Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer

W. Kievit1, M. J. Bolster2,*, G. J. van der Wilt1, P. Bult3, F. B. J. M. Thunnissen4, J. Meijer5, L. J. A. Strobbe6, J. H. G. Klinkenbijl7, T. Wobbes2, E. M. M. Adang1, L. V. A. M. Beex8 and V. C. G. Tjan-Heijnen8

Radboud University Nijmegen Medical Centre, Departments of 1 Medical Technology Assessment, 2 Surgery, 3 Pathology and 8 Medical Oncology, Canisius-Wilhelmina Hospital Nijmegen, Departments of 4 Pathology and 6 Surgery, Nijmegen; 5 Rijnstate Hospital Arnhem, Departments of 5Pathology and 7 Surgery, Arnhem, The Netherlands

* Correspondence to: Dr M. J. Bolster, Radboud University Nijmegen Medical Centre, Department of Surgery (410), PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3617365; Fax: +31-24-3540501; E-mail: M.Bolster{at}CHIR.umcn.nl


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Background: In this study, the potential impact of a new national guideline for adjuvant systemic therapy in breast cancer (introduced in The Netherlands in 1998) was assessed, as well as the modifications of this guideline, issued in 2001. Both the change in total number of patients eligible for adjuvant therapy, as well as the cost-effectiveness of the changed clinical management of these patients were analysed.

Patients and methods: Percentages of patients who would be eligible for adjuvant therapy in 1994, 1998 and 2001 were estimated, based on clinical data from 127 patients, who were operated on in 1994. Ten-year overall survival rates were used as a measure of effectiveness, based on the two most recent EBCTCG meta-analyses. Actual resource costs were calculated. With a decision analytic model, the incremental cost-effectiveness ratios (1998 versus 1994, and 2001 versus 1998) were calculated.

Results: The introduction of the 1998 guideline resulted in a relative increase of 80% in the total number of patients eligible for adjuvant therapy, compared with 1994 (from 40% to 72% of all patients with primary breast cancer). With an estimated absolute increase of 10-year overall survival of 2%, the 1998 guideline was found to have an expected incremental cost-effectiveness ratio of about {euro}4837 per life-year gained.

Conclusions: Introduction of the new guideline considerably affected the number of patients eligible for adjuvant systemic therapy for breast cancer. The associated incremental cost-effectiveness ratio is well within the range of values that are generally considered acceptable.

Key words: adjuvant therapy, breast cancer, cost-effectiveness, guidelines


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Breast cancer is a substantial health care problem, both in terms of burden of disease and in terms of health care costs. The total health care costs of breast cancer in The Netherlands were estimated at {euro}115 million in 1988, which is ~13% of the total health care costs of cancer, and are estimated at {euro}141 million in 2005 [1Go].

Most patients with primary breast cancer will receive locoregional treatment, i.e. surgery, with adjuvant radiotherapy on indication [2Go]. The most important prognostic factor in primary breast cancer is the axillary lymph node status [3Go]. To provide information about the axillary lymph node status, a sentinel lymph node biopsy and/or an axillary lymph node dissection (ALND) is performed. Subsequent adjuvant systemic therapy can be given to high-risk patients to eliminate microscopic disseminated tumour cells. Adjuvant systemic therapy for breast cancer may consist of chemotherapy, endocrine therapy or a combination of both. Adjuvant chemotherapy as well as adjuvant endocrine therapy results in a relative reduction in recurrence and mortality of 25% and 16%, respectively [4Go–7Go]. The relative risk reduction appears to be about the same for node-positive (N+) as high-risk node-negative (N0) breast cancer.

In 1998, the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology published a new guideline for adjuvant systemic therapy for patients with resectable breast cancer [8Go], based on the St Gallen guidelines [9Go, 10Go]. These guidelines are the result of a trade-off of the improved survival that can be achieved on one hand and, on the other hand, possible side-effects and over-treatment. In The Netherlands, it was agreed that adjuvant systemic therapy was indicated in case of an expected absolute increase in 10-year survival of 5% or more [9Go]. Therefore, the 1998 Dutch guidelines were adjusted with respect to the policy in patients with N0 disease. These patients were categorised into low and high risk, the latter of whom were then advised to receive adjuvant systemic therapy. High-risk was defined by primary tumour characteristics, i.e. tumour size and grade of differentiation or mitotic activity index (MAI).

In 2001, this guideline was slightly modified. First, patients of 35 years of age or younger were now recommended always to be treated with adjuvant systemic therapy, regardless of the lymph node status or primary tumour characteristics. Secondly, postmenopausal patients 50–59 years of age, with a hormone receptor-positive tumour, were recommended for adjuvant chemotherapy, in addition to the use of adjuvant endocrine therapy.

To our knowledge, there is only one report on the impact of new guidelines of adjuvant therapies in breast cancer on numbers of patients to be treated [11Go]. The purpose of the present study is to assess the change in the number of patients eligible for adjuvant systemic therapy for breast cancer after the introduction of the guidelines of 1998 and 2001, and the impact on costs and effectiveness of treatment of patients with primary breast cancer in case of full compliance with these guidelines.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Design
One university hospital and two regional teaching hospitals participated in this study. The design of the study was a retrospective cohort study. Clinical data, involving patients with primary invasive breast cancer operated in 1994, were used to estimate the effect of the various guidelines on the number of patients who would have been candidates for adjuvant systemic treatment. The consequences of this were expressed in terms of survival gain and costs of treatment. The effect on the annual number of patients eligible for adjuvant systemic therapy and on the cost-effectiveness was studied using decision analytic modelling.

Patients
Subjects with histological proven primary invasive breast cancer, in whom a modified radical mastectomy or breast conservative surgery with an ALND was performed, were included in this study. Patients who had an ipsilateral breast carcinoma in the past (prior ALND) or who were classified as having M1 or T4 disease (TNM classification [12Go]) were excluded.

In the participating hospitals, sentinel lymph node biopsies have been performed since 1997. Therefore, a retrospective cohort of consecutive patients operated in year 1994 was selected, to prevent biases from changes in pathology procedures. It was estimated that 50% (expert opinion) of all node-negative patients would be eligible for adjuvant therapy based on primary tumour characteristics and 2.5% based on age <35 years [11Go]. All node-positive patients (40% of all newly diagnosed breast cancer patients) are eligible for adjuvant therapy according to the conventional policy. This results in the estimation that 71.5% of patients would be eligible [40% + (52.5%*60%)] for adjuvant therapy according to the 2001 guidelines. To estimate this percentage with 8% accuracy and a confidence interval of 95% (95% CI), 110 patients had to be included in this study.

Decision analytic model: structure, assumptions, input and outcome parameters
Structure.
A decision analytic model was constructed using decision analysis DATA 4.0® (Decision Analysis by TreeAge) software. The structure of the model is shown in Figure 1.



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Figure 1. Decision analytic model. MAI, mitotic activity index; BR, Bloom–Richardson differentiation grade.

 
Model assumptions.
For the baseline model it was assumed that endocrine therapy consisted of tamoxifen for a period of 5 years (20 mg a day), and that polychemotherapy consisted of the classical CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil) for six cycles. Combination therapy consisted of CMF regimen followed by a 5-year period of tamoxifen.

Hormone receptor status was considered positive if either the level of estrogen or progesterone receptor was ≥10 fmol receptor protein per mg of cytosol protein, or if the immunohistochemical assay showed that the quick score was 3 or more. The quick score is the sum of the intensity of the staining (intensity score) and the proportion of tumour cells being positive (proportion score), and was determined using a modification of the quick score method described by Bames et al. [13Go].

Patients were considered to be postmenopausal if either: (i) the last menstruation was at least 12 months ago and in case of use of contraceptives the last intake was at least 12 months ago and there was no use of hormonal substitution; (ii) there was an ovarian ablation performed; or (iii) patients had biochemical confirmation of lack of ovarian function (follicle-stimulating hormone and 17ß-estradiol levels in postmenopausal range according to local laboratory values).

Probabilities.
The probability of being eligible for adjuvant systemic therapy and the probabilities for receiving either of the two adjuvant systemic therapies was determined by the characteristics (i.e. nodal status, hormone receptor status, menopausal status, tumour size, Bloom–Richardson differentiation grade or MAI, and age) of the individual patient. These probabilities and their 95% CIs were determined on the basis of data from the clinical records and pathological reports of the patients operated in 1994, using SPSS® software version 11.0.

Costs.
The study was conducted from a health care perspective, implying that only direct medical costs were included. Full cost prices were calculated for every treatment included in the model, using a time horizon of 10 years. Drug costs, costs of personnel, blood tests, use of equipment, annual mammography and anti-emetics were included. In accordance with national guidelines for cost calculations in health care, 35% overhead costs were added to the total direct costs, and future costs were discounted to present values by a discount rate of 4% [14Go].

Effectiveness.
Results from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis were used to estimate effectiveness of the various adjuvant therapies [4Go–7Go] for the different subgroups of patients in terms of 10-year overall survival rates. Two experts (V.C.G.T.-H. and L.V.A.M.B.) estimated 10-year overall survival rates for subgroups for which no data could be obtained from the literature. The estimated 10-year overall survival rates were discounted to present values by a discount rate of 4%. Life-years saved were calculated based on the 10-year survival rate, by determining the area under the curve.

Cost-effectiveness.
The incremental cost-effectiveness ratio was expressed as costs per life-year gained. It was expected that the largest differences in costs and effectiveness would be for N0 patients. Therefore, separate incremental cost effectiveness ratios were calculated for this subgroup of patients.

Sensitivity analysis
To assess the robustness of the study results, one-way sensitivity analyses were performed for a number of variables. The discount rate was varied from 0% to 6% for cost and effectiveness data [14Go]. The probability of having a primary tumour with a diameter of ≥3 cm was varied between 3.4% and 25.9%. The probability of having a primary tumour with a diameter of 1–3 cm and a MAI ≥10 or a differentiation grade III was varied between 22.2% and 62.5%. Both ranges of probabilities were based on the minimum and maximum probability for the three hospitals. Furthermore, a probabilistic sensitivity analysis was performed, where a beta distribution was estimated for every 10-year survival rate. In a Monte Carlo simulation 100 drawings were sampled from these distributions, resulting in a mean survival rate with 95% CIs for the overall estimated survival rates.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Number of patients eligible for adjuvant therapy
The total number of patients included in this study and used for analysis was 127. The mean age of all patients was 58 years (range 35–83). The majority of patients was node-negative (60%) and had a hormonal receptor-positive tumour (72%). Only 3.9% of patients had a tumour with a size smaller than 1 cm (Table 1). Of all patients, 72% were eligible for adjuvant systemic therapy according to the guidelines of 1998 and 2001, in contrast to 40% according to the conventional policy. This resulted in a significant (P < 0.0001) relative increase of 80% in the total number of eligible patients (Table 2).


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Table 1. Patients' demographics

 

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Table 2. Total number of patients eligible for adjuvant systemic therapy according to the conventional policy and guidelines 1998 and 2001

 
Cost-effectiveness
Detailed information on the values of the probabilities, costs and survival rates are shown in the Appendix.

The treatment with a combination of polychemotherapy and endocrine therapy was the most expensive option, and ‘no treatment’ the least expensive option (Table 3). Treatment according to the guidelines 1998 or 2001 was more expensive (10-year incremental discounted costs per patient {euro}360) than treatment according to the conventional policy. Effectiveness of treatment in accordance with 1998 and 2001 guidelines resulted in an estimated discounted 49% 10-year overall survival for the whole group (treatment and no treatment) (Table 4). Treatment with a time horizon of 10 years of follow-up resulted for the 1998 guideline in an additional 1.5% 10-year survival, which equates to a 0.07 life-years gain compared with the conventional guideline. The incremental cost-effectiveness ratio was {euro}4837 per life-year saved, in favour of the 1998 guidelines (Table 4). Treatment according to 2001 guidelines was slightly more expensive, but not more effective, than treatment according to 1998 guidelines.


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Table 3. The discounted (4%) costs of all treatment options including 10 years follow-up for a teaching hospital

 

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Table 4. Discount rate (4%) corrected increments in costs and estimated overall survival and incremented costs/life-year saved as a result of treatment according to the three different guidelines

 
N0 patients
When considering the node-negative patients as a subgroup (n = 77), the discounted 10-year overall survival was 53.5% and 55.9% for all N0 patients according to the conventional policy and the 1998 and 2001 guidelines, respectively. This resulted in an incremental cost-effectiveness ratio of {euro}4837 per life-year saved (Table 4) in favour of the 1998 guidelines. Treatment according to guidelines 2001 was slightly more expensive, but no more effective, than treatment according to 1998 guidelines.

Sensitivity analyses
Results of the sensitivity analyses are shown in Table 5. If survival rates were not discounted to present values, the incremental cost-effectiveness ratio decreased to {euro}3268. The impact of the discount rate on survival rates was thus relatively large. In Table 5, it is shown that even substantial variations in incidences of primary tumour characteristics—relevant for treatment decisions in the node-negative group—had little impact on the incremental cost-effectiveness ratios.


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Table 5. Results of the sensitivity analyses on the incremental cost-effectiveness

 
The probabilistic sensitivity analysis on survival showed that the mean survival rates (95% CI) were 48.7% (43.7% to 53%) and 50.4% (45.3% to 55%) according to conventional policy and the 1998 guidelines, respectively. The mean incremental cost-effectiveness ratio (95% CI) was {euro}4240 (4505–3604) per life-year saved in favour of the 1998 guideline.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
This modelling study compared the change in number of patients with primary breast cancer receiving adjuvant systemic therapy since the introduction of the Dutch breast cancer guidelines of 1998 and 2001 compared with the conventional policy before these. In addition, the potential consequences of introducing these guidelines on cost-effectiveness of the changed clinical management of patients with breast cancer were investigated.

According to the conventional policy (in 1994), 40% of patients with primary breast cancer were eligible for adjuvant therapy. When the new guidelines were applied to this patient population, this figure rose to 72%, a relative increase of 80%, mainly due to the use of adjuvant treatment for patients with high risk N0 breast cancer.

Treatment according to the 1998 or 2001 guidelines was more expensive than treatment according to the conventional policy and resulted in an additional 1.5% 10-year overall survival per patient (treatment and no treatment) for the whole population, an additional 2.5% 10-year survival for the N0 population, that is, an additional 5% 10-year survival for the high-risk N0 population who actually became candidates for adjuvant therapy. The incremental cost-effectiveness ratio was {euro}4837 per life-year saved, in favour of the 1998 guidelines. This figure is well within the range of incremental cost-effectiveness ratios, which are generally considered acceptable [15Go].

Although no clear statement can be found on a cost-effectiveness threshold above which health technologies are automatically rejected and below which technologies are accepted, Dutch health authorities have accepted technologies with cost-effectiveness ratios below {euro}50 000 [16Go]. The Australian reimbursement authorities have been unlikely to recommend a drug if the cost-effectiveness ratio exceeded AU$76 000 per life-year saved and unlikely to reject it if less than AU$42 000 per life-year saved [17Go]. An upper threshold of about £30 000 per quality-adjusted life-year seems to have emerged at NICE [18Go]. Nevertheless, uncertainty of cost-effectiveness results and the burden of disease explain reimbursement decisions better than cost-effectiveness alone [19Go].

Treatment according to the 2001 guidelines was more expensive, but no more effective, than treatment according to the 1998 guidelines for the overall group of patients. For N0 breast cancer, treatment according to the conventional policy versus the 1998 and 2001 guidelines resulted in an incremental cost-effectiveness ratio of {euro}4837 per life-year saved in favour of the 1998 guidelines.

To our knowledge, there are no cost-effectiveness analyses of the guidelines for adjuvant therapy for breast cancer in literature. However, costs of adjuvant therapy can be found. In this study, the discounted costs of the 6 months' polychemotherapy and 5 years' tamoxifen, for a follow-up period of 5 years, were estimated to be {euro}2023 and {euro}2418, respectively. Messori et al. [20Go] estimated direct medical costs (including drugs costs, costs of administration, nursing time and device) of six cycles of CMF to be US$797.58 ({euro}906.45). Those costs did not include costs generated during follow-up. Furthermore, in literature the costs of polychemotherapy were found to be US$3838 ({euro}4361.89) [21Go] and of US$6000 ({euro}6764.40) [22Go]. Drummond et al. [22Go] estimated the costs for tamoxifen treatment to be US$1000 ({euro}1127.40). However, Kattlove et al. and Drummond et al. used charges to calculate costs [21Go, 22Go], as our results were based on real cost prices. Also, it should be mentioned that cost prices, charges and procedures are not necessarily equal in different (international) settings.

As with all modelling studies, this study had to make certain assumptions. Calculations were made assuming full compliance with the guidelines. In reality, it is not likely that a compliance of 100% will ever be attained. There will always be other factors influencing the choice for treatment. In the literature, a compliance of 90% with guidelines from the National Institute of Health was found for women who received any drug therapy (chemotherapy or endocrine therapy) [23Go]. Yet, this assumption applies to all three guidelines and a change in compliance will not affect the relevant differences in costs, effectiveness and cost-effectiveness. Furthermore, it was assumed that polychemotherapy treatment consisted solely of a CMF regimen. An anthracycline- or taxane-based regimen is another treatment of choice for polychemotherapy. The use of these treatments will probably affect the outcomes of the cost-effectiveness analyses. When taking only drug costs into account, in The Netherlands the costs of six cycles of CMF is {euro}492, of five cycles FEC90 (5-fluorouracil, epirubicine, cyclophosphamide) is {euro}2250 and of six cycles TAC (docetaxel, adriamycine, cyclophosphamide) is {euro}9000. However, incremental cost-effectiveness ratios cannot simply be translated from one chemotherapy regimen to another by using only drug costs. The extra drug costs of the FEC90 regimen may be partially compensated by the lower drug administration costs (five visits for FEC versus 12 visits for CMF), while the administration of the taxane regimen will bear even more costs. FEC90 may result in a 2% 10-year survival benefit compared with classical CMF for the subgroup of patients treated with chemotherapy [5Go], making the regimen possibly yet more cost-effective compared with CMF despite the additional drug costs of FEC. The TAC regimen was reported to result in a 6% 5-year survival benefit over FAC in node-positive patients [24Go]. This increased efficacy may outweigh some of the costs, but probably not all. Similarly, it was assumed that endocrine therapy consisted of tamoxifen for a period of 5 years. However, both the latest St Gallen (2005) guideline and ASCO now recommend the use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen for postmenopausal women with hormone receptor-positive breast cancer [25Go]. The cost price of tamoxifen is {euro}750 per patient, of sequential tamoxifen/aromatase inhibitor {euro}4000 and of upfront aromatase inhibitor {euro}7500, for 5 years of treatment. Of note, for nearly all studies on adjuvant aromatase inhibitors only disease-free survival was significantly improved, not overall survival, at least not within 5 years of follow-up. So, with no proof of life-years gained, but only quality adjusted life-years gained, the incremental cost-effectiveness ratio of adjuvant endocrine therapy will increase substantially with the routine use of aromatase inhibitors.

Owing to the perspective from which our study was conducted, only direct medical costs were included. It is conceivable, however, that adjuvant systemic therapy also incurs substantial non-medical and personal costs for patients, e.g. travel costs to the hospital, costs due to side-effects, home nursing costs, etc. Medical costs involving only short-term side-effects of polychemotherapy were included in the calculation of the true resource costs. This means that only the costs of anti-emetics, used during a polychemotherapy treatment, were included. Endometrial cancer, thrombosis, pulmonary emboli and stroke are side-effects that can occur in the treatment with tamoxifen. Although these side-effects could induce substantial costs, their incidence is low [26Go]. For this reason, it was decided to exclude the costs of these side-effects.

Effectiveness of adjuvant treatment in terms of increased overall survival was estimated on the basis of the findings of the EBCTCG meta-analyses [5Go, 6Go]. Although it is preferable to use primary data [27Go], it was not feasible in our study design. We performed a probabilistic sensitivity analysis on these estimated survival rates in the subclasses of patients as described in the Appendix. This analysis showed that the 95% CIs for the overall survival rates (conventional policy 43.7% to 53.0% and 1998 guidelines 45.3% to 55.0%) were acceptable, as well as the 95% CI for the incremental cost-effectiveness ratio ({euro}4505 to {euro}3604 per life-year gained).

Another limitation of our study was that we did not include data on the possible consequences of the guidelines on the quality of life of patients with breast cancer. To our knowledge, such data are not available from the literature for the various subgroups that were included in our model.

In conclusion, it was demonstrated that introduction of new guidelines resulted in a substantial increase in the number of patients eligible for adjuvant systemic therapy, and thus this implies more costs. Of note, the incremental cost-effectiveness ratio is well within the range of values that are generally considered acceptable. When implementing new guidelines, one should consider the effect on efficiency of the new guideline.


    Appendix
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Detailed information on the model input


Model variable


Base case value


Data source
Probabilities: the probability that a breast cancer patient

Probability




N+ is 0.398 Data from retrospective cohort
N+ and hormone receptor positive (ER+ or PgR+) is 0.659 Data from retrospective cohort
N+ and ER+ or PgR+ and postmenopausal is 0.586 Data from retrospective cohort
N+ and ER+ or PgR+ and postmenopausal and ≥70 years is 0.412 Data from retrospective cohort
N+ and ER– and PgR– and postmenopausal is 0.667 Data from retrospective cohort
N+ and ER+ or PgR+ and postmenopausal and 50–59 years is 0.188 Data from retrospective cohort
N+ and ER+ or PgR+ and postmenopausal and 60–69 years is 0.375 Data from retrospective cohort
N+ and ER– and PgR– and postmenopausal and ≥70 years is 0.3 Data from retrospective cohort
N0 is and a tumour <1 cm has 0.052 Data from retrospective cohort
N0 is and a tumour of 1–3 cm has 0.792 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI <10 or BR I/II has 0.579 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI ≥10 or BR III has and ER+ or PgR+ is 0.583 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI ≥10 or BR III has and ER+ or PgR+ and postmenopausal is 0.538 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI ≥10 or BR III has and ER+ or PgR+ and postmenopausal and ≥70 years is 0.429 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI ≥10 or BR III has and ER– and PgR– and postmenopausal is 0.7 Data from retrospective cohort
N0 is and a tumour of 1–3 cm and MAI ≥10 or BR III has and ER– and PgR– and postmenopausal and ≥70 years is 0.286 Data from retrospective cohort
N0 is and a tumour >3 cm has and ER+ or PgR+ is 0.818 Data from retrospective cohort
N0 is and a tumour >3 cm has and ER+ or PgR+ and postmenopausal is 0.75 Data from retrospective cohort
N0 is and a tumour >3 cm has and ER+ or PgR+ and postmenopausal and ≥70 years is 0.667 Data from retrospective cohort
N0 is and a tumour >3 cm has and ER– and PgR– and postmenopausal is 0 Data from retrospective cohort
N0 is and a tumour >3 cm has and ER– and PgR– and postmenopausal and ≥70 years is 0 Data from retrospective cohort
N0 and ≤35 years is 0.013 Data from retrospective cohort
N0 and ≤35 years and ER+ and/or PgR+ is 0 Data from retrospective cohort

Costs


Costs ({euro})


Data source

Nurses wage (per minute) 0.37 RUN MC collective agreement
Specialists wage (per minute) 0.90 RUN MC collective agreement
Blood test (per test) 1.32 COTG
Mammography (per mammography) 49.01 COTG
Tamoxifen (per tablet) 0.50 Pharmacist
CMF chemotherapy (per cycle) 16.49 Hospital pharmacist
Anti-emetics (per cycle CMF) 13.82 Hospital pharmacist
Intravenous system and pump (per cycle CMF) 4.05 Purchase department RUN MC
Effectiveness

10-year overall survival



N+, ER+ or PgR+, postmenopausal, ≥70 years, tamoxifen 30 EBCTCG overview
N+, ER+ or PgR+, postmenopausal, <70 years, tamoxifen 62 EBCTCG overview
N+, ER+ or PgR+, postmenopausal, 50–59 years, combination therapy 64 Expert opinion
N+, ER+ or PgR+, postmenopausal, 60–69 years, tamoxifen 62 EBCTCG overview
N+, ER+ or PgR+, premenopausal, combination therapy 70 Expert opinion
N+, ER– and PgR–, postmenopausal, ≥70 years, no therapy 15 EBCTCG overview
N+, ER– and PgR–, postmenopausal, <70 years, polychemotherapy 49 EBCTCG overview
N+, ER– and PgR–, premenopausal, polychemotherapy 53 EBCTCG overview
N0, no therapy 80 Expert opinion
N0, low risk,a no therapy 90 EBCTCG overview
N0, high risk,b ER+ or PgR+, postmenopausal, ≥70 years, tamoxifen 65 EBCTCG overview
N0, high risk, ER+ or PgR+, postmenopausal, <70 years, tamoxifen 81 EBCTCG overview
N0, high risk, ER+ or PgR+, premenopausal, combination therapy 86 Expert opinion
N0, high risk, ER– and PgR–, postmenopausal, ≥70 years, no therapy 53 EBCTCG overview
N0, high risk, ER– and PgR–, postmenopausal, <70 years, polychemotherapy 69 EBCTCG overview
N0, high risk, ER– and PgR–, premenopausal, polychemotherapy 78 EBCTCG overview
N0, ≤35 years, ER+ or PgR+, combination therapy 86 Expert opinion
N0, ≤35 years, ER– and PgR–, polychemotherapy

78

Expert opinion

a Low risk is defined as a tumour <1 cm or a tumour of 1–3 cm and MAI <10 or BR I/II.

b High risk is defined as a tumour 1–3 cm and MAI ≥10 or BR III or a tumour >3 cm.

N+, lymph node positive; N0, lymph node negative; ER, estrogen receptor; PgR, progesterone receptor; MAI, mitotic activity index; BR, Bloom–Richardson differentiation grade; CMF, cyclophosphamide, methotrexate, 5-fluorouracil.


    Notes
 
W. Kievit and M. J. Bolster contributed equally to this work.

Received for publication October 31, 2004. Revision received May 3, 2005. Accepted for publication July 15, 2005.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
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