Chemotherapy for metastatic breast cancer

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1 Annals of Oncology 16 (Supplement 4): iv23 iv27, 2005 doi: /annonc/mdi904 Chemotherapy for metastatic breast cancer S. Barni* & M. Mandalà Division of Medical Oncology, Treviglio Hospital, Treviglio, Italy Key words: chemotherapy, breast cancer, advanced, tailored therapy General strategy Breast cancer is a biologically heterogeneous disease and its course may vary from slow and indolent to rapidly progressive. In the adjuvant setting, tumour size, axillary lymph-node status and grading are the most important prognostic factors. On the other hand, metastatic disease is characterised by a variety of interactions between tumour and patient-related biological factors, site of disease involvement, disease-free interval, exposure and response to previous treatment. These features might modify the clinical course of the disease influencing chemotherapeutic response, time to progression and finally overall survival [1]. In addition, metastatic disease carries several genetic alterations that are responsible for the tumour dissemination and resistance to the therapy. Metastatic breast cancer (MBC) is incurable and standard therapies provide typically palliation or prolonged symptomfree survival. The median survival after appearance of metastases is approximately months. Life with metastatic disease might be prolonged and may exceed several years. A subset of patients with very limited extension of disease, particularly those with soft tissue and solitary bone disease, and without vital organ involvement, may survive for more than 10 years. Furthermore among those who achieve a complete remission after standard chemotherapy, a few remain progression free for extended periods of time, occasionally exceeding 20 years [2]. Decision on treatment choice includes quality of life considerations, attention to potential endocrine responsiveness and markers of aggressiveness of the disease, as well as considering the preferences of the patient. Endocrine therapy is the most important approach for hormone responsive patients because this strategy combines efficacy with minimal toxicity and as a consequence preserves a good quality of life. On the other hand, most patients with endocrine resistant or rapidly progressive disease are candidates for cytotoxic chemotherapy. The short term end points of chemotherapy are to increase response rate and palliate symptoms, the mid term *Correspondence to: Dr Sandro Barni, Division of Medical Oncology, Treviglio Hospital, P.le Ospedale 1, 24047, Treviglio, Italy; Tel: ; Fax: ; [email protected] end point is to delay disease progression and, finally, the long term end points are to achieve cure and prolong survival. All the above end points should maintain and improve the patient s quality of life. The recently published overview of MBC treatments, analysing the effect of different types of systemic therapies, showed a relatively modest benefit in terms of survival, despite differences in response rate of various combinations upon others [3]. In addition it was stated that despite some evidence of effectiveness of specific regimens, the lack of evaluation of quality-of-life impact of these treatments does not allow a definite conclusion about their relevance on the overall strategy for proper patient care. As a consequence the optimal chemotherapy for MBC patients remains a challenge and should be based on the toxicity, the extent of disease, the patient s preference and the presence of life threatening metastases or imminent complications that require aggressive management and rapid tumour control. Polychemotherapy regimens containing anthracyclines or taxanes are often used as first line systemic treatment for patients with MBC, and their use is associated with high response rates [4]. Results of second-line chemotherapy in patients who received anthracyclines containing treatment in the adjuvant setting, or taxanes as first-line chemotherapy for metastatic disease, are less impressive, the response rate being, for most second-line regimens, between 10% to 30% [5]. In addition, while the benefit of a first line chemotherapy for MBC patients is generally accepted, the role of second and subsequent lines of chemotherapy is more controversial in terms of quality of life and survival benefit [5]. Finally several questions arise in general practice: (i) Does combination chemotherapy improve survival as compared to sequential single agent chemotherapy? (ii) What is the optimal duration of treatment? (iii) What is the treatment of choice for taxane- and anthracycline-resistant patients? (iv) Are we ready to move on from the clinical-based choice to molecular tailored chemotherapy? Does combination chemotherapy improve survival as compared to sequential single agent chemotherapy? For many years, combination chemotherapy has represented the clinical dogma and the standard for hormone-refractory MBC. Its use was based on the assumption that the use of non q 2005 European Society for Medical Oncology

2 iv24 cross-resistant agents with non overlapping toxicities would result in therapeutic synergy, overcoming drug resistance. Furthermore in the meta-analysis by Fossati et al. 15 studies comparing polychemotherapy with single agent treatment were evaluated. The authors found that the response rate and overall survival was higher in the polychemotherapy pooled data [3]. The E1193 Intergroup Trial strongly contributed to clarify the relative role of a single sequential therapy versus a combination therapy for MBC [6]. In this study 739 chemotherapynaive breast cancer patients were randomized to receive doxorubicin 60 mg/mq or paclitaxel 175 mg/mq as single agents or the combination of doxorubicin (50 mg/mq) and paclitaxel (150 mg/mq). Patients who received single agent chemotherapy were crossed over to the other agent as the disease progressed. Despite the statistically significant improvements in response rate and time to treatment failure for combination as opposed to single-agent therapy, there was no significant difference in overall survival and the quality of life between the three arms. In a multicentre study O Shaughnessy et al. randomized 511 antracycline-pretreated MBC patients to receive docetaxel and capecitabine or docetaxel as a single agent [7]. The authors reported higher response rate, improved time to progression and the overall survival for the combination treated group. Unfortunately only 17% patients initially treated with docetaxel subsequently received capecitabine at progression. This consideration raises concern as it does not allow an accurate comparison between the concomitant and sequential administration of both drugs. A third trial, by Soto et al., has been reported only in abstract form. In this study 217 antracycline- pretreated MBC patients were randomized to receive capecitabine plus docetaxel or paclitaxel in combination, or capecitabine followed by a taxane at disease progression [8]. The preliminary results for 105 recruited patients showed no significant differences between the three arms in terms of overall survival. A fourth trial was reported two years ago by Heidemann et al. In this study 260 patients were randomized to mitoxantrone 12 mg/mq vs FEC (5FU 500 mg/mq, Epirubicin 50 mg/mq, Cyclophosphamide 500 mg/mq) every 3 weeks, in first line chemotherapy [9]. The treatment schedule was continued until complete remission plus two cycles, or until disease progression. Second line chemotherapy was planned and consisted of mitomycin in combination with vindesine and prednisolone. Third line chemotherapy was left to the discretion of the oncologist, assuming that subsequent lines of chemotherapy would not contribute significantly to the overall survival. In order to measure palliation and quality of life and the opinion of patients and oncologists, a Brunner s score was adopted. No statistical differences were detected in term of response rate, time to response, time to best response, time to progression and overall survival. Furthermore the Brunner s score was worse in the FEC group. This study has at least three limitations: first of all the limited sample size (119 patients for each arm were evaluable for efficacy and quality of life) does not exclude a small but significant advantage for FEC arm in terms of outcome. Secondly the relative low dose of epirubicin may compromise the efficacy of polychemotherapy. In a French study 412 MBC patients were randomized to receive single agent epirubicin at 75 mg/mq versus two regimens of FEC with epirubicin administered at two different doses: 75 mg/mq and 50 mg/mq. The combination regimens were superior to the single agent, and FEC 75 was superior to FEC 50 in terms of response rate and overall survival [10]. The third concern regarding Heidemann s study is that no information was given about the number of patients who received second-line chemotherapy. No benefit from combination chemotherapy compared to single agent treatment was shown by a Finnish group [11]. However, in that trial, the majority of patients were considered low risk when the authors compared weekly epirubicin to FEC (60). There was no difference in median time to progression and overall survival. In the meta-analysis by Fossati et al., 15 studies comparing polychemotherapy with single agent treatment were evaluated. The authors found that response rate was higher in the polychemotherapy pooled data, but overall survival was superimposable [3]. What did we learn from these data? Is sequential monotherapy the best choice in MBC patients? There is no definite answer to this intriguing question. The treatment choice should be personalised. In several trials, overall response was superior in the group undergoing polychemotherapy as compared to the group undergoing monochemotherapy. This may translate in a practical clinical choice: to select polychemotherapy for very high risk patients, such as those with multiorgan involvement and a rapid double time clinical growth, in order to avoid organ failure and hence rapidly compromise the possibility of administering an efficient chemotherapy. On the other hand, patients with low risk disease, such as no liver or multi-organ involvement and a longer disease-free interval, may benefit from a sequential monochemotherapy avoiding unnecessary toxicity, in order to obtain response and to preserve the quality of life. What is the optimal duration of treatment? In the late 1980s Coates et al. published a landmark study specifically designed to compare intermittent and continuous treatment strategies in MBC patients [12]. In this prospective study, 305 patients were randomised to receive continuous chemotherapy, administered until disease progression, or three cycles of chemotherapy with intermittent schedule, repeated only when there was evidence of disease progression. The intermittent chemotherapy resulted in a significantly worse response disease free survival and overall survival. The authors reported a better quality of life in the continuous chemotherapy group. A second study performed by Muss et al. investigated the optimal duration of chemotherapy in metastatic setting [13]. The authors reported that intermittent chemotherapy resulted in a significantly worse response

3 iv25 and disease free survival, without compromising overall survival. Similar data were provided by Harris et al [14]. More recently in a French study the optimal duration of FEC therapy in the metastatic setting was evaluated in 392 MBC patients randomised between 11 cycles of FEC 75, four cycles of FEC 100 followed by eight cycles of FEC 50, and four cycles of FEC 100, then restarting the same regimen at disease progression in cases where there had been a previous response or stabilisation [15]. The response rate and the time to progression was higher using the FEC 100 regimen, but overall survival was similar for the three groups. Gregory et al. achieved similar results treating MBC patients with vincristine, doxorubicin and cyclophosphamide (VAC), VEC (vincristine, epirubicin and cyclophosphamide) or mitoxantrone, methotrexate and mitomycin C (MMC) [16]. Nooij et al. evaluated the advantages of continuing chemotherapy after the induction phase. For this purpose 204 chemotherapy naive patients were treated with the classical CMF regimen for MBC. After 6 cycles of treatment, patients were randomized to stop (Arm A) or continue (Arm B) treatment until progression. The overall response rate was not increased by continuing chemotherapy. Patients randomized in the Arm A had longer progression free survival as compared to patients in Arm B. Furthermore median time to death and mean quality -adjusted survival were similar in the study arm [17]. What did we learn from the above mentioned data? The decision to select the palliative treatment for MBC patients should be based on the patient s preference and comorbidity, the activity and tolerability of the treatment. Since survival seems to be little influenced by the use of short-term rather than continuous treatment, patients who wish to stop treatment due to drug induced toxicity can be assured that intermittent therapy is not detrimental to survival. In patients with symptomatic disease and responsive to treatment, continuous therapy may be a good choice in order to prolong the time to disease progression. What is the treatment of choice for taxane and anthracycline-resistant patients? The treatment of patients with anthracycline- and taxane-pretreated MBC represents a significant challenge for the oncologist. Recent years have seen a general shift toward the use of more aggressive therapy in the adjuvant setting. The strategy, particularly for patients with node positive and ER/PgR negative disease, may include anthracyclines and taxanes. In patients with a progressive disease after anthracyclines and taxanes, the treatment options are very limited. As no standard therapy exists for these patients, a personalised management for each single patient would allow us to provide the best therapy where the major goal is to control disease without compromising quality of life. Among potential active cytotoxic drugs, capecitabine, vinorelbine, liposomal doxorubicin and gemcitabine are the most commonly-used agents. Capecitabine has been approved by the Food and Drug Administration in the treatment of MBC patients resistant to anthracyclines and/or taxanes. The approval of capecitabine monotherapy in this setting was based on the results of a large, multicentre phase II study [18]. In this trial among patients with measurable disease (135) the authors retrospectively described 42 with unequivocal clinical resistance to both paclitaxel and doxorubicin, as determined by clear-cut clinical progression while receiving the drug. The response rate in this subgroup was 29%. Fumoleau et al. reported similar results in a phase II study specifically designed to evaluate efficacy, safety and impact on the quality of life of capecitabine in patients pretreated with anthracyclines and taxanes [19]. In this trial the authors reported a 28% objective response, a median time to progression of 4.9 months and an improvement in the quality of life as measured by the EORTC QLQ-C30 questionnaire. The oral formulation of capecitabine enables home-based therapy, which should be the treatment of choice for most patients, provided similar efficacy. To the best of our knowledge, there is no phase III study comparing capecitabine with vinorelbine (NVB) or gemcitabine. With regards to NVB in anthracycline-refractory or anthracycline-taxane-refractory patients, at least four phase II studies have been published [20 23]. In a phase III trial, Jones et al. randomised 183 anthracycline refractory patients to receive NVB (30 mg/m2 weekly) or melphalan (ALK) (25 mg/m2 every 4 weeks) i.v. In total, 46.5% NVB patients and 28.2% ALK patients achieved an objective response or stabilization of disease [20]. Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P<001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P <001). The effect of NVB on survival was also statistically significant: 1-year survival rates were 35.7% with NVB, and 21.7% with ALK, and the median survival rate was 35 weeks and 31 weeks respectively. The activity of NVB in anthracycline refractory patients has been confirmed by Degardin et al. [21]. In anthracycline and taxane refractory disease at least two studies have reported an overall response in 20 25% treated patients [22, 23]. The efficacy and toxicity profiles of oral NVB compare favourably with those of NVB IV, and this new formulation seems to be a potentially useful alternative to the IV form [24]. Gemcitabine, a novel nucleoside analogue with demonstrated anti-tumour activity and a favourable safety profile, has been evaluated in a number of recent clinical trials as a single-agent therapy for MBC patients, including studies of first- and second-line therapy, as well as the salvage setting for patients with taxane- and/or anthracycline-refractory advanced disease [25 29]. In a French study 47 patients with MBC who had received one prior chemotherapy regimen with an anthracycline or anthracenedione for metastatic disease, were treated with gemcitabine mg/mq, administered as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day schedule. Objective responses were seen in 12 of the 41

4 iv26 assessable patients (29%). The median response duration was 8.1 months (range: months). Similar results have been reported by Brodowicz in anthracycline resistant disease [26] and by Rha and Valerio [27, 28] in taxane- and anthracycline-resistant MBC. On the contrary disappointing results have been reported by Smoremburg [29]. All the above mentioned studies suggest the efficacy of gemcitabine in anthracycline- and taxane-resistant patients. Previous studies have shown that the incidence of anthracycline-induced cardiac heart failure increased in relation to the total dose of drug administered; the risk of anthracyclineinduced cardiotoxicity increased for patients who were more than 65 years old, had undergone previous adjuvant anthracycline therapy and had one or more cardiac risk factor [30]. Pegylated liposomal doxorubicin (PLD) offers an alternative to doxorubicin for women with MBC because of similar efficacy. In addition PLD had a different safety profile, with significantly reduced alopecia, nausea, vomiting, myelosuppression and cardiac toxicity as compared with doxorubicin. Keller et al. randomised 301 MBC patients, previously treated with a taxane-containing regimen [31]. Patients were assigned to receive PLD (50 mg/m 2 every 28 days), vinorelbine (30 mg/m 2 weekly) or mitomycin C (10 mg/m 2 day 1 and every 28 days) plus vinblastine (5 mg/m 2 day 1, day 14, day 28, and day 42) every 6 to 8 weeks. The authors reported similar efficacy for the three arms. These results suggest that liposomal doxorubicin is an important new therapeutic option in MBC patients who are at increased cardiac risk (the elderly, patients with specific cardiac risk factors and patients who have been previously treated with anthracyclines). When we consider all the above mentioned data, in the absence of convincing and evident differences on informal comparison between single-agents, treatment selection may be guided by a consideration of the overall therapeutic index for the patients. Are we ready to move on from the clinical-based choice to molecular tailored chemotherapy? Despite the advances in the last decades, classical medical treatment for solid tumours produces only modest results. This low efficacy has also been attributed in part to the lack of specificity of available agents which are unable to take advantage of genotypic and phenotypic differences in patients tumours. Evidence suggests that patients with histologically and biologically identical breast cancer may benefit in different ways from identical chemotherapy [32]. In general, burdens and benefits cannot be reliably predicted for an individual patient. Treatment tailoring has become, therefore, the major challenge for the oncologists today. The selection of patients and treatment tailoring are essential to avoid both excessive treatment and toxicity, especially in MBC patients. Identifying new targets for biological agents may translate in a new clinical strategy and in new concepts in the clinical study design. Unfortunately no predictive markers are currently recommended for routine clinical use in order to predict response to chemotherapy, in view of the fact that most data derive from retrospective studies, and as a consequence there has not been validation in prospective trials. In addition quality control measures have not been undertaken to ensure that the value of the marker can be reproduced from one laboratory to the other. In addition, none of these markers have been shown to have a high predictive value, which means that if the marker is present the chance of response is very high. If the marker is absent, the chance of response is almost nil. It is important to note that in the new era of target and biological therapies we lack the specific targets for this new class of drugs. It is of common knowledge that if an assay had not existed to identify the patient population likely to respond to therapy, trastuzumab might have been discarded during development because of insufficient activity in an unselected patient population [33]. To date only one biological agent has been approved of for the treatment of MBC patients: trastuzumab a monoclonal antibody directed to the extracellular domain of HER-2 receptor. Despite its activity as a monotherapy or in combination with chemotherapy, several issues remain dubious regarding the optimal use of trastuzumab: the optimal schedule (weekly or every three weeks), the duration of treatment (maintenance therapy beyond disease progression when combined with a different cytotoxic agent), the dose, the mechanisms of resistance, and finally strategies to prevent or reverse resistance to trastuzumab. It is now clear that the expression of target is necessary but not sufficient to elicit a therapeutic response. This may result from multiple causes. First of all the signalling pathway relevant to the target molecule may be interrupted downstream. In such case the target assay is not able to disclose this molecular mechanism. Second the pathway signalling is not critical while other signalling events might be crucial. This issue may be relevant for advanced cancer where several molecular events might have developed and multiple drivers might be operative at any one time. In the future multiple potential molecular abnormalities should be screened to determine which abnormalities are present and which are most likely to drive the malignant process. New technologies such as cdna micro-arrays, genomic and proteomics should help clinicians to better characterize the biology of breast cancer, to tailor treatment based on distinct molecular profiles with prognostic and predictive value. To date, except for clinical studies, tailoring strategies should be based on the patient s comorbidity, the activity and tolerability of the treatment, and most of all on the patient s wishes. Acknowledgement We are indebted to Kristina for editing our manuscript. References 1. Hortobágyi GN, Piccart-Gebhart MJ. Current management of advanced breast cancer. 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