patients is known to vary according to several risk factors. Subgroup analyses were therefore performed to explore any differences in cost effectiveness by age, node status, estrogen-receptor status, and tumor grade. The risk of relapse in the TAC and FAC arms was estimated by fitting disease-free survival functions to data for individual patient subgroups. Mortality rates were adjusted for the analysis by age.

the TAC arm (including febrile neutropenia) to £3,000 per episode resulted in a modest increase in the IC/QALY from £18,188 to £20,754. Increasing the impact of events on HRQoL resulted in estimates of less than £19,000/QALY.

The sensitivity of the base-case analysis to other input parameter estimates was investigated by varying all parameters by ⫾ 50% of their base-case value (including the cost of chemotherapy). The results were most sensitive to the value of the utility weight for 931

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patients in remission. If the estimate were reduced to 0.5 (similar to estimates reported for metastatic disease)17 the IC/QALY increased to £32,431. If all TAC patients were assumed to receive primary G-CSF prophylaxis (with filgrastim or lenograstim), the total cost of supportive G-CSF was estimated as £1,966 (including primary and secondary prophylaxis and treatment of febrile neutropenia). The cost of adverse events was reduced from £1,014 to £402 per patient as a result of a reduction in the incidence of febrile neutropenia. The number of patients discontinuing chemotherapy because of adverse events was reduced, resulting in an increase in the mean cost of chemotherapy and administration. The overall impact on the IC/QALY estimates was a modest increase from £18,188 to £20,432. If primary prophylaxis was with pegfilgrastim, the average cost of G-CSF was £4,176 and the IC/QALY was £57,320 (95% CI, £34,806 to £113,676). Subgroup analysis suggests that TAC is more cost effective in patients who are younger, estrogen-receptor–negative, and with fewer positive nodes and lower tumor grades (Table 4; Appendix). DISCUSSION

We can conclude that adjuvant TAC is cost effective compared with FAC in the UK. The IC/QALY over a 10-year timeframe was £18,188 (95% CI, £14,161 to £32,422 [€ 27,108; 95% CI, €21,106 to €48,324] using an exchange rate of £1.00 ⫽ €1.49046). If all expected costs and benefits over patients’ lifetimes were estimated (using a 40-year time-horizon), the IC/QALY was £9,865 (95% CI, £7,864 to £15,891). In univariate sensitivity analysis, the IC/QALY remained lower than £26,000 with the exception of the analysis timeframe of 5 years, which yielded an estimate of £58,201. These estimates are comparable with recent estimates for other adjuvant treatments for EBC for the UK (using lifetime analysis timeframes), for example for trastuzumab (£18,000/ QALY),24 anastrozole (£12,310/QALY)25 and letrozole (£9,325/ QALY),25 and is more favorable than for estimates for gemcitabine combination therapy for advanced breast cancer (£42,800/QALY).26 TAC supported by primary G-CSF prophylaxis was also cost effective. The IC/QALY for TAC supported by primary lenograstim or filgrastim was estimated as £20,432 (€30,453). Primary prophylaxis with pegfilgrastim was less cost effective, at £57,320/QALY. Although FAC is rarely used in the UK, we believe it provides a reasonable surrogate for the commonly used regimen in the UK, FEC (usually administered at epirubicin doses of 60 to 75 mg/m2 in the UK).27 Direct comparison of the two regimens in metastatic breast cancer has demonstrated equivalence.28,29 In addition, the recent Oxford overview30 performed an indirect comparison of FAC and FEC in EBC and concluded that these two most widely studied regimens “appear to be of comparable efficacy.” This analysis is not applicable to TAC compared with FEC at higher epirubicin doses (more than 75 mg/m2). The primary uncertainty in the analysis is the extrapolation of outcomes beyond the available trial follow-up. Assuming the same risk of relapse in both FAC and TAC cohorts after trial end resulted in a gradual convergence of the DFS curves beyond 5 years (Fig 2B). Since the recent Oxford overview30 suggests that DFS curves for alternative adjuvant regimens continue to diverge until at least 10 932

years post–random assignment, it is likely that this analysis provides a conservative estimate of the long-term benefit of TAC. Using several alternative methods of estimating the long-term risk of relapse, the IC/QALY varied from £15,588 to £28,782. Thus, the considerable uncertainty inherent in the extrapolation is unlikely to alter the cost effectiveness of TAC over FAC. In univariate sensitivity analysis, the results were most sensitive to the utility weight for remission. Reducing the value to 0.5 (similar to estimates reported for metastatic disease)17 increased the IC/QALY estimate to £32,430. We believe a utility of 0.5 to be implausible because the HRQoL of EBC patients in remission after their chemotherapy has been demonstrated to return to levels similar to that of the general population.31 Truncation of the model timeframe to 5 years yielded an estimate of £58,201. This analysis effectively assumes that there are no differences in costs and benefits between the patient cohorts after 5 years, which is inconsistent with long-term follow-up data for other chemotherapy regimens.30 The analysis provides useful insight into the impact of serious adverse events associated with TAC on costs and HRQoL. The average cost of managing adverse events, including G-CSF, was £1,123 more per patient receiving TAC than for patients receiving FAC, whereas the impact on HRQoL of grade 3 and 4 adverse events was estimated as an average loss of only 1.4 quality-adjusted life days. Although the utility decrements applied to the periods of time that patients experience adverse events were large (0.35 to 0.38, placing them at a lower utility value than distant disease), the difference in HRQoL experienced by patients receiving TAC and FAC is small when averaged over the whole population, because QoL is impaired by serious adverse events for a relatively short time and for a small additional number of patients. These short-term disadvantages of TAC are small compared with the long-term benefits to be realized from the lower risk of relapse with this regimen. Although the incidence of febrile neutropenia was high in trial BCIRG001, where primary G-CSF prophylaxis was not permitted, there were no septic deaths and fewer noncancer deaths than have been reported for alternative effective adjuvant regimens such as E3 CMF.32 Furthermore, GEICAM9805 has demonstrated that if TAC is supported by primary prophylactic G-CSF, the rate of febrile neutropenia is reduced to acceptable levels,6 and this analysis confirms that the TAC regimen remains cost effective compared with FAC, even when supported by primary G-CSF prophylaxis. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Sorrel E. Wolowacz, Sanofi-aventis; David A. Cameron, Sanofi-aventis; Helen C. Tate, Sanofi-aventis; Adrian Bagust, Sanofi-aventis Stock: N/A Honoraria: David A. Cameron, Sanofi-aventis; Adrian Bagust, Sanofi-aventis JOURNAL OF CLINICAL ONCOLOGY



Research Funds: Sorrel E. Wolowacz, Sanofi-aventis; David A. Cameron, Sanofi-aventis Testimony: N/A Other: N/A

AUTHOR CONTRIBUTIONS Conception and design: Sorrel E. Wolowacz, David A. Cameron Provision of study materials or patients: David A. Cameron

REFERENCES 1. Montero A, Fossella F, Hortobagyi G, et al: Docetaxel for treatment of solid tumours: A systematic review of clinical data. Lancet Oncol 6:229-239, 2005 2. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 3. Roche´ H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 Trial. J Clin Oncol 24:5664-5671, 2006 4. Dooley MJ, Singh S, Michael M: Implications of dose rounding of chemotherapy to nearest vial size. Support Care Cancer 12:653-656, 2004 5. Hodgetts A, Raffle A: Prescribing Issues in Breast Cancer, a report on behalf of the Avon Somerset & Wiltshire Cancer Drug Policy Forum. Bristol, United Kingdom, Avon, Somerset and Wiltshire, 2001 6. Martın M, Lluch A, Seguı MA, et al: Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): Impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. Ann Oncol 17:12051212, 2006 7. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178-1184, 2005 8. Smith DH, Adams JR, Johnston SRD, 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 9. Twelves C, Boyer M, Findlay M, et al: Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal cancer. Eur J Cancer 37:597-604, 2001 10. Aristides M, Jackson D, Liepa AM, et al: Costs of managing toxicities in non-small cell lung cancer with pemetrexed compared with docetaxel as

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second-line chemotherapy: Application to the UK setting. Presented at the 6th Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research, November 9-11, 2003, Barcelona, Spain 11. Ossa D, Briggs A, Cowell W, et al: Utility associated with severity of cancer-related anaemia (CRA): A societal valuation. Presented at the 7th Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research, October 24-26, 2004, Hamburg, Germany 12. Launois R, Reboul-Marty J, Henry B, et al: A cost-utility analysis of second-line chemotherapy in metastatic breast cancer: Docetaxel versus paclitaxel versus vinorelbine. Pharmacoeconomics 10: 504-521, 1996 13. Brown R, Hutton J: Cost-utility model comparing docetaxel and paclitaxel in advanced breast cancer patients. Anticancer Drugs 9:899-907, 1998 14. Weiss R, Woolf S, Demakos E, et al: Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate and fluorouracil-based adjuvant chemotherapy: A study by the Cancer and Leukemia Group B. J Clin Oncol 21:1825-1835, 2003 15. Office for National Statistics 2004: Life expectancy at birth: Methodological options for small populations. http://www.statistics.gov.uk/methods_quality/publications.asp 16. Kind P: Measuring the value of quality of life in cancer: An index based on EORTC QLQC-30. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL 17. Hillner BE, Smith TJ: Efficacy and costeffectiveness of adjuvant chemotherapy in women with node-negative breast cancer. N Engl J Med 324:160-168, 1991 18. National Institute for Health and Clinical Excellence: Guidance on cancer services: Improving outcomes in breast cancer. Manual Update, August 2002. http://www.nice.org.uk/nicemedia/pdf/Breast_cancer _info_public.pdf 19. Scottish Intercollegiate Guidelines Network, Management of Breast Cancer in Women: A draft for the National Meeting, Edinburgh, United Kingdom, 2003 20. Wolowacz S, Roskell N, Christie A, et al: Per-patient cost of hospital care for advanced breast

cancer in the UK based on a large patient-level resource utilisation dataset. Value Health 8:A42, 2005 (abstr; PCN29) 21. Brown RE, Hutton J, Burrell A: Cost-effectiveness of treatment options in advanced breast cancer in the UK. Pharmacoeconomics 19:1091-1102, 2001 22. British National Formulary, BNF50, September 2005. http://www.bnf.org/bnf/bnf/current/ BNF50 23. Curtis L, Netten A: Unit costs of health & social care, 2004. Manchester, United Kingdom, Personal Social Services Research Unit, 2004 24. NICE Guidance No. 107: Trastuzumab for the adjuvant treatment of early stage HER2-positive breast cancer (2006). http://www.nice.org.uk/guidance/index .jsp?action⫽download&o⫽33459 25. NICE Guidance No. 112: Hormonal therapies for the adjuvant treatment of early oestrogen-receptorpositive breast cancer (2006) http://www.nice.org.uk/ guidance/index.jsp?action⫽download&o⫽33642 26. NICE Final Appraisal Determination: Gemcitabine for the treatment of metastatic breast cancer (2006). http://www.nice.org.uk/page.aspx?o⫽389951 27. IMS Healthcare Oncology Analyzer, MAT, Q2, 2005 28. Italian Multicentre Breast Study with Epirubicin: Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: An Italian multicentre trial. J Clin Oncol 6:976-982, 1988 29. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6:679-688, 1988 30. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005 31. Hall P, Walkington J, Douglas S, et al: Quality of life after 5 years tamoxifen for women with early breast cancer. Presented at the British Cancer Research Meeting, July 2-5, 2003, Bournemouth, United Kingdom 32. Poole CJ, Earl HM, Hiller L, et al: Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 355:1851-1862, 2006

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Acknowledgment We thank the following contributors: Gill Kerr and Morag Gibson (resource utilization data set); Paul Kind (EORTC QLQ-C30 algorithm); Neil Roskell, Lori McLeod, and Meghan Wills (statistical analysis); and Steven Beard, Fiona Maciver, Louise McCrink, and Angela Christie (model development). Appendix The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).

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