1 Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies, University of Pisa, Via Roma, Pisa, Italy; 2 Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; 3 Senior consultant of SAS®, Pisa; 4 U.O. Oncologia Medica, Ospedale Civile, Livorno, Italy
* 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: g.bocci{at}med.unipi.it
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Abstract |
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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.
Key words: metastatic breast cancer, metronomic chemotherapy, cyclophosphamide, methotrexate, pharmacoeconomics, cost-effectiveness ratio, sensitivity analysis
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Introduction |
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Metronomic chemotherapythe chronic administration of chemotherapy at relatively low, non-toxic 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 dose-dense 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 x 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 cost-effectiveness 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.
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Methods |
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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.
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Chemotherapy administration and health professional costs were taken from the current Italian-based 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 34 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:
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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:
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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).
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Results |
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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/5-FU [23
], docetaxel alone [24
], docetaxel/vinorelbine [25
], docetaxel/carboplatin [26
], gemcitabine alone [27
], paclitaxel/trastuzumab [28
]) are shown in Tables 46. 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.
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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 low-dose 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.
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Discussion |
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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 non-randomized 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 gono 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.
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Acknowledgements |
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An appendix to this article is available as supplementary data online at http://www.annonc.oupjournals.org
Received for publication January 12, 2005. Accepted for publication March 4, 2005.
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