Elsevier

European Journal of Cancer

Volume 47, Issue 17, November 2011, Pages 2517-2530
European Journal of Cancer

The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses

https://doi.org/10.1016/j.ejca.2011.06.019Get rights and content

Abstract

Background

The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs).

Methods

A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions.

Findings

For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel.

Interpretation

To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.

Introduction

For women with early breast cancer, surgery to remove the primary tumour is often followed by adjuvant chemotherapy, a combination of cytotoxic drugs given to reduce the risk of disease recurrence. Recent decades have seen major advances in chemotherapy treatment as new and potentially more effective classes of drugs and modes of administration are developed. Randomised controlled trials (RCTs) have evaluated first generation alkylating-based chemotherapy regimens, second generation anthracycline-based regimens and third generation taxane-based regimens.1, 2, 3, 4, 5

Health economic evaluation has been used to assess the cost-effectiveness of adjuvant chemotherapy regimens; most recently, those containing the taxane agents docetaxel and paclitaxel.6, 7, 8, 9 However, these evaluations, and the RCTs providing the corresponding clinical data, conducted pair-wise comparisons in which the new generation therapy was assessed only against the previous generation’s therapy. To our knowledge, no clinical or economic assessment has to date simultaneously compared all potential adjuvant chemotherapy treatment strategies; that is, first, second, and third generation regimens, as well as a policy of using no adjuvant chemotherapy. A simultaneous comparison of this kind would prove informative for several reasons. Firstly, there has been considerable recent research on the effectiveness of all adjuvant chemotherapies, including meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) and systematic reviews by the Cochrane Breast Cancer Group.1, 10 This evidence should inform and update economic analysis and policy. Secondly, there are factors relating to the progression and treatment of early breast cancer that mean different chemotherapy regimens may be cost-effective for different patient groups. The risk of recurrence, for example, can vary substantially between women depending upon prognostic factors including age, axillary lymph node status, and tumour grade, size, and oestrogen receptor (ER) status.11, 12, 13 Also, the proportional reduction in the risk of recurrence with chemotherapy is known to vary by age, and women with ER positive tumours now routinely receive adjuvant anti-hormone therapy, which also reduces the risk of recurrence, but independently of chemotherapy.1 Finally, advances in treatment effectiveness come at a cost, as new chemotherapy regimens are usually more expensive than older regimens and potentially more toxic, resulting in an increase in adverse events and a detrimental impact on patient health related quality of life (HRQoL). Given all of these factors, it would appear important to review each of the relevant treatment options for all types of patient.

This paper describes a cost-effectiveness analysis in which the lifetime costs and quality adjusted life years (QALYs) (life years adjusted for HRQoL) of adjuvant chemotherapy treatment options for women with early breast cancer are estimated and compared. Reflecting the full range of management options which have been used in the adjuvant setting in United Kingdom trials over recent years, the strategies considered are:

  • I.

    no chemotherapy,

  • II.

    first generation chemotherapy with CMF (six cycles of cyclophosphamide, methotrexate, fluorouracil),

  • III.

    second generation chemotherapy with FEC60 (eight cycles of fluorouracil, epirubicin, cyclophosphamide) or E-CMF (four cycles of epirubicin followed by four cycles of CMF), and

  • IV.

    third generation chemotherapy with FEC-D (four cycles of FEC60 followed by four cycles of docetaxel).

These chemotherapy regimens are defined in accordance with the protocols of three pragmatic UK-led RCTs – the Adjuvant Breast Cancer (ABC) Trial which began in 1992 and compared CMF with no chemotherapy, the National Epirubicin Adjuvant Trial (NEAT) which began in 1996 and compared E-CMF with CMF, and the Taxotere as Adjuvant Chemotherapy Trial (TACT) which began in 2001 and compared FEC-D with FEC60 or E-CMF.3, 4, 5 Docetaxel is not currently licensed in the UK for use as a single agent following FEC. This regimen is, however, advocated by the majority of breast cancer oncologists in the UK and indeed worldwide, because when used on its own, docetaxel carries a lower risk of adverse events than if used simultaneously with other agents.14 In line with the TACT trial protocol and indirect evidence from the trial results, our analysis assumes equivalence of FEC60 and E-CMF in terms of effectiveness and toxicity.

Section snippets

Overview and model structure

The analysis followed the methodological guidelines from the National Institute of Health and Clinical Excellence (NICE).15 It was conducted from a UK National Health Service (NHS) perspective and the annual discount rate used for costs (expressed as 2009 Pound Sterling) and effects was 3.5%.16 Fig. 1 shows the structure of the economic model. Following local surgery, (a hypothetical cohort of) patients enter a short term decision tree (panel a) and are assigned to one of the four treatment

Reference case cohort

For the reference-case cohort (for whom the predicted probability of remaining recurrence free out to 10 years in the absence of chemotherapy and (given the ER negative status of the group) anti-hormone therapy is 44%), expected costs and QALYs estimated for the four treatment strategies are shown in Table 3 and Fig. 3. FEC-D on average generates the greatest amount of health gain but also has the greatest cost. When compared with E-CMF/FEC60 (the next most effective alternative) the expected

Discussion

This study used decision analytic modelling to estimate and compare the lifetime costs and effects of no chemotherapy and first, second, and third generation adjuvant chemotherapy for women with early breast cancer. Sub-group analyses showed different treatment strategies have the potential to be cost-effective for different types of patients. Assuming the cost-effectiveness threshold to be £20,000 per QALY, and summarising for younger women first, FEC-D appears cost-effective for patients,

Conclusion

This paper has presented the first known comparison of the cost-effectiveness of three different generations of adjuvant chemotherapy for early breast cancer patients with differing prognoses. The results are necessarily complex, with cost-effectiveness shown to vary not only with the underlying risk of a recurrence, but also according to age and ER status. The findings are also subject to uncertainty, particularly in relation to the effectiveness of FEC-D, a parameter on which further research

Funding

Cancer Research UK (C14185/A5946), UK Medical Research Council.

Individual contributions

HC developed, populated, and analysed the economic model and drafted the manuscript. DE assisted in the development of the economic model, conducted analyses of trial data for use in the model, and helped draft the manuscript. DB was the clinical lead for the project, provided input into the modelling process, helped write the manuscript, and co-ordinated manuscript circulation across the authorship. SG advised on the development and population of the economic model and provided comments on

Conflict of interest statement

HC had access to all data used in this study and had final responsibility for the decision to submit the paper for publication. DB received educational travel grants from Roche and Astra-Zeneca. DC received research funding, honoraria, consultancies and travel grants from Pfizer and Sanofi-Aventis. PBL in the past received an honorarium for roles on Advisory boards of Sanofi-Aventis and Pfizer. HE has received unrestricted educational grants for research trials from Pfizer (epirubicin), and

Role of funding source

The funding source had no involvement in the study design or analysis, the interpretation of the results, the writing of the paper, or the decision to submit for publication.

Acknowledgements

We would like to thank all of the staff who worked on the ABC, NEAT, and TACT trials, and in the Oxford Breast Care team, including surgeons, oncologists, pathologists, nurses, data managers, QoL study coordinators, support staff, and N Atkins (ICR-CTSU) for helping to prepare the manuscript for submission. We are also grateful to the two anonymous reviewers for their helpful and constructive comments. Above all though, we would like to thank the patients themselves. The research costs of the

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