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Volume 16
Issue 8
August 2005
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Cyclophosphamide-methotrexate
‘metronomic’ chemotherapy for the palliative
treatment of metastatic breast cancer. A
comparative pharmacoeconomic evaluation
G. Bocci
G. Bocci
*
Correspondence to: Dr G. Bocci, Division of Pharmacology and Chemotherapy, Department of
Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma,
55, I-56126 Pisa, Italy. Tel: +39-050-830148; Fax: +39-050-562020; Email:
[email protected]
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M. Tuccori
M. Tuccori
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U. Emmenegger
U. Emmenegger
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V. Liguori
V. Liguori
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A. Falcone
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R. S. Kerbel
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M. Del Tacca
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Ann Oncol (2005) 16 (8): 1243-1252.
DOI:
https://doi.org/10.1093/annonc/mdi240
Published:
19 May 2005
Article history
Received:
12 January 2005
Accepted:
04 March 2005
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G. Bocci, M. Tuccori, U. Emmenegger, V. Liguori, A. Falcone, R. S. Kerbel, M. Del
Tacca; Cyclophosphamide-methotrexate ‘metronomic’ chemotherapy for the palliative
treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann
Oncol 2005; 16 (8): 1243-1252. doi: 10.1093/annonc/mdi240
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Abstract
Background:: Metronomic chemotherapy—the chronic administration of chemotherapy at
relatively low, minimally toxic doses on a frequent schedule of administration at close regular
intervals, with no prolonged drug-free breaks—is a potentially novel approach to the control of
advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and
has, as an advantage, the property of significantly reducing undesirable toxic side-effects. The
aim of the present study was to evaluate the cost effectiveness of cyclophosphamidemethotrexate ‘metronomic’ chemotherapy in the palliative treatment of pretreated metastatic
breast cancer.
Methods:: Low-dose cyclophosphamide-methotrexate ‘metronomic’ chemotherapy was
compared with outcome and resource utilisation data of published phase II trials regarding
metastatic breast cancer, performed in western countries, mostly in Europe. All direct costs
associated with metastatic breast cancer treatment were included and adjusted to year 2003
values. Sensitivity analyses were performed and variations to the values of key parameters were
assessed.
Results:: Low-dose cyclophosphamide-methotrexate ‘metronomic’ therapy was assessed to be a
cost-effective/cost-saving therapy for palliative treatment for metastatic breast cancer when
compared with novel chemotherapy strategies (phase II trials). Compared with the 11 phase II
mono- and combination chemotherapies, metronomic treatment showed marked cost savings in
each case and improved cost effectiveness. Sensitivity analyses showed the results were robust to
variations to the values of key parameters with very few exceptions.
Conclusions:: Metronomic cyclophosphamide-methotrexate is significantly cost effective. If
validated by prospective randomized trials, the treatment concept could reduce healthcare costs,
especially those associated with the combined use of new, highly expensive, molecularly
targeted therapies.
metastatic breast cancer, metronomic chemotherapy, cyclophosphamide, methotrexate,
pharmacoeconomics, cost-effectiveness ratio, sensitivity analysis
Introduction
The objective of chemotherapeutic treatment in metastatic breast cancer has historically been
primarily palliative [1]. Indeed, the major aim of chemotherapy in such patients is to obtain
maximum symptom control, prevent serious complications, and increase survival without
diminishing quality of life. Several chemotherapeutic agents are used for the aforementioned
purpose, including 5-fluorouracil, taxanes, platinum analogs, vinorelbine, capecitabine and
gemcitabine, but a universal standard regimen has not yet been established [2]. These agents
when used at the maximum tolerated doses (MTDs) may be difficult to administer and are often
associated with severe side-effects, sometimes requiring hospitalization. Not surprisingly,
therefore, patient attitudes to receiving toxic chemotherapy regimens for metastatic breast cancer
are often negative, as the adverse effects of treatment often seem to outweigh any potential
benefits. Thus, the introduction of newer approaches, having improved or at least equivalent
efficacy but reduced toxicity, are highly desirable. Such approaches could include using less
toxic drugs, more convenient routes of administration (e.g. oral) and home-based (outpatient)
rather than hospital-based therapies. In this regard, an European expert panel stated about
metastatic breast cancer that ‘treatment should control disease in at least 20–30% of patients with
an acceptable side-effect profile’ [2].
Metronomic chemotherapy—the chronic administration of chemotherapy at relatively low, nontoxic doses on a frequent schedule of administration, with no prolonged drug-free breaks [3]—
has recently attracted attention as a promising experimental and clinical research strategy,
involving alternative or complementary ways of using both old and new anticancer
chemotherapeutic agents. Metronomic chemotherapy has been defined as a variation of dosedense therapy with the important exception that it is not necessarily dose intense, i.e. the
cumulative dose might actually be significantly less or equal to MTD-based chemotherapy, thus
reducing or perhaps even eliminating in some cases serious drug-induced toxicities, and hence
the need for growth-factor support [3]. Unlike MTD chemotherapy that presumably mainly
targets (proliferating) tumor cells, frequent or continuous low-dose chemotherapy appears to
inhibit preferentially the endothelial cell activity of the tumors growing vasculature [4]. The
basis of this surprising selectivity may have a number of mechanisms. For example, human
vascular endothelial cells in vitro are sensitive to the growth inhibiting effects of ultra low
concentrations of paclitaxel, in contrast to many other normal cell types or tumor cell types [5].
These effects can be amplified by long-term, continuous exposure, which can also result in
apoptosis of endothelial cells [6]. Such effects may be secondary to induction of an endogenous
inhibitor of angiogenesis, e.g. thrombospondin-1, induced by low-dose chemotherapy by as yet
unknown mechanisms [7], rather than direct inhibition of endothelial cell growth, or survival. In
addition, the mobilization, viability and levels of angiogenesis contributing circulating
endothelial progenitor cells may be strongly suppressed, and in a sustained manner, by
metronomic chemotherapy [8]. Among the numerous preclinical schedules using different
cytotoxic drugs, the oral and daily low-dose administration of cyclophosphamide has been
extremely successful in human prostate, non-small-cell lung cancer and breast cancer xenograft
mouse models [9, 10]. It has also been successful in spontaneously arising islet cell pancreatic
carcinoma [10, 11], even when the treatment is initiated on advanced, late stage bulky tumors, at
least when combined with a targeted antiangiogenic drug and upfront MTD chemotherapy [12].
This efficacy is accompanied by absent or low-grade toxicity on tissues otherwise highly
sensitive to the respective regimen of the same drug [13].
Truly metronomic long-term low-dose chemotherapy (with no prolonged drug-free break
periods) has been uncommon in adult oncology practise [3]. However, recently Colleoni et al.
[14] tested an oral metronomic chemotherapy regimen in a non-randomized phase II clinical trial
for the treatment of metastatic breast cancer patients, and reported an impressive efficacy using
this generally well tolerated protocol. Cyclophosphamide was administered at a dose of
50 mg/day, every day, with no breaks for up to 2 years and methotrexate was administered on
days 1 and 2, orally (2 × 2.5 mg/day) every week. Encouragingly, the overall clinical benefit was
31.7% (CI 20.6% to 44.6%), if stable disease lasting 6 months or longer is included. This was
achieved in the absence of any serious adverse events in 64 patients despite earlier treatments
with standard chemotherapy regimens in most cases. Furthermore, Glode et al. [15] and Vogt et
al. [16] tested in clinical settings metronomic chemotherapy protocols using alkylating agents
(cyclophosphamide and trofosfamide, respectively), which were combined with drugs thought to
have some antiangiogenic ‘side-effect’ activity (i.e. dexamethasone, rofecoxib and pioglitazone)
demonstrating efficacy as a salvage therapy in the treatment of patients with hormone-refractory
prostate carcinoma [15] or as a feasible alternative in the palliative treatment of patients with
advanced malignant vascular tumors [16]. However, these studies were single arm phase II trials
and the results clearly need to be validated in well designed prospective randomized phase III
clinical trials.
There is increasing pressure on health care resources that is leading to concerns about the
economic impact of therapeutic alternatives. The extremely high cost of new drugs that can
extend survival of cancer patients but which cannot cure the disease, makes the financial burden
of certain new therapeutic options virtually unsustainable. Furthermore, as pointed out by a
recent editorial by Schrag [17], ‘at this pace, escalating drug costs will pose an insurmountable
obstacle for the realization of advances in biomedical research’. Information on relative costeffectiveness of new and promising treatments is therefore required for the decision-making
process, from a clinical and ethical perspective. As part of an effort to investigate, for the first
time from a pharmacoeconomic point of view, the use of low-dose metronomic
cyclophosphamide and methotrexate as a treatment for metastatic breast cancer patients, a
comparative cost-effectiveness study on published phase II trials has been performed, which
contains an evaluation of the metronomic cyclophosphamide/methotrexate schedule relative to
alternative novel chemotherapeutic combinations.
Methods
Patients and treatments
Outcome and resource utilization data for the pharmacoeconomic analysis were based on
published phase II clinical trials regarding metastatic breast cancer, performed in western
countries, mostly in Europe, as to best evidence for comparative clinical performance, and to
minimize other potential measurement biases. Protocol-driven costs, including hospitalization
and visits to health care professionals have been calculated in the analysis referring to the
‘patients and methods’ section of the reviewed studies.
The evaluation of ‘metronomic’ low-dose cyclophosphamide/metho-trexate (CTX/MTX) was
based on a phase II clinical trial of 64 patients (63 evaluated) [14]. All patients had
‘histologically confirmed metastatic breast carcinoma (MBC) that had either progressed, or not,
after a first line chemotherapy for metastatic disease’.
The first cost-effectiveness analysis of ‘metronomic’ low-dose CTX/MTX [14] evaluates cost
savings versus oral chemotherapies in patients with metastatic breast cancer. In particular, the
first comparison involved 162 MBC patients administered with capecitabine [18] and treated at
least with two, but not more than three, prior chemotherapy regimens, one of which contained
paclitaxel. In the second comparison, 40 MBC patients, administered with estramustin phosphate
[19], had received at least one line of chemotherapy, including taxanes and/or anthracyclines.
The second cost-effectiveness evaluation of ‘metronomic’ low-dose CTX/MTX [14] versus
intravenous chemotherapies was based on an analysis of nine studies, involving MBC patients
treated with: (1) weekly vinorelbine (n=40) [20], previously treated with taxanes and
anthracyclines; (2) vinorelbine 96 h continuous infusion (n=47) [21], heavily pretreated with
taxanes and/or anthracyclines; (3) docetaxel/5-fluorouracil (5-FU; n=41) [22] previously treated
with anthracyclines; (4) oxaliplatin/leucovorin/5-FU (n=50) [23], pretreated with taxanes or
anthracyclines; (5) docetaxel alone (n=35) [24], patients with at least one prior chemotherapy
regimen including anthracyclines; (6) docetaxel/vinorelbine (n=49) [25] with a previous
treatment with anthracyclines; (7) docetaxel/carboplatin (n=36) [26] pretreated with
anthracyclines; (8) gemcitabine single agent (n=47) [27] pretreated with a prior chemotherapy
regimen with an anthracycline or anthracenedione; (9) paclitaxel/trastuzumab (n=38) [28]
pretreated with up to three chemotherapy regimens.
The doses and treatment schedules, the median administration period and the outcomes are
summarized in Table 1.
Study methodology
Each economic evaluation was undertaken from the perspective of the National Health Service
(NHS) in Italy, and included direct health care costs attributable to the NHS. Data on resource
utilization and outcomes from the clinical studies were combined with unit cost data from
various national sources. Costs included those associated with chemotherapy acquisition and
administration, hospitalization, visits to health professionals, use of concomitant medications and
clinical examinations. Unit costs were taken from several sources and were expressed in Euro
(€). All costs referred to the median time the patients were receiving chemotherapy. Costs of
chemotherapy and other medications were taken from the Italian National Formulary [29], while
hospitalization costs were from the current Italian National Schedule of Reference Costs, Italian
Ministry of Health (www.ministerosalute.it/imgs/c_17_normativa_176_allegato.doc).
Chemotherapy administration and health professional costs were taken from the current Italianbased sources of unit costs in healthcare [30, 31]. All costs relate to the year 2003.
The anti-emetic supportive/preventive therapies were counted as indirect costs only when they
were clearly mentioned in the ‘methods’ section of the reviewed publications. Doses and
frequency of administration were derived from the description given by the authors or as
suggested by the manufacturer's instructions. The costs for ondansetron (ondansetron always
orally administered) were also applied when authors declared a treatment with generally called
‘setrons’. The therapeutic scheme of administration for ondansetron was considered 8 mg/day for
3 days.
The costs of filgrastim (recombinant G-CSF) administration were applied only on the basis of a
clear statement in the manuscript. Doses and frequency of administration were derived from the
description given by the authors or as suggested by the manufacturer. In contrast, costs of a
growth factor supportive therapy were not applied when grade 3 or 4 neutropenias were treated
with a dose reduction in the programmed schedule. The standard therapeutic scheme of
administration for filgrastim was considered 5 μg/kg/day for 10 days
Concomitant treatments with filgrastim, when allowed by the study protocol but not clearly
specified regarding duration or number of administrations in the paper, were applied for each
chemotherapy cycle in patients with grade 3–4 neutropenia and the total costs were equally
distributed to all the patient population. However, it was not possible to quantify the real costs of
antibacterial chemotherapy associated with the high risk of infectious complications in
neutropenic patients. In all likelihood, the antimicrobial treatment cost incidence could be
considered minor.
Price of concomitant medication was varied by ±50% in performing sensitivity analysis to
reduce biases due to higher dose or prolonged medication applied in particular cases.
Efficacy
Parameters of efficacy chosen for this study were progression-free life years, calculated as
percentage of days free from disease progression in a year, and overall tumor response (complete
plus partial response to chemotherapy administration and stable disease). These two parameters
were not always simultaneously available in the ‘results’ sections of the selected papers and,
consequently, they were used only when clearly declared.
Evaluation
Cost-effectiveness analyses were performed as previously described by Lopert and collegues
[32] and Vogenberg [33]. Briefly, the cost-effectiveness ratio (CER), the cost per unit of benefit
of a drug or other therapeutic intervention, was calculated by applying the following formula:
\[CER=Cost_{A}/Effect_{A}\]
Incremental CER (ICER), representing the change in cost and health benefits when one health
care intervention is compared with an alternative one, was calculated as follow:
\[ICER=(Cost_{A}{-}Cost_{B})/(Effect_{A}{-}Effect_{B})\]
Sensitivity analysis
Sensitivity analysis is the study of how the variation in the output of a model (numerical or
otherwise) can be apportioned, qualitatively or quantitatively, to different sources of variation,
and how the given model depends upon the information fed into it [34]. When dealing with
uncertainty, as in this study where numerous variables have a range of values, such as costs
and/or outcomes, sensitivity analyses are conducted to test the robustness of the results [33].
Sensitivity analyses consist in varying different values of parameters considered important for
the evaluation model and verifying the obtained results. Through the comparison between the
varied values, it is possible to point out ‘critical parameters’ for the economic evaluation and, at
the same time, to examine the robustness of the cost-effectiveness ratios.
Where 95% confidence intervals (CIs) were available for outcome measures, these were used to
explore variation in treatment costs. At baseline, the median costs associated with the
hospitalization, concomitant medication, chemotherapy administration, drug treatment costs,
were used and in the sensitivity analyses these parameters were varied by up to 50% in each
direction.
Sensitivity analysis was performed using SAS® v.9.0 software (SAS Institute Inc., Cary, North
Carolina, USA).
Results
Metronomic chemotherapy (cyclophosphamide/methotrexate) versus oral
chemotherapy phase II trials
The costs associated with low-dose CTX/MTX regimen [14], capecitabine [18], estramustine
[19] and the incremental costs as the difference among the three treatments are summarized in
Table 2. Capecitabine and estramustine trials were associated with more resource-use than
metronomic CTX/MTX, essentially due to the cost of chemotherapy drugs (both capecitabine
and estramustine) and clinical examinations or health professional costs (for both capecitabine
and estramustine).
The cost-effectiveness ratios are displayed in Table 3. These demonstrate that the incremental
costs per progression-free life year gained were €605 280 for metronomic CTX/MTX compared
with capecitabine. The incremental cost per overall tumor response gained was €129 334 and
€38 901 for low-dose CTX/MTX compared with capecitabine and estramustine, respectively.
Several sensitivity analyses were conducted to test the robustness of baseline results. When only
the costs of chemotherapy drug acquisition were included in the analysis, varying them ±50%,
the incremental costs per progression-free life year of CTX/MTX ranged from €476 200 to
€734 360 compared with capecitabine administration. On the other hand, the incremental costs
per overall tumor response ranged from €101 752 to €156 914 and from €34 806 to €42 996 in
comparison to capecitabine and estramustine, respectively. When outcomes were varied using
the 95% CIs, the resulting incremental costs per gained overall tumor response ranged from
€85 491 to €408 973 and from €14 274 to €58 766 for capecitabine and estramustine,
respectively.
Metronomic chemotherapy (cyclophosphamide/methotrexate) versus intravenous
chemotherapy phase II trials
Median costs per patient for metronomic CTX/MTX and the nine phase II intravenous/infusional
chemotherapy trials (vinorelbine alone [20, 21], docetaxel/5-FU [22], oxaliplatin/leucovorin/5FU [23], docetaxel alone [24], docetaxel/vinorelbine [25], docetaxel/carboplatin [26],
gemcitabine alone [27], paclitaxel/trastuzumab [28]) are shown in Tables 4–6. The metronomic
regimen was associated with a lower level of resource use in each case. This was mainly due to
the higher costs of chemotherapy acquisition and administration in patients receiving continuous
infusions, hospitalization and sometimes concomitant medications.
Cost-effectiveness ratios calculated on the basis of cost and median outcome results discussed
above are also displayed in Table 7. These ratios suggest that CTX-based metronomic regimen is
a cost-effective alternative to phase II intravenous infusion chemotherapy regimens for
pretreated metastatic breast cancer. A gained incremental cost per progression-free life year with
CTX/MTX therapy was observed in all the comparisons and varied from a minimum of €17 388
(gemcitabine infusion) [27] and a maximum of €217 182 compared with 96-h infusion of
vinorelbine [21]. Similarly, a gained incremental costs per overall tumor response was
demonstrated in each comparison and ranged from a minimum of €56 433 (96-h infusion
vinorelbine) to a maximum of €1 030 522 (docetaxel alone) [24].
Sensitivity analyses were conducted to assess the robustness of the baseline results. Only the
analyses that demonstrated the most noticeable impact on baseline results are reported here.
If costs of chemotherapy drug acquisition were decreased by 50%, cost savings for metronomic
chemotherapy per progression-free life year were observed in each comparison except for
continuous infusion of gemcitabine [27]. Incremental cost saving for gemcitabine per
progression-free life year reached €12 733.
When hospitalization costs were reduced by 50%, resulting data confirmed a general gain in cost
per progression-free life year for metronomic regimen in comparison with the selected phase II
trials, ranging from €22 694 compared with docetaxel/vinorelbine [25], to €141 273 compared
with vinorelbine alone [21]. Only gemcitabine appeared to be cost-effective compared with lowdose oral CTX/MTX with an incremental cost gained per progression-free life year of €14 806.
Varying the administration costs or the concomitant treatment costs by 50% in both directions
(negative and positive), the sensitivity analysis confirmed the cost saving per progression-free
life year for metronomic regimen compared with all treatment.
Outcome results were varied using the 95% CIs in order to assess the robustness of our data.
When lower limit of progression-free life year for metronomic chemotherapy was compared with
the upper limit of the same parameter for the selected phase II intravenous chemotherapy trials
(the most unfavourable scenario for the metronomic regimen), in four analyses CTX/MTX
regimen showed a saving in cost per progression-free life year ranging from €31 730 in
comparison with docetaxel [24] administration, to €100 802 in comparison with vinorelbine [21]
chemotherapy. However, in these conditions, gemcitabine [27] regimen (cost gained for
progression-free life year €3 664), oxaliplatin/leucovorin/5-FU [23] treatment (cost gained for
progression-free life year €13 965), docetaxel/vinorelbine [25] chemotherapy (cost gained for
progression-free life year €17 560), and docetaxel/carboplatin [26] administration (cost gained
for progression-free life year €14 904) showed a small but favourable cost-effectiveness ratio in
comparison with metronomic treatment.
It is important to note that another relevant result obtained by the same sensitivity analyses on
overall tumor response confirmed the cost saving for low-dose CTX/MTX regimen in
comparison with all nine of the selected phase II chemotherapy regimens we evaluated.
Discussion
The comparative pharmacoeconomic evaluation we have undertaken was stimulated, to a large
extent, by the rapidly growing concern about the hugely escalating costs of recently approved
cancer drugs and the treatment protocols involved in using these drugs [17, 35]. In particular,
many of the new molecularly targeted drugs—especially monoclonal antibodies—can cost
thousands of US dollars per injection/course of treatment [17, 35]. In addition, these drugs are
often used in combination with standard chemotherapy regimens, sometimes involving
expensive chemotherapeutics as well as supportive care drugs, adding significantly to the burden
of overall costs, which are escalating to ‘unsustainable’ levels [17, 35]. Thus, a pro-active
response to help deal with this impending crisis is clearly needed [17]. In this regard, validation
through appropriate prospective randomized phase III clinical trials of metronomic
chemotherapy regimens, especially those involving relatively non-toxic doses administered
orally on an outpatient basis assumes a high priority. The available data about metronomic
clinical trials still involves phase II studies. An example of such a regimen is the CTX/MTX
protocol of Colleoni et al. [14] used for the treatment of refractory advanced metastatic breast
cancer, which we have used for our comparative analysis. The results of this analysis show a
clear cut financial cost-saving benefit compared to a number of other phase II novel regimens,
which can now be added to other potential or actual benefits such as reduced toxicity/increased
quality of life, reduced hospital visitations (as the therapy can be taken orally), and the potential
to combine such a chemotherapy regimen in a chronic manner with targeted non-cytotoxic drugs
[3].
Early phase clinical studies have shown that cyclophosphamide-based metronomic
chemotherapy may have the potential to be an effective and safe regimen for use as a palliative
treatment of patients with drug-resistant metastatic breast cancer and prostate cancer [14, 15],
although this conclusion clearly needs to be confirmed in larger randomized phase III clinical
trials. In preclinical models, weekly or daily low-dose cyclophosphamide has been used either
alone or in combination with other agents (e.g. antiangiogenic drugs) [10, 36] with good and
sometimes outstanding antitumor activity [9, 10, 36] and a very low toxicity profile [13].
The present economic evaluation, although performed on data obtained from single arm nonrandomized phase II clinical trials, indicates that cyclophosphamide-based metronomic
chemotherapy is highly cost effective in the management of metastatic breast cancer patients
when compared with other novel and experimental treatment protocols. To our knowledge, our
study is the first attempt to evaluate the cost effectiveness of a metronomic chemotherapy
regimen. Given that breast cancer is one of the most common cancers affecting the female
population, direct and indirect costs associated with the management of these patients represents
a significant economic burden on health care systems. As an example, at the beginning of the
1990s a retrospective analysis of the direct costs involved in managing advanced breast cancer
from the time to relapse until death (median time of 17 months) found that the maximum cost of
treatment per patient was £27 860 based on 1991 costs [37].
There are no previous examples of pharmacoeconomic studies involving metastatic breast cancer
treated with cyclophosphamide containing regimens to compare with our data. However,
Messori et al. [38] previously studied the cost-effectiveness ratio of adjuvant chemotherapy with
cyclophosphamide + methotrexate + fluorouracil combination in patients with node-positive
breast cancer. The results were found to be particularly favourable compared with estimates of
cost per life year saved, previously calculated for other types of pharmacological intervention
[38].
The incremental cost per overall tumor response and per progression-free life year gained when
comparing CTX/MTX to the other novel but still experimental treatments (i.e. phase II trials)
were quite remarkable, although we acknowledge that tumour responses must be interpreted
cautiously as an outcome of metastatic breast cancer therapy. Sensitivity analyses demonstrated
these results to be robust with very few exceptions.
In most cases the metronomic regimen dominated the other phase II trials, with superior
incremental cost savings ranging from a saving of €19 157 (cost per progression free life year)
versus docetaxel 60 mg/m2 + vinorelbine 25 mg/m2 intravenously administered [25] to
€1 030 522 (cost per progression-free life year) versus docetaxel 40 mg/m2 administered as a
30 min i.v. infusion for 6 consecutive weeks followed by a 2 week break [24]. It is also important
to note that the cost savings held up even after using sensitivity analyses with highly negative
assumptions (the most unfavourable scenarios for metronomic chemotherapy). One of the very
few instances where low-dose CTX/MTX was more expensive was against gemcitabine [27]
after chemotherapy drug acquisition costs were increased by 50%, or using the upper limit of
progression-free life year. In this case the incremental cost per progression-free life year was
€12 733 and €3 644, respectively, which would still indicate low-dose CTX/MTX to be good
value for money. The evaluations undertaken here are based on the schedules and doses outlined
in Table 1.
Nonetheless, the necessity for this pharmacoeconomic evaluation is evident by the high
incidence of the disease, the personal and social costs associated with metastatic breast cancer
and by the continuous development of new therapeutic approaches. Moreover, toxicity and
frequent visits to the health structures represent a significant burden to the national health
services. Indeed, increased attention to the quality of life of these patients favors the use of active
oral treatments having greatly reduced side-effects. Not all patients with pretreated and resistant
metastatic breast cancer are eligible for MTD regimens and a significant proportion will refuse
chemotherapy that they consider highly toxic. For these particular patients, the
cyclophosphamide-methotrexate metronomic treatment could be an efficaceous and appropriate
alternative, having a proven and significantly lower cost burden for both national health services
and private insurers.
It is acknowledged that there are limitations to the generalizability of analyses, which are based
on cost and outcome results from published trials. However, any limitations with this approach
must be considered in the light of limitations of alternative approaches where analysts make
systematic adjustments to the data or pursue predominantly analyses based on models [39].
These analytical ‘trade-offs’ are recognized in the Australian pharmacoeconomic guidelines for
reimbursement [40]. In these guidelines, analyses based on head-to-head trials are seen as a
pivotal step in value-for-money assessment, which can be complemented later by modelled
analyses. Another important aspect of an early pharmacoeconomic analysis of phase II trial costs
is that it could improve the drug development programs and help pharmaceutical industries
and/or public institutions in the difficult ‘go–no go’ decision [41] before going to phase III trials.
Future comparisons between other novel anti-cancer approaches, i.e. involving various targeted
therapies and the combination of daily low-dose cyclophosphamide plus methotrexate, will be
necessary to fully evaluate the cost effectiveness of the metronomic regimen. However, the cost
savings will probably be remarkable if the current prices of such new drugs are maintained [42].
Even in the worst situation the incremental cost-effectiveness ratio is very low, indicating that
low-dose CTX/MTX is a truly cost-effective alternative. Also worth stressing is most of the new
targeted therapies such as trastuzumab, the humanized anti-erbB-2/Her2 monoclonal antibody,
bevacizumab, the humanized anti-vascular endothelial growth factor (VEGF) antibody, and
erbitux/cetuximab, the chimeric anti-epidermal growth factor receptor (EGFR) antibody, as well
as small molecule inhibitors, are used primarily in combination with standard chemotherapy
regimens. Combination with metronomic chemotherapy regimens could permit chronic
combination therapy, which is not possible using MTD chemotherapy regimens because of its
associated toxicity and high costs [3].
In conclusion, cyclophosphamide-methotrexate metronomic regimens represent a potentially
significant cost-effective palliative treatment for metastatic breast cancer compared with other
novel, unapproved chemotherapy strategies (phase II trials). Its use represents good value for
money and efficient use of health care resources, at least for those patients with pretreated
metastatic breast cancer that are eligible for palliative chemotherapy. Hopefully this will provide
an additional incentive to undertake randomized phase III trials testing metronomic
cyclophosphamide regimens such as the CTX/MTX protocol used by Colleoni et al. [14] to
validate its efficacy and costs. Such trials would be aided by progress being made in dealing with
one of the major disadvantages of metronomic chemotherapy: determining the optimal
therapeutic/biological dose. This requires surrogate markers such as those being developed for
targeted antiangiogenic drugs [43], which may also be applicable for metronomic chemotherapy.
Table 1.
Dosage regimens used in the comparative clinical studies
Route
Treatment
Scheduled regimen
Low-dose oral cyclophosphamide and methotrexate
Low-dose oral
Methotrexate 2.5 mg bd on days
cyclophosphamide/
1 and 2, and cyclophosphamide
Oral
methotrexate [14]
50 mg every day
Treatment
duration and
outcome
MAP:
75PFLY: 23
(95% CI 17.3–
48.5)OTR:
31.7 (95% CI
20.6–44.7)
Phase II trial chemotherapy regimens for metastatic breast cancer
Oral
Oral
Intravenous
Intravenous
Intravenous
Capecitabine [18]
Estramustine [19]
Vinorelbine [20]
Vinorelbine [21]
Docetaxel/5-FU [22]
Oxaliplatin/leucovorin/
Intravenous 5-FU [23]
Intravenous
Docetaxel [24]
MAP: 241
Capecitabine 2510 mg/m2/day
PFLY: 25.5
given for 2 weeks followed by 1 (95% CI na)
week rest period
OTR: 20 (95%
CI 14–28)
MAP: 168
Estramustine phosphate 10 mg/kg PFLY: na
administered daily
OTR: 17.5
(95% CI 6–30)
MAP: 180
PFLY: na
Vinorelbine 30 mg/m2 week
OTR: 25 (95%
CI 13–41)
MAP: 63
PFLY: 19.7
Vinorelbine 8 mg/m2 day 1 then
(95% CI 15–
vinorelbine 8 mg/m2 on days 1–4
24.4) OTR: 19
in a continuous infusion, at home
(95% CI 7.88–
42.94)
MAP: 126
2
Docetaxel 85 mg/m 1-h infusion PFLY: 43.56
immediately followed by 5-FU (95% CI 4.11–
750 mg/m2 as a continuous
157.81) OTR:
infusion for 5 days
34 (95% CI
21–49)
2
Oxaliplatin 85 mg/m as a 2-h
infusion, leucovorin 200 mg/m2 MAP: 126
daily as 2-h infusion followed by PFLY: 55
bolus of 5-FU 400 mg/m2 day
(95% CI 42.5–
and a 22-h infusion of 5-FU
70.68) OTR:
600 mg/m2 daily repeated for 2
70 (95% CI
consecutive days; treatment was 53.6–86.4)
repeated every 3 weeks
MAP: 168
2
Docetaxel 40 mg/m administered PFLY: 69
as a 30 min i.v. infusion for 6
(95% CI
consecutive weeks, followed by 48.85–92)
2 weeks without treatment
OTR: 34 (95%
CI 19–50)
Docetaxel/vinorelbine
Intravenous [25]
Docetaxel/carboplatin
Intravenous [26]
Intravenous
Gemcitabine [27]
Paclitaxel/trastuzumab
Intravenous [28]
Route
Treatment
MAP: 112
PFLY: 90.4
Vinorelbine 25 mg/m2 and
(95% CI 70.7–
docetaxel 60 mg/m2; cycles 14
110.9) OTR:
days
45 (95% CI
31–60)
MAP: 126
Docetaxel 75 mg/m2 as 1-h i.v.
PFLY: 82.2
infusion followed
by carboplatin (95% CI 16.4–
AUC 6 mg/ml × min as 30 min i.v. 135.6) OTR:
infusion: cycles 3 week
61 (95% CI
45.2–77.0)
MAP: 84
PFLY: 66.57
Gemcitabine 1200 mg/m2 30 min
(95% CI
i.v. infusion on
days 1,8 and 15
20.55–225.2)
of 28-days cycle
OTR: 29 (95%
CI 16–46)
MAP: 168
Trastuzumab 4 mg/kg i.v. loading PFLY: 70.7
dose+2 mg/kg i.v. week;
(95% CI 20.5–
paclitaxel 60/90 /m2 i.v. infusion
199) OTR: 56
week
(95% CI 36.5–
75.5)
Scheduled regimen
Treatment
duration and
outcome
Low-dose oral cyclophosphamide and methotrexate
Oral
Low-dose oral
cyclophosphamide/
methotrexate [14]
Methotrexate 2.5 mg bd on days
1 and 2, and cyclophosphamide
50 mg every day
MAP:
75PFLY: 23
(95% CI 17.3–
48.5)OTR:
31.7 (95% CI
20.6–44.7)
Phase II trial chemotherapy regimens for metastatic breast cancer
Oral
Oral
Capecitabine [18]
Estramustine [19]
MAP: 241
Capecitabine 2510 mg/m2/day
PFLY: 25.5
given for 2 weeks followed by 1 (95% CI na)
week rest period
OTR: 20 (95%
CI 14–28)
MAP: 168
Estramustine phosphate 10 mg/kg PFLY: na
administered daily
OTR: 17.5
(95% CI 6–30)
Intravenous
Intravenous
Intravenous
Vinorelbine [20]
Vinorelbine 30 mg/m2 week
Vinorelbine [21]
Vinorelbine 8 mg/m2 day 1 then
vinorelbine 8 mg/m2 on days 1–4
in a continuous infusion, at home
Docetaxel/5-FU [22]
Docetaxel 85 mg/m2 1-h infusion
immediately followed by 5-FU
750 mg/m2 as a continuous
infusion for 5 days
Oxaliplatin/leucovorin/
Intravenous 5-FU [23]
Oxaliplatin 85 mg/m2 as a 2-h
infusion, leucovorin 200 mg/m2
daily as 2-h infusion followed by
bolus of 5-FU 400 mg/m2 day
and a 22-h infusion of 5-FU
600 mg/m2 daily repeated for 2
consecutive days; treatment was
repeated every 3 weeks
Docetaxel 40 mg/m administered
as a 30 min i.v. infusion for 6
consecutive weeks, followed by
2 weeks without treatment
2
Intravenous
Docetaxel [24]
Docetaxel/vinorelbine
Intravenous [25]
Vinorelbine 25 mg/m2 and
docetaxel 60 mg/m2; cycles 14
days
Docetaxel/carboplatin
Intravenous [26]
Docetaxel 75 mg/m2 as 1-h i.v.
infusion followed
by carboplatin
AUC 6 mg/ml × min as 30 min i.v.
infusion: cycles 3 week
Intravenous
Gemcitabine [27]
Gemcitabine 1200 mg/m2 30 min
i.v. infusion on
days 1,8 and 15
of 28-days cycle
MAP: 180
PFLY: na
OTR: 25 (95%
CI 13–41)
MAP: 63
PFLY: 19.7
(95% CI 15–
24.4) OTR: 19
(95% CI 7.88–
42.94)
MAP: 126
PFLY: 43.56
(95% CI 4.11–
157.81) OTR:
34 (95% CI
21–49)
MAP: 126
PFLY: 55
(95% CI 42.5–
70.68) OTR:
70 (95% CI
53.6–86.4)
MAP: 168
PFLY: 69
(95% CI
48.85–92)
OTR: 34 (95%
CI 19–50)
MAP: 112
PFLY: 90.4
(95% CI 70.7–
110.9) OTR:
45 (95% CI
31–60)
MAP: 126
PFLY: 82.2
(95% CI 16.4–
135.6) OTR:
61 (95% CI
45.2–77.0)
MAP: 84
PFLY: 66.57
(95% CI
Paclitaxel/trastuzumab
Intravenous [28]
20.55–225.2)
OTR: 29 (95%
CI 16–46)
MAP: 168
PFLY: 70.7
(95% CI 20.5–
199) OTR: 56
(95% CI 36.5–
75.5)
Trastuzumab 4 mg/kg i.v. loading
dose+2 mg/kg i.v. week;
paclitaxel 60/90 /m2 i.v. infusion
week
MAP, median administration period (days); PFLY, progression-free life/year (%); OTR, overall
tumor response (%); na, not available.
Table 2.
Median cost (€; 2003 values) per patient of cyclophosphamide/methotrexate (CTX/MTX)
treatment versus phase II oral chemotherapy trials for metastatic breast cancer
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health professional
costs
Suportive care
Supportive care
administration
Clinical
examinations
Total costs
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
CTX/MTX
[14]
CAP
[18]
Incremental costs
(CTX/MTX versus
CAP)
EST
[19]
Incremental costs
(CTX/MTX versus
EST)
38
6454
−6416
1201
−1163
0
0
0
0
0
0
0
0
0
0
570
1803
−1233
1276
−706
0
299
−299
0
0
0
743
−743
0
0
2916
9357
−6441
6571
−3655
3524
18 656 −15 132
9048
−5524
CTX/MTX
[14]
CAP
[18]
Incremental costs
(CTX/MTX versus
CAP)
EST
[19]
Incremental costs
(CTX/MTX versus
EST)
38
6454
−6416
1201
−1163
0
0
0
0
0
0
0
0
0
0
Resource
component
Health professional
costs
Suportive care
Supportive care
administration
Clinical
examinations
Total costs
CTX/MTX
[14]
CAP
[18]
Incremental costs
(CTX/MTX versus
CAP)
EST
[19]
Incremental costs
(CTX/MTX versus
EST)
570
1803
−1233
1276
−706
0
299
−299
0
0
0
743
−743
0
0
2916
9357
−6441
6571
−3655
3524
18 656 −15 132
9048
−5524
CAP, capecitabine; EST, estramustine.
Table 3.
Outcome measures and associated costs (€; 2003 values) for cyclophosphamide/methotrexate
(CTX/MTX) versus phase II trial oral chemotherapy regimens for metastatic breast cancer
Outcome and
CER
Progression-free
life/year (%)
Cost per
progression-free
life/year
Overall tumor
response (%)
Cost per tumor
response
Outcome and
CER
Progression-free
life/year (%)
Cost per
progression-free
life/year
Overall tumor
response (%)
Cost per tumor
response
CTX/MTX
[14]
CAP
[18]
23
25.5
15 322
Incremental
(CTX/MTX versus
CAP)
−2.5
EST
[19]
Incremental
(CTX/MTX versus
EST)
na
na
73 161 605 280
na
na
31.7
20
17.5
14.2
11 117
93 280 129 334
CTX/MTX
[14]
CAP
[18]
23
25.5
15 322
11.7
Incremental
(CTX/MTX versus
CAP)
−2.5
51 703 38 901
EST
[19]
Incremental
(CTX/MTX versus
EST)
na
na
73 161 605 280
na
na
31.7
20
17.5
14.2
11 117
93 280 129 334
11.7
51 703 38 901
CAP, capecitabine; EST, estramustine; CER, cost-effectiveness ratio; na, not available.
Table 4.
Median costs (€; 2003 values) per patient of resource-use for cyclophosphamide/methotrexate
(CTX/MTX) versus i.v. infusion phase II chemotherapy regimens and the incremental costs (€)
in each case
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Clinical
examination
Supportive
care
Supportive care
administration
Total treatment
costs
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Incremental
Incremental
Incremental
costs
costs
DCT/5costs
CTX/MTX VIN
VIN
(CTX/MTX
(CTX/MTX FU (CTX/MTX
[14]
[20]
[21]
versusVIN
versus VIN [22]
versus
[20] )
[21] )
DCT/5-FU)
38
3690
−3652
612
−574
9808
−9770
0
2545
−2545
297
−297
2970
−2970
0
6427
−6427
3000
−3000
7500
−7500
570
1366
−796
478
92
957
−957
2916
6991
−4075
2476
440
4897
−1981
0
3156
−3156
1022
−1022
25
−25
0
4712
−4712
2806
−2806
0
0
3524
28 887 −25 363
10 691 −7167
26 157 −22 633
Incremental
Incremental
Incremental
costs
costs
DCT/5costs
CTX/MTX VIN
VIN
(CTX/MTX
(CTX/MTX FU (CTX/MTX
[14]
[20]
[21]
versusVIN
versus VIN [22]
versus
[20] )
[21] )
DCT/5-FU)
38
3690
−3652
612
−574
9808
−9770
0
2545
−2545
297
−297
2970
−2970
0
6427
−6427
3000
−3000
7500
−7500
570
1366
−796
478
92
957
−957
Resource
component
Clinical
examination
Supportive
care
Supportive care
administration
Total treatment
costs
Incremental
Incremental
Incremental
costs
costs
DCT/5costs
CTX/MTX VIN
VIN
(CTX/MTX
(CTX/MTX FU (CTX/MTX
[14]
[20]
[21]
versusVIN
versus VIN [22]
versus
[20] )
[21] )
DCT/5-FU)
2916
6991
−4075
2476
440
4897
−1981
0
3156
−3156
1022
−1022
25
−25
0
4712
−4712
2806
−2806
0
0
3524
28 887 −25 363
10 691 −7167
26 157 −22 633
VIN, vinorelbine; DCT, docetaxel; 5-FU, 5-fluorouracil.
Table 5.
Median costs (€; 2003 values) per patient of resource use for methotrexate/cyclophosphamide
(CTX/MTX) versus i.v. infusion phase II chemotherapy regimens and the incremental costs (€)
in each case
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Clinical
examination
Supportive
care
Supportive care
administration
Incremental
Incremental
Incremental
costs
costs
costs
CTX/MTX OX/LE/5- (CTX/MTX DCT
DCT/VIN
(CTX/MTX
(CTX/MTX
[14]
FU [23]
versus
[24]
[25]
versus
versus
OX/LE/5DCT)
DCT/VIN)
FU)
38
5226
−5188
12 6787 −12 749
10 164
−10 126
0
1191
−1191
1782
−1782
792
−792
0
3000
−3000
4500
−4500
2000
−2000
570
956
−387
1276
−706
851
−281
2916
4896
−1981
6830
−3914
4353
−1437
0
2852
−2852
51
−51
1219
−1219
0
5025
−5025
0
0
391
−391
Resource
component
Incremental
Incremental
Incremental
costs
costs
costs
CTX/MTX OX/LE/5- (CTX/MTX DCT
DCT/VIN
(CTX/MTX
(CTX/MTX
[14]
FU [23]
versus
[24]
[25]
versus
versus
OX/LE/5DCT)
DCT/VIN)
FU)
Total treatment
3524
costs
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Clinical
examination
Supportive
care
Supportive care
administration
Total treatment
costs
23 146
−19 622
27 226
−23 702
19 770
−12 912
Incremental
Incremental
Incremental
costs
costs
costs
CTX/MTX OX/LE/5- (CTX/MTX DCT
DCT/VIN
(CTX/MTX
(CTX/MTX
[14]
FU [23]
versus
[24]
[25]
versus
versus
OX/LE/5DCT)
DCT/VIN)
FU)
38
5226
−5188
12 6787 −12 749
10 164
−10 126
0
1191
−1191
1782
−1782
792
−792
0
3000
−3000
4500
−4500
2000
−2000
570
956
−387
1276
−706
851
−281
2916
4896
−1981
6830
−3914
4353
−1437
0
2852
−2852
51
−51
1219
−1219
0
5025
−5025
0
0
391
−391
3524
23 146
−19 622
27 226
−23 702
19 770
−12 912
OX, oxaliplatin; LE, leucovorin; 5-FU, 5-fluorouracil; DCT, docetaxel; VIN, vinorelbine.
Table 6.
Median costs (€; 2003 values) per patient of resource use for methotrexate/cyclophosphamide
(CTX/MTX) versus i.v. infusion phase II chemotherapy regimens and the incremental costs (€)
in each case
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Clinical
examination
Supportive
care
Supportive care
administration
Total treatment
costs
Resource
component
Chemotherapy
drugs
Chemotherapy
administration
Hospitalization
Health
professionals
costs
Clinical
examination
Supportive
care
Supportive care
administration
Total treatment
costs
Incremental
Incremental
Incremental
costs
costs
costs
CTX/MTX
PCT/TSB
DCT/CAR[26] (CTX/MTX GEM[27] (CTX/MTX
(CTX/MTX
[14]
[28]
versus
versus
versus
DCT/CAR)
GEM)
GEM/TSB)
38
8404
−8366
4056
−4018
42 423
−42 385
0
594
−594
891
−891
2375
−2375
0
1500
−1500
2250
−2250
6000
−6000
570
957
−387
638
−68
1276
−706
2916
5014
−2098
3625
−349
6529
−3613
0
3388
−3388
0
0
709
−709
0
1298
−1298
0
0
8376
−8376
3524
21 155
−17 631
11 100
−7576
67 688
−64 164
Incremental
Incremental
Incremental
costs
costs
costs
CTX/MTX
PCT/TSB
DCT/CAR[26] (CTX/MTX GEM[27] (CTX/MTX
(CTX/MTX
[14]
[28]
versus
versus
versus
DCT/CAR)
GEM)
GEM/TSB)
38
8404
−8366
4056
−4018
42 423
−42 385
0
594
−594
891
−891
2375
−2375
0
1500
−1500
2250
−2250
6000
−6000
570
957
−387
638
−68
1276
−706
2916
5014
−2098
3625
−349
6529
−3613
0
3388
−3388
0
0
709
−709
0
1298
−1298
0
0
8376
−8376
3524
21 155
−17 631
11 100
−7576
67 688
−64 164
DCT, docetaxel; CAR, carboplatin; GEM, gemcitabine; PCT, paclitaxel; TSB, trastuzumab.
Table 7.
Outcome measures and associated costs (€; 2003) for cyclophosphamide/methotrexate versus i.v.
infusion phase II chemotherapy regimens for metastatic breast cancer
Outcome and CER
CTX/MTX
[14]
Versus vinorelbine[20]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus vinorelbine[21]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus docetaxel/5-fluorouracil[22]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus oxalilplatin/leucovorin/5-fluorouracil[23]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Comparator
combination
Incremental
na
na
na
na
25
6.7
115 548
378 552
19.7
3.3
54 269
217 182
19
12.7
56 268
56 433
55
−32
47 558
70 728
70
−38.3
37 367
59 094
43.56
−20.56
53 136
95 438
Outcome and CER
Overall tumor response
(%)
Cost per overall tumor
response
Versus docetaxel[24]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
Versus docetaxel/vinorelbine[25]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
Versus docetaxel/carboplatin[26]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
Versus gemcitabine[27]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
CTX/MTX
[14]
Comparator
combination
Incremental
31.7
34
2.3
11 117
68 076
853 130
23
69
−46
15 322
39 458
51 526
31.7
34
−2.3
11 117
80 076
1 030 522
23
90.4
−67.4
15 322
21 879
19 157
31.7
45
−13.3
11 117
43 933
97 083
23
82.2
−59.2
15 322
25 736
29 782
31.7
61
−29.36
11 117
34 680
60 174
23
66.57
−43.57
15 322
16 674
17 388
31.7
29
2.7
Outcome and CER
Cost per overall tumor
response
Versus paclitaxel/trastuzumab[28]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
Outcome and CER
CTX/MTX
[14]
Comparator
combination
Incremental
11 117
38 276
280 592
23
70.7
−47.7
15 322
95 740
134 516
31.7
56
−24.3
11 117
120 871
264 049
CTX/MTX
[14]
Versus vinorelbine[20]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus vinorelbine[21]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus docetaxel/5-fluorouracil[22]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Comparator
combination
Incremental
na
na
na
na
25
6.7
115 548
378 552
19.7
3.3
54 269
217 182
19
12.7
56 268
56 433
55
−32
47 558
70 728
70
−38.3
Outcome and CER
Cost per overall tumor
CTX/MTX
[14]
11 117
response
Versus oxalilplatin/leucovorin/5-fluorouracil[23]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus docetaxel[24]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus docetaxel/vinorelbine[25]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus docetaxel/carboplatin[26]
Progression-free life year
23
(%)
Cost per progression-free
15 322
life year
Overall tumor response
31.7
(%)
Cost per overall tumor
11 117
response
Versus gemcitabine[27]
Comparator
combination
Incremental
37 367
59 094
43.56
−20.56
53 136
95 438
34
2.3
68 076
853 130
69
−46
39 458
51 526
34
−2.3
80 076
1 030 522
90.4
−67.4
21 879
19 157
45
−13.3
43 933
97 083
82.2
−59.2
25 736
29 782
61
−29.36
34 680
60 174
Outcome and CER
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
Versus paclitaxel/trastuzumab[28]
Progression-free life year
(%)
Cost per progression-free
life year
Overall tumor response
(%)
Cost per overall tumor
response
CTX/MTX
[14]
Comparator
combination
Incremental
23
66.57
−43.57
15 322
16 674
17 388
31.7
29
2.7
11 117
38 276
280 592
23
70.7
−47.7
15 322
95 740
134 516
31.7
56
−24.3
11 117
120 871
264 049
CER, cost effectiveness ratio; na, not available.
The authors thank Dr Kathy Pritchard for her critical review of the manuscript and helpful
suggestions, Dr Giulio Francia for his insightful comments and Cassandra Cheng for her
excellent administrative assistance. The work was financially supported by AIRC (The Italian
Association for Cancer Research), Italy. U.E. was supported by the Swiss National Science
Foundation and the Swiss Cancer League/Oncosuisse (BIL SKL 1237–02–2002). R.S.K. was
supported, in part, by the National Cancer Institute of Canada.
An appendix to this article is available as supplementary data online at mdi240_SuppData.doc
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Author notes
1Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and
Advanced Technologies, University of Pisa, Via Roma, Pisa, Italy; 2Molecular and Cellular
Biology Research, Sunnybrook and Women's College Health Sciences Centre, Department of
Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; 3Senior consultant of
SAS®, Pisa; 4U.O. Oncologia Medica, Ospedale Civile, Livorno, Italy
© 2005 European Society for Medical Oncology
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breast cancer metastatic
chemotherapy regimen
cyclophosphamide
cost effectiveness
phase 2 clinical trials
cost savings
economics, pharmaceutical
health care costs
methotrexate
palliative care
sensitivity analysis
chemotherapy, metronomic
Issue Section:
Breast cancer
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Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in
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