## Abstract

Background

The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown.

Patients and methods

A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out.

Results

In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort.

Conclusions

In this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.

## introduction

Breast cancer is a major public health problem [1] and leads to considerable health care consumption [2]. The use of adjuvant systemic therapy has greatly improved disease-free and overall survival in patients with early breast cancer [3]. The efficacy of adjuvant systemic therapies is clearly related to prognosis: patients with high risk of recurrence benefit most of adjuvant systemic therapy. The cost-effectiveness of various adjuvant systemic therapy regimens has been reported in node-positive [4–7] and node-negative breast cancer patients [5].

Recently, we have reported the results of the Dutch MIRROR (Micrometastases or Isolated tumor cells: Relevant and Robust Or Rubbish?) study, in which (sentinel) nodal isolated tumor cells and micrometastases in patients with early-stage breast cancer and favorable primary tumor characteristics who did not receive adjuvant systemic therapy were associated with poorer disease-free survival as compared with node-negative patients. In patients with isolated tumor cells or micrometastases who received adjuvant systemic therapy, disease-free survival was improved [8].

The cost-effectiveness of administering adjuvant systemic therapy to patients with isolated tumor cells or micrometastases has never been assessed before. We present an economic analysis based on patient data derived from the MIRROR study to assess the cost-effectiveness of adjuvant systemic therapy in this patient population.

## patients and methods

### objectives

The primary objective was to determine the incremental cost-effectiveness ratio (ICER) of administration of adjuvant systemic therapy in breast cancer patients with isolated tumor cells or micrometastases as final nodal status. The ICER was expressed as costs per 1% event prevented after 5-year follow-up. Secondary objective was to determine the time frame necessary for the administration of adjuvant systemic therapy to become cost saving (break-even point).

### patients

Details of the patient and tumor characteristics in the MIRROR study have been reported elsewhere [8]. In short, all patients (N = 2707) in The Netherlands who had a sentinel node biopsy before 2006, with isolated tumor cells or micrometastases as final nodal status after central pathology revision and favorable characteristics of the primary tumor, were included, as well as a control group of node-negative patients. For the present analysis, only patients with isolated tumor cells or micrometastases who had a complete follow-up, defined as minimal follow-up of 5 years, or deceased within 5 years were eligible.

### effects

An event was defined as either local, regional, or distant recurrence, contralateral invasive breast cancer, or ductal carcinoma in situ, another malignancy, death from any cause. The event rate per cohort was defined as the percentage events after 5 years of follow-up for the primary objective and as time to event for the secondary objective.

### costs

#### cost prices

Supplemental Table S1 (available at Annals of Oncology online) shows the unit cost price and their sources. In accordance with national guidelines for cost calculation in health care, we added 35% overhead cost to cost of personnel [17]. We calculated full cost prices from date of diagnosis up to 5 years after diagnosis for every treatment delivered for primary breast cancer, follow-up, and local, regional, contralateral, or distant recurrence of disease. All costs were converted to 2008 Euros using the Dutch consumer price index [20].

### cost and effect analyses

Costs were discounted to present values at 3%. Cost differences between both cohorts were explored by linear regression. First, a linear regression model was fitted to the raw data without taking into account potential confounding. Second, a regression model taking into account potential confounders (age, nodal status, log tumor size, tumor grade, and axillary treatment) was fitted to the data. Event rates after 5 years of follow-up were analyzed in a similar way with a generalized linear model (binomial family) using an identity link.

To assess the secondary objective, we analyzed the expected disease-free survival with a parametric regression model using the set of confounders described above and assuming a log-logistic distribution for the disease-free survival times. The costs up to breakeven were assessed using the mean costs of follow-up with adding the expected event rates per cohort, derived from the parametric regression model multiplied by the mean costs of an event.

### cost-effectiveness analysis

We carried out a cost-effectiveness analysis from an inpatient perspective. The sample for this analysis was bootstrapped (N = 1000) to derive a fairly normal distribution of the ICER. The 95% confidence interval (95% CI) of the ICER(s) was estimated using the percentile method. Finally, cost-effectiveness acceptability curves (CEACs) were derived enabling to evaluate efficiency by exploring a range of thresholds (willingness to pay for 1% event prevented in 5 years) [21]. The CEAC shows how many of all bootstrap replications, expressed as the probability (y-axis), result in ICERs lower than or equal to a certain willingness to pay for 1% event prevented (x-axis). For an increasing willingness to pay for 1% event prevented in 5 years, the probability that adjuvant systemic therapy becomes cost-effective increases according to the shape of the acceptability curve.

### sensitivity analyses

One-way sensitivity analyses were carried out on the status of the follow-up: a pessimistic scenario on complete and incomplete follow-up, an optimistic scenario on complete follow-up or incomplete follow-up and the occurrence of an event within 5 years, and two scenarios in which the discount rates were varied between 0% and 6%. These sensitivity analyses were displayed as CEACs. One additional deterministic scenario was carried out in which patients receiving chemotherapy in the base-case analysis received a third-generation chemotherapy regimen [six cycles of docetaxel, doxorubicin and cyclophosphamide (TAC)] instead of a first or second-generation regimen, taking into account additional costs and effectiveness [22].

## results

### patients

Complete follow-up up to 5 years after diagnosis was available for 366 of 856 patients (43%) in the no adjuvant therapy cohort and for 483 of 995 patients (49%) in the adjuvant therapy cohort of the MIRROR study. The characteristics of the patients with complete follow-up in the no adjuvant therapy cohort (N = 366) and the adjuvant therapy cohort (N = 483) are shown in Table 1.

Table 1.

Characteristics of patients in the no adjuvant therapy cohort and the adjuvant therapy cohort

No adjuvant therapy cohort (N = 366), N (%) P value Adjuvant therapy cohort (N = 483), N (%)
Characteristic 57 (32–89) P = 0.58 57 (31–88)
Years of age (median (range)
Tumor size
≤1 cm 100 (27) P = 0.02 99 (23)
1–2 cm 214 (59) 290 (59)
2–3 cm 52 (14) 94 (17)
1 133 (37) P = 0.02 134 (28)
2 213 (60) 325 (68)
3 12 (3) 17 (4)
Unknown 8 (0) 7 (0)
ER/PgR status
ER+ and/or PgR+ 322 (91) P = 0.02 450 (95)
ER− and PgR− 31 (9) 23 (5)
Unknown 13 (0.0) 10 (0)
Final nodal status (revised)
pN0(i+) 259 (71) P < 0.01 183 (38)
pN1mi 107 (29) 300 (62)
ALND and/or AI
No ALND and/or AI 193 (53) P < 0.01 80 (17)
ALND and/or AI 173 (47) 403 (83)
Hormonal therapy — NA 316 (65)
Chemotherapy — 40 (8)
Both — 127 (26)
No adjuvant therapy cohort (N = 366), N (%) P value Adjuvant therapy cohort (N = 483), N (%)
Characteristic 57 (32–89) P = 0.58 57 (31–88)
Years of age (median (range)
Tumor size
≤1 cm 100 (27) P = 0.02 99 (23)
1–2 cm 214 (59) 290 (59)
2–3 cm 52 (14) 94 (17)
1 133 (37) P = 0.02 134 (28)
2 213 (60) 325 (68)
3 12 (3) 17 (4)
Unknown 8 (0) 7 (0)
ER/PgR status
ER+ and/or PgR+ 322 (91) P = 0.02 450 (95)
ER− and PgR− 31 (9) 23 (5)
Unknown 13 (0.0) 10 (0)
Final nodal status (revised)
pN0(i+) 259 (71) P < 0.01 183 (38)
pN1mi 107 (29) 300 (62)
ALND and/or AI
No ALND and/or AI 193 (53) P < 0.01 80 (17)
ALND and/or AI 173 (47) 403 (83)
Hormonal therapy — NA 316 (65)
Chemotherapy — 40 (8)
Both — 127 (26)

AI, axillary irradiation; ALND, axillary lymph node dissection; ER, estrogen receptor; NA, non applicable; PgR, progesterone receptor.

### effects

Of patients with a complete follow-up, 24.9% had an event within 5 years in the no adjuvant therapy cohort and 16.8% of patients in the adjuvant therapy cohort. The difference in event rates between the cohorts was 8.1% (95% CI 2.6% to 13.6%). After correction for confounders, the difference in events between the cohorts was 8.0% (95% CI 2.4% to 13.6%).

### costs

From a random selection of 50 patients with metastatic breast cancer, 46 patients had a follow-up of at least 1 year, and 27 patients had a follow-up of at least 2 years and could be included in the analysis of costs. The mean costs of diagnosis and treatment of metastatic breast cancer for the first year after diagnosis of metastatic disease were €19 156 (N = 46; 95% CI €11 589–€26 722). The mean costs of treatment for the second year after diagnosis of metastatic disease were €15 622 (N = 27; 95% CI €9260–€21 985). These costs were assigned to the patients with metastatic disease in the present study.

Table 2.

Difference in mean costs per patient between the adjuvant therapy cohort and the no adjuvant therapy cohort after 5 years of follow-up

Differences in mean costs per patient (adjuvant therapy cohort minus no adjuvant therapy cohort) 95% CI of difference
Total costs €2939 €1603–€4275
Primary treatmenta €1725 €1180–€2268
ASTb €3008 €2669–€3348
Follow-up −€9 −€31–€14
Recurrence of disease −€1785 −€2982 to −€589
Differences in mean costs per patient (adjuvant therapy cohort minus no adjuvant therapy cohort) 95% CI of difference
Total costs €2939 €1603–€4275
Primary treatmenta €1725 €1180–€2268
ASTb €3008 €2669–€3348
Follow-up −€9 −€31–€14
Recurrence of disease −€1785 −€2982 to −€589

aPrimary treatment = surgery and optionally irradiation.

bAST = chemotherapy and/or endocrine therapy.

AST, adjuvant systemic therapy; CI, confidence interval.

Figure 1.

Mean cumulative costs per patient in the no adjuvant and the adjuvant therapy cohort, classified by type of costs.

Figure 1.

Mean cumulative costs per patient in the no adjuvant and the adjuvant therapy cohort, classified by type of costs.

### cost-effectiveness

The base-case scenario showed an ICER of €363 per 1% event prevented in 5 years (95% CI −€1422 to €4159). The base-case CEAC is displayed in Figure 2. The willingness to pay for 1% event prevented in 5 years, given an 80% probability that adjuvant systemic therapy becomes cost-effective, approached €1000.

Figure 2.

Cost-effectiveness acceptability curves for the base case scenario and the scenarios in the sensitivity analyses.

Figure 2.

Cost-effectiveness acceptability curves for the base case scenario and the scenarios in the sensitivity analyses.

### the break-even point for adjuvant systemic therapy

The mean costs for recurrence of disease were €16 809 in the no adjuvant therapy cohort and €11 627 in the adjuvant therapy cohort. The mean costs of follow-up in the fifth year after diagnosis were €128. Figure 3 shows the extrapolated cumulative mean costs per patient up to 20 years after diagnosis in both cohorts, using the extrapolated event rate. Around 18 years after diagnosis, the extrapolated mean cumulative costs per patient were almost equal in the no adjuvant therapy cohort (€22 652) as compared with the adjuvant therapy cohort (€22 694) and consequently, the no adjuvant systemic therapy and the adjuvant systemic therapy strategy approach breakeven. Beyond 18 years after diagnosis, adjuvant systemic therapy becomes the dominant strategy, i.e. cost saving and more effective.

Figure 3.

Extrapolated cumulative mean costs per patient up to 20 years after diagnosis in the no adjuvant and adjuvant therapy cohort.

Figure 3.

Extrapolated cumulative mean costs per patient up to 20 years after diagnosis in the no adjuvant and adjuvant therapy cohort.

### sensitivity analyses

Sensitivity analyses resulted in ICERs ranging from €129 to €478 for 1% event prevented. Figure 2 shows the CEACs for the different scenarios. Varying the discount rate did not alter the results in any way. The optimistic scenario showed that the willingness to pay for 1% event prevented in 5 years with a 95% probability that adjuvant systemic therapy became cost-effective approached €500; the pessimistic scenario resulted in a willingness to pay for 1% event prevented in 5 years with a 80% probability that adjuvant systemic therapy became cost-effective approached €1200. The deterministic established scenario, the administration of six cycles of TAC, resulted in an ICER of €743 per 1% event prevented.

## discussion

The MIRROR study has shown that disease-free survival was decreased in patients with isolated tumor cells or micrometastases as compared with node-negative patients and significantly improved in patients with isolated tumor cells or micrometastases who received adjuvant systemic therapy [8]. The present study assessed whether the administration of adjuvant systemic therapy in patients with early-stage breast cancer and lymph nodes containing isolated tumor cells or micrometastases is cost-effective.

The ICER was €363 per 1% event prevented after 5 years of follow-up. An alternative interpretation is that to prevent one event in 5 years in the study population, €36 300 has to be invested extra. However, in breast cancer, disease recurrence frequently occurs >10 years after diagnosis [23]. To assess whether and when administering adjuvant systemic therapy would breakeven and consequently would become cost saving, we extrapolated our outcome to a longer time horizon. We showed that ∼18 years after diagnosis, the expected mean costs in both cohorts were approaching breakeven; beyond 18 years, the administration of adjuvant systemic therapy in patients with isolated tumor cells or micrometastases was expected to become dominant, resulting in both prevention of events and saving of costs. The mean age of patients in this study was 57 years. The life expectancy of a 55-year-old healthy woman in The Netherlands is 29 years [24]. Therefore, the administration of adjuvant systemic therapy becomes cost saving far before a substantial part of the patients without disease recurrence in this study are expected to die.

In various breast cancer patient populations, cost-effectiveness and cost–utility studies have been carried out. Messori et al. [4] and Kievit et al. [30] studied first-generation chemotherapy regimens in node positive and in both node negative and positive patients, respectively, resulting in ICERs of US$447 and €4837 per life year gained, the last study including also endocrine therapy. Recently, the cost-utility of third versus second-generation chemotherapy regimens were analyzed in node-positive patients [6, 7, 31–33], resulting in ICERs of €2631/QALY (quality-adjusted life year) [31] up to GBP20432/QALY [6]. Adjuvant systemic therapy is less cost-effective in patients with lower risk of disease recurrence, illustrated by Kattlove et al. [5], who showed that an investment of$50 000 was necessary to save one life in 10 years in node-negative patients who received cyclophosphamide, methotrexate, 5-fluorouracil (CMF) polychemotherapy versus no chemotherapy, versus an investment of \$23 000 in node-positive breast cancer patients. These economic analyses are difficult to compare, as the included patients' risk profiles and the timeframes for costs and effects vary, different end points have been used, and sensitivity analyses and discounting have not always been carried out. In patients with nodal isolated tumor cells or micrometastases, cost-effectiveness or cost–utility analyses have never been reported.

In The Netherlands, treatment of serious diseases is considered cost-effective if costs of treatment do not exceed €80 000 per QALY [34]. In our study, we did not have data with respect to quality of life (QoL) of the included patients. However, QALY is not a very common parameter in economic analyses of adjuvant systemic therapy in breast cancer, as the impact of adjuvant systemic therapy on QoL is transient and minor compared with patients' adaptation and coping after diagnosis and surgery [35]. Moreover, recurrence of disease is associated with decrease in QoL, which we have taken into account by using the percentage of events prevented as effect parameter. Finally, QoL is less important as administering adjuvant systemic therapy was not only expected to be more effective but also cost saving beyond 18 years of follow-up.

This study was carried out in The Netherlands. As health care policies and costs of treatment might vary, the exact results of this cost-effectiveness analysis may be difficult to extrapolate to other countries. However, as adjuvant systemic therapy was expected to become cost saving beyond 18 years of follow-up, it seems reasonable to assume that in the long run adjuvant therapy becomes cost saving in all Western countries. This study was carried out from an inpatient perspective. Therefore, costs for extramural care were not taken into account. Especially in metastatic disease, these costs can be considerable, accounting for almost 15% of total costs of metastatic disease [36]. If extramural costs would have been taken into account, the administration of adjuvant systemic therapy was expected to become more cost-effective, as more patients in the no adjuvant therapy cohort had distant metastatic disease.

In conclusion, we carried out a cost-effectiveness analysis within a large nationwide cohort study to assess the cost-effectiveness of administering adjuvant systemic therapy to patients with nodal isolated tumor cells or micrometastases. To prevent one event in 5 years in this population of early breast cancer patients, €36 300 had to be invested to be considered cost-effective. Beyond 18 years after diagnosis, the administration of adjuvant systemic therapy in this population was cost saving.

## funding

Netherlands Organization for Health Research and Development (ZonMw) (945-06-509) and the Dutch Breast Cancer Trialists Group (BOOG).

## disclosure

The authors have declared no conflicts of interest.

## acknowledgements

We thank J.M. van Beek-Schoester for her assistance with data management and W.A.J.G. Lemmens for his assistance with statistical analyses. This study was presented in part at the American Society of Clinical Oncology Annual Meeting 2010 (poster, #614), Chicago, IL, June 4–8, 2010.

## references

1
Parkin
DM
Bray
F
Ferlay
J
, et al.  .
Global cancer statistics, 2002
CA Cancer J Clin
,
2005
, vol.
55
(pg.
74
-
108
)
2
Broekx
S
Hond
ED
Torfs
R
, et al.  .
The costs of breast cancer prior to and following diagnosis
Eur J Health Econ
,
2011
, vol.
12
(pg.
311
-
317
)
3
Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
Lancet
,
2005
, vol.
365
(pg.
1687
-
1717
)
4
Messori
A
Becagli
P
Trippoli
S
, et al.  .
Cost-effectiveness of adjuvant chemotherapy with cyclophosphamide+methotrexate+fluorouracil in patients with node-positive breast cancer
Eur J Clin Pharmacol
,
1996
, vol.
51
(pg.
111
-
116
)
5
Kattlove
H
Liberati
A
Keeler
E
, et al.  .
Benefits and costs of screening and treatment for early breast cancer. Development of a basic benefit package
JAMA
,
1995
, vol.
273
(pg.
142
-
148
)
6
Wolowacz
SE
Cameron
DA
Tate
HC
, et al.  .
Docetaxel in combination with doxorubicin and cyclophosphamide as adjuvant treatment for early node-positive breast cancer: a cost-effectiveness and cost-utility analysis
J Clin Oncol
,
2008
, vol.
26
(pg.
925
-
933
)
7
Marino
P
Siani
C
Roche
H
, et al.  .
Cost-effectiveness of adjuvant docetaxel for node-positive breast cancer patients: results of the PACS 01 economic study
Ann Oncol
,
2010
, vol.
21
(pg.
1448
-
1454
)
8
de Boer
M
van Deurzen
CH
van Dijck
JA
, et al.  .
Micrometastases or isolated tumor cells and the outcome of breast cancer
N Engl J Med
,
2009
, vol.
361
(pg.
653
-
663
)
9
McLaughlin
SA
Wright
MJ
Morris
KT
, et al.  .
Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements
J Clin Oncol
,
2008
, vol.
26
(pg.
5213
-
5219
)
10
Lucci
A
McCall
LM
Beitsch
PD
, et al.  .
Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011
J Clin Oncol
,
2007
, vol.
25
(pg.
3657
-
3663
)
11
Langer
I
Guller
U
Berclaz
G
, et al.  .
Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients
Ann Surg
,
2007
, vol.
245
(pg.
452
-
461
)
12
von Minckwitz
G
Kummel
S
Vogel
P
, et al.  .
Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial
J Natl Cancer Inst
,
2008
, vol.
100
(pg.
542
-
551
)
13
Martin
M
Lluch
A
Segui
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
,
2006
, vol.
17
(pg.
1205
-
1212
)
14
Aapro
MS
Cameron
DA
Pettengell
R
, et al.  .
EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours
Eur J Cancer
,
2006
, vol.
42
(pg.
2433
-
2453
)
15
Struikmans
H
Nortier
JW
Rutgers
EJ
, et al.  .
Guideline ‘Treatment of breast cancer 2008’ (revision)
Ned Tijdschr Geneeskd
,
2008
, vol.
152
(pg.
2507
-
2511
)
16
Dutch Health Care Insurance Board
Diagnostic Compass
,
2003
Amstelveen, the Netherlands
Dutch Health Care Insurance Board
17
Oostenbrink
JB
Bouwmans
CAM
Koopmanschap
MA
Rutten
FFH
Manual For Cost Analysis, Methods and Guidelines Prices in Health Care Economic Evaluations
,
2004
Amstelveen, the Netherlands
College voor Zorgverzekeringen (CVZ)
18
Health Care Insurance Board. Cost of Medicine

www.medicijnkosten.nl (9 April 2009, date last accessed)
19
Dutch Healthcare Authority

Tariffs in Health Care. http://dbc-tarieven.nza.nl/Nzatarieven/top.do (9 April 2009, date last accessed)
21
O'Brien
BJ
Briggs
AH
Analysis of uncertainty in health care cost-effectiveness studies: an introduction to statistical issues and methods
Stat Methods Med Res
,
2002
, vol.
11
(pg.
455
-
468
)
22
Peto
R

The worldwide overview: new results for systemic adjuvant therapies. Presented at the San Antonio Breast Cancer Symposium. San Antonio, TX, December 13–16, 2007
23
Dimecheli
R
Abbattista
A
Miceli
R
, et al.  .
Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy
Breast Cancer Res Treat
,
1996
, vol.
41
(pg.
177
-
185
)
24
Statistics Netherlands

25
Rutgers
EJ
Nortier
JW
Tuut
MK
, et al.  .
Dutch Institute for Healthcare Improvement guideline, “Treatment of breast cancer”
Ned Tijdschr Geneeskd
,
2002
, vol.
146
(pg.
2144
-
2151
)
26
Martin
M
Pienkowski
T
Mackey
J
, et al.  .
Adjuvant docetaxel for node-positive breast cancer
N Engl J Med
,
2005
, vol.
352
(pg.
2302
-
2313
)
27
Martin
M
Segui
MA
Anton
A
, et al.  .
Adjuvant docetaxel for high-risk, node-negative breast cancer
N Engl J Med
,
2010
, vol.
363
(pg.
2200
-
2210
)
28
Coombes
RC
Kilburn
LS
Snowdon
CF
, et al.  .
Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial
Lancet
,
2007
, vol.
369
(pg.
559
-
570
)
29
Smith
I
Procter
M
Gelber
RD
, et al.  .
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
Lancet
,
2007
, vol.
369
(pg.
29
-
36
)
30
Kievit
W
Bolster
MJ
van der Wilt
GJ
, et al.  .
Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer
Ann Oncol
,
2005
, vol.
16
(pg.
1874
-
1881
)
31
Martin-Jimenez
M
Rodriguez-Lescure
A
Ruiz-Borrego
M
, et al.  .
Cost-effectiveness analysis of docetaxel (Taxotere) vs. 5-fluorouracil in combined therapy in the initial phases of breast cancer
Clin Transl Oncol
,
2009
, vol.
11
(pg.
41
-
47
)
32
Au
HJ
K
Younis
T
, et al.  .
Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects
Breast Cancer Res Treat
,
2009
, vol.
114
(pg.
579
-
587
)
33
Younis
T
Rayson
D
Sellon
M
, et al.  .
Adjuvant chemotherapy for breast cancer: a cost-utility analysis of FEC-D vs. FEC 100
Breast Cancer Res Treat
,
2008
, vol.
111
(pg.
261
-
267
)
34
Raad voor de Volksgezondheid en Zorg (RVZ) (Council for Public Health and Health Care)
Sensible and Durable Care
,
2006
Zoetermeer, the Netherlands
Raad voor de Volksgezondheid en Zorg (Council for Public Health and Health Care)
35
Hürny
C
Bernhard
J
Coates
AS
, et al.  .
International Breast Cancer Study Group. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer
Lancet
,
1996
, vol.
347
(pg.
1279
-
1284
. Erratum in Lancet 1997; 350: 298
36
Dahlberg
L
Lundkvist
J
Lindman
H
Health care costs for treatment of disseminated breast cancer
Eur J Cancer
,
2009
, vol.
45
(pg.
1987
-
1991
)