Treatment of advanced breast cancer: the good, the bad and the ugly

M. Colleoni1,*, S. Gelber2,3 and A. Goldhirsch1

1 Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy2 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA3 Statistical Center, International Breast Cancer Study Group, Boston, MA, USA

* Email: marco.colleoni{at}ieo.it

Every year more than 1 million women are newly diagnosed with breast cancer, and this figure will likely reach 1.5 million with the increased number of cases arising in developing countries [1Go]. Many of these patients will be offered adjuvant treatment based on consideration of disease responsiveness to specific therapies [2Go], and almost half eventually will have local or distant relapses.

 Metastatic, or advanced, breast cancer is a chronic disease requiring specific strategies to control disease progression and related symptoms. The treatment choice is often based on evidence obtained from trials designed to investigate therapy-related issues such as whether one treatment yields better responses or longer time to progression. These trials frequently evaluate whether a given treatment is effective in a selected group of patients, usually using measurable or evaluable disease to guide patient selection and avoiding, for example, those with only bone metastases—one-third of newly relapsed patients. In addition, the follow-up monitoring is also treatment-oriented, with the definitions of ‘good’ and ‘bad’ selected to promote a new compound or regimen as the standard treatment option. Very few trials test treatment strategies, treatment-effect monitoring policies for sequencing therapies [3Go] or the minimal burden of side-effects necessary for reasonable control of disease. This may be attributable to both the methodological difficulties of conducting such trials (e.g. sequencing treatments) and to a lack of a clear incentive for testing a strategy rather than a compound or a regimen, the results of which are much easier to market. Consideration of the convenience of a given treatment for the individual patient, or for a specifically targeted population, requires an assessment of benefits and costs. Despite the relatively large population of patients with advanced breast disease, there is insufficient information on the direct and indirect costs of treatments, which is crucial for understanding cost savings and cost-effectiveness of therapeutic interventions. There are limited quality-of-life data for these patients treated on randomized studies designed to estimate the cost–benefit ratios, and the available data are difficult to interpret [4Go]. In addition, the expenses related to caregiver burden are often ignored.

Should oncologists take into account the economic implications of adopting a new, expensive standard therapy and replacing less costly options? The ethical responsibility of oncologists to focus on the needs of individual patients is viewed by many as a hierarchically superior consideration to that of the societal duty to consider costs containment (i.e. avoiding prescriptions of expensive treatments) [5Go, 6Go]. Consequently, most physicians and ethicists agree that economic questions should be answered at a political level and should not directly influence practice of patient care.

On the other hand, resource implications are anchored to reality. Care for patients with cancer is one of the fastest growing cost segments of a national health budget. In a recent study on advanced breast cancer, the pharmacy costs were approximately US$298 per patient per month, with most of the drugs administered being chemotherapy agents [7Go]. Expensive new treatments are in development for cancer, although it is wrong to assume that new always relates to unacceptably increased costs. Some new drugs offer significant benefits in terms of survival and are cost-effective. An example is the introduction of capecitabine in the treatment of advanced breast cancer [8Go]. In the majority of developed countries insurance programs for health care function within a budget and additional costs for breast cancer treatment may result in fewer resources being available for other services. In the past there have been relatively few economical analyses of medical interventions to assist decision-makers in allocating resources for cancer treatments or other health-care interventions. Only recently have some government regulatory task forces required economic analyses as part of new drug submissions from the pharmaceutical industry. Yet physicians are rarely encouraged to evaluate expenditures when prescribing treatments or diagnostic and follow-up tests. Metastatic breast cancer is a field in which much could be done to improve the yield of therapeutic and monitoring treatment effects. Providing information on the cost, as well as the benefits, of new therapies to care providers and agencies managing health-care resources would be a significant step forward [9Go]. Although, as stated above, physicians have an ethical responsibility to prescribe the most appropriate treatment for an individual patient, they also must participate in the political decisions regarding fiscally responsible health-care policy.

Taking these considerations into account, the study by Bocci et al. [10Go] in this issue of Annals of Oncology is particularly welcomed and of interest. Metronomic, low-dose chemotherapy is increasingly recognized as a useful tool for the treatment of several types of cancer, such as hormone-refractory prostate carcinoma [11Go], heavily pretreated sarcoma [12Go] and melanoma [13Go], and also breast cancer. The treatment offers a low profile of side-effects and is commonly administered in an out-patient setting without the need for frequent hematological checks. According to the authors’ conclusions, the costs of the metronomic chemotherapy were usually two orders of magnitude smaller that those of the alternatives, with comparable outcomes.

Should these data be interpreted as a recommendation for the use of metronomic chemotherapy in place of well established treatments for metastatic breast cancer? We do not think this is the case. Metronomic low-dose chemotherapy is an additional therapeutic tool that provides disease control for a significant proportion of patients. Patients previously exposed to full cytotoxics doses have often enjoyed treatment efficacy when the same drugs were used subsequently in a metronomic schedule. Such observations counter the assumption of induction of drug resistance, similar to that observed in a microbiological environment, and are the basis for using metronomic therapies as a legitimate therapeutic tool. Since these regimens may be administered for a longer duration than common cytotoxic therapies, without significant toxicity or teratogenicity, they are particularly appropriate to test in patients with endocrine non-responsive breast cancer, for whom endocrine therapies are not useful, or patients with limited tumor burden and no related symptoms.

However, this line of reasoning was not followed in the Bocci et al. [10Go] paper. The authors based their conclusions on ‘classical’ parameters of efficacy, such as progression-free life years and overall tumor response. These traditional end points are not always applicable to the results in the reviewed papers owing to the large proportion of the patients who did not have progressive disease when the metronomic regimen began. In fact, patient selection differences among the studies probably had a significant impact on treatment outcomes, thus influencing the cost-effectiveness analyses. Furthermore, the trials analyzed are not comparable in terms of the indications for commencement of treatment. Thus, the cost-effectiveness comparison might have been substantially different had a direct comparison been made using a hypothetical randomized comparison, possibly increasing the benefit in favor of the low-dose, metronomic approach. However, as previously mentioned, this is not the underlying rationale for using this regimen. It is the new use of older drugs with renewed efficacy that is the issue. The fact that these metronomic, low-dose regimens may also be economically inexpensive and therapeutically convenient only increases their attractiveness. Obviously, there are side-effects of having a less expensive treatment regimen: it draws attention as to how inexpensive an anticancer treatment might be; it increases the awareness of the economic costs to care providers; it reduces side-effects, some of which draw additional resources (i.e. hospitalizations due to high grade toxic events); and it frees resources for treatment of other patients who do not have the luxury to enjoy expensive therapies.

Recently, recommendations have been presented regarding trials with concurrent economic analyses, including guidelines for data collection of costs, efficacy and proper sample size [14Go]. In particular, for equivalence trials, side-effects, ease of treatment administration and cost comparisons have been identified as the major parameters for guiding policy development. Prospectively collected information on economical costs, health states, quality of life and patient preferences require specific attention to ensure the proper extraction of information from source documents, interviews with patients and the use of patient diaries [14Go]. In fact, recently published data suggest that reports from medical care providers, compared with those of patients, might underestimate the amount of resources consumed, such as medications and care products [15Go].

The increased number of treatment options for metastatic breast cancer provide the individual patient choices for effective therapy, while allowing her to conduct her life as close to her expectations as possible. The debate should not be about a gradual shift from ‘aggressive standard’ chemotherapy to a ‘soft alternative’ regimen, but rather how to tailor treatments to improve responsiveness while palliating symptoms. And it is within this context that a metronomic chemotherapy has an important role. The fact that it is cheap just makes it ‘good’.

References

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