Cancer Treatment Reviews 40 (2014) 942–950
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Anti-Tumour Treatment
Metronomic therapy and breast cancer: A systematic review Emilia Montagna ⇑, Giuseppe Cancello, Silvia Dellapasqua, Elisabetta Munzone, Marco Colleoni Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
a r t i c l e
i n f o
Article history: Received 8 April 2014 Received in revised form 4 June 2014 Accepted 6 June 2014
Keywords: Metronomic Chemotherapy Breast cancer
a b s t r a c t Metronomic therapy (MT) refers to repetitive, low doses of chemotherapy drugs. MT exerts an effect not only on tumour cells, but also on their microenvironment. In particular, the low-dose schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect. In addition to the anti-angiogenic effect, MT could have an immunological action through the restoration of the anticancer effect of the immune system and induction of tumour dormancy. Consequently the association of targeted therapy with anti-angiogenic properties or specific immunologic drugs could enhance the efficacy of MT. During the past 15 years, several studies have been published evaluating the metronomic strategy in breast cancer. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The analyses included the efficacy and toxicity data of MT, and the future development of this strategy in breast cancer are also discussed. The systematic review presented here suggests that MT is a treatment option for breast cancer patients, has a low toxicity profile, efficacy in most patients and has potentially significant cost-effective advantages for public health. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Metastatic breast cancer (MBC) is generally an incurable disease. The median survival rate of the patient with metastasis is within the range of 3 years [1]. However, some patients with metastatic involvement live several years after diagnosis [2]. In such a scenario, one would wish to consider a therapeutic strategy with a low toxicity profile, good tumor control and economically viable for the healthcare system. Moreover, a therapeutic program of metastatic disease must be driven by multiple considerations, including not only the heterogeneity of breast cancer subtypes but also the heterogeneity of breast cancer patients, taking into account patient age, preferences, frailty, co-morbidities and possible contraindications to more intensive regimens. Although there is as yet no universally accepted definition, the metronomic schedule refers to repetitive, low doses of chemotherapy drugs administered at close regular intervals with no extended interruption. The term ‘‘metronomic’’ was used for the first time by Hanahan et al. commenting on two papers on the use of continuous, low dose chemotherapy in cancer treatment [3–5]. Metronomic therapy (MT) has an effect not only on tumor cells, but also on their microenvironment. In particular, the low-dose ⇑ Corresponding author. Tel.: +39 02 57489439; fax: +39 02 574829212. E-mail address: [email protected] (E. Montagna). http://dx.doi.org/10.1016/j.ctrv.2014.06.002 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.
schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect [4]. In addition to the antiangiogenic effect, MT could exert an immunological action through the restoration of the anticancer effect of the immune system and induction of tumor dormancy [6]. Over the years, different drugs have been tested with a metronomic schedule in different types of tumors [7–8]. Moreover, a hybrid approach including higherdoses of chemotherapy with planned treatment breaks combined with metronomic drugs has also been evaluated. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The Medline database was searched for fully published articles using the key words ‘metronomic’ and ‘chemotherapy’ and ‘cancer’ or ‘breast’. The search was restricted to the English language. Exclusion criteria included the following: pediatric trials, studies applying MT in all tumor sites, not only the breast, editorials, case reports and review articles. For studies with multiple presentations and/or publications, only the latest versions were included in the analysis. Metronomic therapy in breast cancer patients The first study on MT in metastatic breast cancer was published in 2002 [9]. From 2002 the number of published papers has increased, especially in the most recent years, as reported in Fig. 1. Patients
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
18 16 14 12 10 8 6 4 2 0
2002-2005 2006-2009 2010-2011 2012-2014
Fig. 1. Number of published papers over the years.
included in early trials who were candidates for MT were frail or heavily pretreated while the most recent trials also included patients at the first or second line of therapy. The results from a national survey conducted in Italy indicated a significant interest in MT, with 72% of responders having been administered a regimen of MT at least once [10]. This interest is confirmed by the higher number of publications on MT reporting Italian studies, as shown in Fig. 2. The largest number of published studies are phase II trials with a relatively low of number of patients as reported in Table 1. In the development of the MT strategy, several drugs were tested, in particular those with an oral formulation. Nevertheless, the identification of the optimal dosage has yet to be established [11]. The classical metronomic drug, widely clinically tested, is cyclophosphamide. Initial studies reported the efficacy data of single or combined metronomic chemotherapy drugs. Subsequent studies evaluated how to enhance the metronomic activity by an association with hormonal therapy, biological drugs or other agents. Single or combined metronomic chemotherapy in breast cancer patients The first trial on MT for MBC patients was conducted by Colleoni et al. The authors analyzed, in 63 pretreated MBC patients, a combination of metronomic chemotherapy with low-dose oral cyclophosphamide, 50 mg daily, and methotrexate, 2.5 mg twice daily, 2 days per week. This regimen was active and well tolerated, yielding an objective response rate (ORR) of about 20% and a clinical benefit (CB) (objective response and stable disease for at least 24 weeks) of 31.7%, in the absence of serious toxicity [9]. A few years later, the same authors reported results and longterm follow-up for patients with MBC who obtained prolonged CB (for 12 months or more) with metronomic cyclophosphamide and methotrexate (CM). Of one-hundred and fifty-three patients, 15.7% achieved prolonged CB with a time to progression (TTP) of 21 months [12]. Clinical activity and the absence of severe grades of toxicity of metronomic cyclophosphamide combined or not combined with methotrexate were also confirmed by the study of Miscoria et al.
Italy Europe USA-Canada China-Japan Fig. 2. Number of published papers according to country/region.
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and by a retrospective analysis conducted on 61 MBC patients [13–14]. Continuous infusion of 5-fluorouracil (5-FU) has been developed in an attempt to improve efficacy and has been shown to exert antiangiogenic activity in preclinical models. The combination of low dose oral 5-FU with eniluracil is a simpler and convenient alternative to continuous infusion of 5-FU. In the study of Smith et al., 33 untreated MBC patients received oral 5-FU 1.0 mg/m2 with eniluracil 10 mg/m2, both administered twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity. Sixteen partial responses were seen in 29 assessable patients. Seven patients had stable disease for at least 3 months with symptom improvement. Toxicity was mild [15]. Moreover, the oral daily administration of capecitabine mimics the activity of a continuous intravenous infusion of fluorouracil and the pharmacokinetics and toxicity profile render capecitabine particularly suitable for metronomic administration. In two small randomized trials, continuous use of low dose capecitabine (650 or 800 mg/m2 b.i.d. with no drug-free breaks) proved to be just as effective in MBC patients as did the intermittent use of higher doses (1000 or 1250 mg/m2 b.i.d. days 1–14 every 21 days) [16–17]. Taguchi et al. used a low dose schedule of capecitabine (852 mg/m2 twice daily on days 1–21 of a 28-day cycle) as firstline therapy for 33 MBC patients. The authors reported a median progression-free survival (PFS) of 6.9 months with an overall survival (OS) of 24.8 months, and grade 3 toxicities which included hand and foot syndrome (15%) and neutropenia (6%) [18]. The metronomic schedule of capecitabine was also evaluated in heavily pretreated patients with MBC. Sixty patients received oral capecitabine in a single daily dose of 1500 mg. The CB was 62% and the OS was 17 months. Grade 3–4 adverse events were uncommon [19]. Other studies evaluated the efficacy and safety of an all-oral doublet combination of MT including cyclophosphamide and capecitabine. In the study of Wang et al., 68 anthracycline- and taxane-pretreated MBC patients received 21-day cycles of oral cyclophosphamide (65 mg/m2 daily) and oral capecitabine (1000 mg/m2 twice daily on days 1–14 followed by a 7-day rest period). The median time to progression was 5.2 months and the OS was 16.9 months. The ORR and CB were 30.3% and 53.0% respectively. Treatment was well tolerated, and grade 3 hand–foot syndrome was reported by the 4.4% of patients [20]. The same combination of MT with different dosages was evaluated in the study of Yoshimoto et al. Fifty-one patients received capecitabine 828 mg/m2 twice daily with cyclophosphamide 33 mg/m2 twice daily, days 1–14 every 3 weeks. ORR was 44.4% and the CB was 57.8%. Hematologic toxicity included grade 3 leucopenia (26%) and neutropenia (16%). No grade 3 hand-foot syndrome was reported [21]. Given the availability of an oral formulation and due to its pharmacokinetic profile, vinorelbine can be used with a metronomic schedule. In the Phase I trial conducted by Briasoulis et al. in advanced cancer, the vinorelbine dose of 50 mg given three times a week was identified as the optimal dose for a metronomic schedule, yielding sustainable antitumor activity without overt toxicity [22]. In 34 elderly patients not pretreated for MBC, vinorelbine was administered at 70 mg/m2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week off, every 4 weeks. The ORR was 38%. Median PFS and median OS were 7.7 and 15.9 months respectively. The treatment was well tolerated [23]. According to the synergistic activity of the vinorelbine and capecitabine combination, Saridaki et al. conducted a phase I study to identify the metronomic dosage of this doublet, using eight
Author and year
N patients
Colleoni 2002
63
Colleoni 2005
171
Orlando 2006
153
Orlando 2006
22
Bottini 2006
114 46
Garcia-Saenz 2008
24
Watanabe 2009
733
Treatment
Phase
Previous treatment and setting
ORR (%)
CB (%)
OS (months)
Reference number
Cyclophosphamide Methotrexate Cyclophosphamide Methotrexate ± thalidomide Cyclophosphamide Methotrexate Cyclophosphamide Methotrexate Trastuzumab Letrozole ± cyclophosphamide
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC
19
31.7%
/
9
20.9 vs. 11.8 /
41.5 vs 41.5
/
56
15.7% with CB>12 months 46
/
12
/
39
Cyclophosphamide Capecitabine Bevacizumab Cyclophosphamide Capecitabine Bevacizumab Oral fluorouracil and tegafur vs.CMF*
Randomized II Retrospective II
Randomized II II
Not pretreated Locally advanced Pretreated MBC
71.9 vs. 87.7 48
/
/
33
68
/
43
II
Pretreated MBC
31.8
63.6
13.9
42
Randomized III II
Early BC
/
/
/
63
Not pretreated MBC Not pretreated MBC Not pretreated MBC Pretreated MBC Pretreated MBC Pretreated-not Pretreated MBC Not pretreated Locally advanced Pretreated MBC
55
/
/
15
18
44
24.8
18
15.9
23
Smith 2010
33
Tagushi 2010
33
Oral fluorouracil Eniluracil Capecitabine
Addeo 2010
34
Vinorelbine
II
Munzone 2010
52
Liposomal doxorubicin
Retrospective
Licchetta 2010
29
II
Wong 2010
41
Cyclophosphamide Megestrol acetate dalCMP**
Dellapasqua 2011
29
Soriano 2011
21
Gebbia 2011
61
Saloustros 2011
13
Wang 2012
68
Addeo 2012
36
Fedele 2012
60
Montagna 2012
24
Saridaki 2012
36
Yoshimoto 2012
51
18
II
I/II
Liposomal doxorubicin and cyclophosphamide Cyclophosphamide Methotrexate 1E10-Alum Cyclophosphamide (22) Cyclophosphamide Methotrexate (39) Vinorelbine Bevacizumab Capecitabine Cyclophosphamide Vinorelbine Temozolomide Capecitabine
II
Cyclophosphamide Capecitabine Bevacizumab Erlotinib Vinorelbine Capecitabine Capecitabine
II
II
38 57
45
/
27
31
/
13.4
36
17
24
12
53
62
/
/
29
23.8
/
12.9
58
Retrospective
Pretreated MBC
18
/
/
14
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC Not pretreated
7.7
/
/
44
30.3
53
16.9
20
52
/
11
26
24
62
17
19
62
75
/
50
(46)
/
/
24
44
57.8
/
21
II II II
MBC I II
Pretreated MBC Pretreated
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
Dellapasqua 2008
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Table 1 Published trials of metronomic therapy in breast cancer.
Young 2012
47
Dellapasqua 2012
69
Mayer 2012
23
Aurilio 2012
33 (22 evaluable for response) 62
Otsuka 2013
40
Manso 2013
84
Perroud 2013
15
Schwartzberg 2013 Crivellari 2013
41
Cazzaniga 2014
77 12 + 22
II
MBC Pretreated MBC
34
42
/
61
Retrospective
Pretreated and not MBC
/
/
/
70
I
Pretreated MBC
(10)
(25)
/
45
Retrospective
Pretreated MBC
/
56
43.6
35
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC
/
/
7.1
13
26
30
II ***
Cyclophosphamide Methotrexate Celecoxib Capecitabine Fulvestrant Cyclophosphamide Methotrexate vs. liposomal doxorubicin Capecitabine Vinorelbine
Retrospective II
II III I–II
Pretreated MBC Early BC Pretreated MBC
Abbreviations: ORR, overall response rate; CB, clinical benefit (defined as ORR + SD > 24 weeks); SD, stable disease; OS, overall survival. BC, breast cancer; MBC, metastatic breast cancer. * CMF cyclophosphamide, methotrexate, fluorouracil. ** Dalteparin, cyclophosphamide, methotrexate, prednisone. *** Non-pegylated liposomal doxorubicin +5 fluorouracil + vincristine + oral cyclophosphamide + prednisone.
47 45
/
21
28
6.7
46.7
/
62
24.4
58.1
28.6
34
/
/
/
64
58
25
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
Miscoria 2012
Cyclophosphamide Docetaxel Capecitabine Celecoxib Capecitabine Cyclophosphamide Bevacizumab Erlotinib Cyclophosphamide Methotrexate Vandetanib Cyclophosphamide Methotrexate Fulvestrant Cyclophosphamide Methotrexate Irinotecan Tegafur Metronomic Cooper type
945
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E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
escalating dose levels. The dose-limiting toxicity (DLT) level was reached at 70 mg for oral metronomic vinorelbine and at 1250 mg/m2 for capecitabine. The metronomic combination was well tolerated and feasible [24]. More recently in another phase I–II study, the maximum tolerated dose identified of vinorelbine in association with a fixed dose of capecitabine (500 mg thrice a day) was 40 mg thrice a week. With this schedule, in 31 patients evaluable for efficacy, the CB was 58.1% [25]. The activity of combination of metronomic vinorelbine and temozolomide was evaluated in a population of 36 MBC patients with brain involvement. Temozolomide was administered orally at a dose of 75 mg/m2 during whole-brain radiotherapy, followed by 4 weeks off-therapy and a subsequent administration of oral vinorelbine 70 mg/m2 fractionated in days 1, 3, and 5, weekly for three consecutive weeks plus temozolomide at 75 mg/m2 on days 1–21. The authors reported an ORR of 52 % and an OS of 11 months. The schedule was well tolerated with an improvement in quality of life in [26]. Caelyx is a pegylated liposomal doxorubicin (PLD), used as single agent in MBC at standard doses ranging from 40 to 50 mg/m2 every 3–4 weeks. The pharmacokinetic characteristics (reduced volume of distribution, long intravascular circulating half-life) supported the rationale for using PLD in a metronomic schedule. Munzone et al. in a case-series report carried out in pre-treated MBC patients, tested the efficacy and tolerability of PLD administered with a metronomic schedule of 20 mg/m2 i.v. every two weeks. Forty-four patients were assessed for either response or toxicity. The CB was 45%. Neither grade 3 nor grade 4 hematological or clinical side effects were recorded, except for 2 patients with grade 3 palmar-plantar erythrodysesthesia (PPE). No cardiac toxicity was recorded [27]. The retrospective study of Manso et al. also confirmed that a chemotherapy combination including metronomic non PLD was effective and safe in pretreated MBC patients [28]. Dellapasqua et al. reported the data on eight courses of PLD (20 mg/m2 in every two weeks) in association with low-dose metronomic cyclophosphamide (50 mg/day) as a primary treatment in 29 locally advanced breast cancer patients. The rate of breastconserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) experienced a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities [29]. In a phase II study from a Japanese group, 40 MBC patients were treated with metronomic irinotecan (60 mg/m2) on days 1, 8, and 15 every 4 weeks plus tegafur (at a dose of 80 mg/m2/day orally on days 3–7, 10–14 and 17–21 every 4 weeks). The ORR was 47 % whereas median PFS and OS were 14 and 26 months respectively. The most common grade 3–4 toxicities included neutropenia (15 %), leucopenia (12.5 %) and diarrhea (7.5 %) [30].
Metronomic chemotherapy and hormonal therapy in breast cancer patients The first studies reported no additional benefit from the combination of tamoxifen and chemotherapy [31]. However with the introduction of new hormonal drugs (aromatase inhibitors) and a better understanding of hormonal resistance, the combined hormonal and chemotherapy approach stimulated new interest [32]. The low toxicity profile of MT makes this modality feasible in combination strategies, particularly in elderly patients. In a phase II trial, 114 elderly patients with clinical T2-4 N0-1 endocrine responsive breast cancer were randomized to receive a
preoperative treatment with either letrozole or letrozole plus metronomic cyclophosphamide for six months. The ORR was 71.9% in the letrozole arm and 87.7% in the letrozole plus cyclophosphamide arm, with a significantly greater suppression of Ki67 and vascular endothelial growth factor A (VEGF-A) expression by the combination therapy [33]. In a phase II study, Schwartzberg et al. explored the activity of fulvestrant and low-dose metronomic capecitabine in 41 patients with hormone receptor-positive, HER2-negative MBC patients. The median duration of therapy was 11 months , with a median PFS of 14.98 months, and a median TTP of 26.94 months. Treatment was well tolerated [34]. The activity of fulvestrant combined with CM was also evaluated in a retrospective analysis by Aurilio et al. showing a prolonged CB in a high proportion of patients with MBC [35]. In a phase II study, the safety and antitumor activity of a combination of cyclophosphamide and megestrol acetate were evaluated. Twenty-nine pretreated post-menopausal MBC patients received treatment with cyclophosphamide (50 mg/daily, day 1–21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall ORR was 31.0% and the mean OS was 13.4 months [36].
Metronomic chemotherapy and targeted therapy in breast cancer patients It has previously been shown that the metronomic CM combination leads to a marked decrease in circulating VEGF [9]. Moreover, experimental studies suggest that neutralizing antibodies against HER2 or epidermal growth factor receptor (EGFR) result in down-regulation of angiogenesis, through VEGF gene suppression [37]. Trastuzumab, a humanized anti-HER-2 monoclonal antibody, can modulate the effects of different pro and anti-angiogenic factors [38]. Given these considerations, Orlando et al. reported the data of the combination of trastuzumab plus metronomic CM in 22 metastatic breast cancer patients with overexpressed or amplified HER2, who were pre-treated with trastuzumab. The authors reported a CB of 46%; the median TTP was 6 months and the toxicity was generally mild [39]. Moreover in preclinical models, the combination of metronomic chemotherapy with a VEGFR2 antibody resulted in sustained regressions of large tumors [40]. Bevacizumab is a recombinant humanized monoclonal antibody against human VEGF and may enhance the antiangiogenic activity of MT. In a randomized phase II trial comparing metronomic CM with the same regimen plus bevacizumab in pretreated MBC patients, a planned interim analysis revealed a significant advantage in favor of the combination arm in terms of objective responses (41%)[41]. A similar trial explored the activity of CM and bevacizumab 10 mg/kg i.v. every 14 days in an anthracycline and taxane refractory MBC population. Trastuzumab was added in HER2-overexpressing tumors. Among the 22 patients evaluable for response, the CB was 63.6% and the OS was 13.6 months [42]. In another phase II trial, bevacizumab was added to a metronomic regimen with cyclophosphamide and capecitabine. The authors reported in 46 assessable patients an ORR of 48% and an overall CB of 68%. The toxicity was generally mild [43]. On the other hand, in a very small study the combination of oral metronomic vinorelbine and bevacizumab showed good tolerance but minimal activity in terms of ORR in pretreated patients with MBC [44].
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
In a phase I study the safety and tolerability of a new antiangiogenic therapy and MT were evaluated. The authors used vandetanib, an oral drug that inhibits the tyrosine kinase activity of VEGFR2, EGFR and rearranged during transfection (RET) receptor, in three dose-escalation doses in association with metronomic CM in MBC patients. Of the 20 patients evaluable for response, 10% demonstrated partial response and 15 % a stable disease.[45] Preclinical evidence also suggests that the pathways mediated by EGFR may be involved in angiogenesis control [46,47]. EGFR is also a target for several developed drugs, including therapeutic antibodies (cetuximab) and small-molecule tyrosine kinase inhibitors such as erlotinib. The combination of erlotinib with bevacizumab has shown promising activity in lung cancer and limited activity in unselected patients with previously treated MBC [48,49]. In a phase II trial, the safety and efficacy of metronomic chemotherapy with cyclophosphamide and capecitabine in combination with erlotinib and bevacizumab were explored in patients with advanced triple-negative or estrogen (ER)- and progesterone (PR) receptor-poor HER2-negative breast cancer. In 24 patients assessable for response, the authors reported an ORR of 62% and a CB of 75%. Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2) [50]. In a phase I–II study by Wong et al., the combination of MT and other agents with anti-angiogenic properties, such as corticosteroids [51] and low-molecular-weight heparins [52] was evaluated. The study treatment was daily dalteparin, cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP) for 41 MBC patients. The CB, the primary end point of the study, was 24%. The median TTP was 10 weeks and median OS was 48 weeks. The toxicities included transient grade 3 elevation of liver transaminases in 27% of patients and vomiting in 2% of patients [53].
Metronomic chemotherapy and immunologic agents in breast cancer patients The mechanism of action of MT may also have an immunologic component and consequently the association of specific immunologic drugs could enhance its efficacy. Thalidomide, a derivative of glutamic acid, inhibits angiogenesis [54] and also has an immune-modulating activity secondary to inhibition of lymphocyte proliferation [55]. Colleoni et al. investigated the association of thalidomide with a metronomic chemotherapy (CM regimen). Patients with MBC were randomized to receive CM (arm A) or the same regimen plus thalidomide (200 mg daily) (arm B). In 171 evaluable patients the ORR was 20.9% in arm A and 11.8% in arm B. The CB was 41.5% in both arms. Higher neurological toxicity and constipation were observed in arm B [56]. Moreover, during MT therapy, several immunological effects have been reported. Generali et al. showed that the combination of hormonal therapy with metronomic cyclophosphamide induced a significant reduction in the number of a specific subpopulation of CD4+ CD25+ regulatory T cells (Treg) in elderly breast cancer patients [57]. Given these results, the combination of MT and vaccines might increase the efficacy of the treatment. Soriano et al., in an exploratory study in MBC patients, evaluated the safety and efficacy of metronomic chemotherapy with CM in combination with 1E10Alum vaccine (racotumomab). Twenty-one patients were enrolled. Five patients achieved an objective response, eight showed stable disease and eight had disease progression. Overall toxicity was generally mild [58].
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Metronomic chemotherapy and anti COX2 drugs in breast cancer patients Another strategy to increase the efficacy of MT is to evaluate the combination of anti- cyclooxygenase 2 drugs. Cyclooxygenase 2 is a prostaglandin synthase enzyme implicated in the malignancy process [59]. Celecoxib, a selective inhibitor of cyclooxygenase 2 has shown an anti-angiogenic effect in breast cancer cell lines [60]. Young et al. used a combination of docetaxel and capecitabine plus concurrent treatment with celecoxib (200 mg twice daily) in MBC patients with prior anthracycline exposure. Of the 47 patients enrolled, none achieved a complete response and 34% of patients experienced a partial response. The most common non-hematologic toxicities were diarrhea, palmar-plantar erythrodysesthesia, fatigue, and mucositis [61]. Perroud et al. added celecoxib to metronomic chemotherapy with cyclophosphamide in advanced breast cancer patients. In 15 patients the CB was 46.7% and the one-year OS rate was 46.7%. No grade 3 or 4 toxicity was reported. [62] Adjuvant metronomic chemotherapy in breast cancer patients There is a rationale for the development of metronomic strategies in the adjuvant treatment of early breast cancer. The lack of targeted therapies in triple-negative disease renders this subtype of breast cancer suitable for studies with MT. Moreover, the toxicity profile of MT permits consideration of an adjuvant chemotherapy in frail patients. MT could also be used in combination with other targeted agents (such as endocrine and anti-HER2). Given these considerations, in recent years, the role of MT has been evaluated in the adjuvant setting. Metronomic chemotherapy using tegafur/uracil (UFT), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in the preclinical model. Watanabe T et al. in a phase III trial showed that oral UFT was as effective as classical CMF as adjuvant treatment, in women with nodenegative, high-risk breast cancer. The quality of life scores were better for patients who were given UFT than for those who were given CMF. The outcome with oral UFT was similar to that with classical CMF [63]. In a phase III trial, the adjuvant metronomic CM regimen was compared to adjuvant pegylated liposomal doxorubicin in older breast cancer patients with endocrine non-responsive disease who were not candidates for standard chemotherapy. Definitive results are not available from this trial because of its early closure due to slow and inadequate accrual. After two years, only 77 patients were enrolled (38 in the PLD and 36 in the metronomic arm). The metronomic regimen was associated with better quality of life and cognitive function as compared to the PLD regimen [64]. The maintenance trial (IBCSG 22–00) investigated a tailored chemotherapy approach aimed at reducing the risk of relapse and improving survival of patients with endocrine non-responsive tumors. In this trial, one year of CM was compared with no further therapy after the standard adjuvant chemotherapy program. The trial was recently terminated with the enrolment of 1086 patients, and its results are eagerly awaited. Discussion To the best of our knowledge, this is the first systematic review of MT in breast cancer. However, even though interest in the metronomic strategy has increased in recent years, the data now available are unlikely to provide definitive answers to several questions on MT. The reported data are extracted from relatively small phase II trials with a minimum of 13 and a maximum of 171 patients
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enrolled. In addition, the study patients were often very heterogeneous at both an individual trial level, as well as in terms of the number and type of prior therapies. Moreover, the primary endpoint, the type and dosage of metronomic drugs differ among the studies. A hybrid approach including higher doses of chemotherapy with planned treatment breaks combined with metronomic drugs has also been evaluated, but the results are not comparable with those achieved with a ‘‘pure’’ metronomic strategy. Another aspect is the need to identify predictive and dynamic biomarkers of benefit from MT. Bertolini et al. reported that metronomic cyclophosphamide acts by reducing the circulating endothelial progenitor cells (CEP) while the same drug, at the maximum tolerated dose (MTD) of drugs, causes an opposite effect with a marked drop followed by a rapid rebound of CEP [65]. Similarly, Shaked et al. found that the maximum angiogenic activity of MT is strikingly correlated with the maximum reduction of circulating VEGFR-2+ and CEP in viable peripheral blood [66]. Different studies also reported a predictive potential role of baseline values of CEP in patients with advanced breast cancer treated with metronomic chemotherapy and bevacizumab [43]. Circulating endothelial cells (CEC) and CEC kinetics correlate well with more invasive biomarkers of angiogenesis [67]. CEC were found to be dynamic markers of clinical response in breast cancer patients receiving a CM regimen [68]. However no standardization of CEC and CEP dosage is available and the role of CEC and CEP needs to be confirmed in larger clinical trials. Moreover, Bocci et al. characterized the role in MT of thrombospondin-1 (TSP-1), a potent and endothelial-specific inhibitor of angiogenesis. The authors reported that protracted exposure of endothelial cells in vitro to metronomic chemotherapy caused marked induction of gene and protein expression of TSP-1 [69]. However the clinical evidence did not confirm the role of TSP-1 as a secondary mediator of the antiangiogenic effects of MT. Recently, Dellapasqua et al. showed that in advanced breast cancer patients an increase in the mean corpuscular volume of red blood cells may predict response to metronomic capecitabine
and cyclophosphamide in combination with bevacizumab. This finding awaits future confirmation [70]. As shown in Table 2, there are still several ongoing trials of MT in breast cancer. The aims are to identify the optimal regimen and schedule of MT in different patient settings, particularly the metastatic setting. Generally the toxicity profile of MT is lower compared to the classical approach considering the MTD. Results were recently presented of a multicenter, randomized phase III trial of bevacizumab therapy with either a weekly paclitaxel (arm A) or daily oral metronomic capecitabine and cyclophosphamide as first-line treatment in 147 patients with HER2-negative MBC. The incidence rates of grade 3–5 adverse events were 25% for arm A and 24% for arm B. ORR were 58% and 50% in arms A and B, respectively (p = 0.45). Less hair loss in arm B was the only clinically and statistically significant difference in quality of life [71]. Oral administration is generally appreciated by patients and reduces the cost of hospitalization. This aspect is critical, particularly in breast cancer where the number of long-term survivors is growing dramatically. New targeted treatments often incur very high public health costs. Therefore, therapies such as metronomic CM and similar regimens position themselves as potentially significant cost-effective palliative treatments for metastatic breast cancer when compared with other novel therapeutic strategies [72].
Future approaches and conclusion The systematic review presented here suggests that MT is a treatment option for breast cancer patients. In fact, the low burden of personal costs for the patient and the possibility to continue the treatment for several months, supports the use of metronomic chemotherapy as an additional therapeutic tool for metastatic and pre-treated patients with breast cancer, particularly with indolent disease. Moreover most ongoing clinical trials with MT are aimed at patients with triple-negative disease, since in this setting chemotherapy still represents one of the most reliable options.
Table 2 Ongoing trials with metronomic chemotherapy in breast cancer. Schedule
Phase
Setting
Ref.
Capecitabine 1000 m/m2 d1 – 14 + VNB 60 mg/m2 d1 – 8 q21d vs. VNB 50 mg/d d1,3,5/wk
II Randomized III II
M+, 2 cm any N TN or inflammatory M+, TN M+
NCT01112826 NCT01329627
M+, HER-2 neg M+, ER+, postmenopausal
Standard ADJ CT + capecitabine 650 mg/m2 bid PTX 100 mg/m2/wk x 8 ? DOX 24 mg/m2/wk + CTX 100 mg/d os 9 wks CDDP 25 mg/m2 d1 – 3 q3w + CTX 150 mg/d os d1 – 14 TXT 75 mg/m2 + CTX 50 mg/d 21 d, q3w Capecitabine 1500 mg/d + CTX 50 mg/d Capecitabine 1500 mg/d + AI Pertuzumab + Trastuzumab + CTX 50 mg/d ? T-DM1 (if PD) DOX 24 mg/m2 + CTX 60 mg/m2 os/wk 12 ? PTX 80 mg/m2 + CBDCA AUC 2/wk 12 Capecitabine 1000 mg/d + digoxin TXT 75 mg/m2 + capecitbine 1000 mg/m2 bid d1–14 6 cycles ? capecitabine 500 mg/m2 tid d1–21 vs. 1000 mg/m2 bid d1 – 14 Aflibercept 6 mg/kg iv q3w + Capecitabine 1100 – 1600 mg/m2/d vs. 1700 – 2500 mg/m2/ d 2 wks q3w Bevacizumab 10 mg/kg q2wks + PTX 90 mg/m2 d1,8,15 vs. Bevacizumab 10 mg/kg q2wks + CTX 50 mg/d + capecitabine 1500 mg/d CM + ASA 325 mg/d (cyc 3 – 4) 4 cycles Capecitabine 700 mg/m2 bid, d1 – 14 + etoposide 30 mg/m2/d, d1 – 7 q3w AI + CM + PDN vs. CM + PDN CTX 50 mg/d po + veliparib/placebo
II II Randomized II II II Randomized II II III
NCT01910870 NCT01526499
M+, HER-2 pos, >60 yrs
NCT01526512 NCT01924078 NCT01597414
NeoADJ, TN M+ M+
NCT00542191 NCT01887288 NCT01917279
I
M+
NCT01843725
III
M+, locally advanced
NCT01131195
II II II I/II Randomized
Post-neoADJ (no pCR) M+ M+, ER+, postmenopausal M+
NCT01612247 NCT01589159 NCT00687648 NCT01351909
Abbreviations: VNB: vinorelbine; M: metastatic; ADJ: adjuvant; PTX: paclitaxel; CTX: cyclophosphamide; DOX: doxorubicin; TN: triple negative; CDDP: cisplatin; CBDCA: carboplatin; ER: estrogen receptor; pCR: pathologic complete response; TXT: taxotere; ASA: acetylsalicilic acid; PDN: prednisone.
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
Another attractive development for metronomic chemotherapy could be the combination with hormonal therapy or antiangiogenic drugs. The potential development of metronomic chemotherapy in breast cancer cannot disregard the potential of further research to identify biomarkers and individual tumor characteristics which can better address the use of this treatment strategy in the future. Funding None. Conflict of interest The authors declare no conflict of interest related to this study. All authors declare no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. Acknowledgement We thank William Russell-Edu for his assistance with the manuscript. References [1] Perez EA. Impact, mechanism, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Res Treat 2009;114:195–201. [2] Cardoso F, Costa A, Norton L. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast 2012;21:242–52. [3] Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105(8):1045–7. [4] Browder T, Butterfield CE, Kräling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60(7):1878–86. [5] Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105(8):R15–24. [6] Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 2010;7(8):455–65. [7] Romiti A, Cox MC, Sarcina I, et al. Metronomic chemotherapy for cancer treatment: a decade of clinical studies. Cancer Chemother Pharmacol 2013;72(1):13–33. [8] Lien K, Georgsdottir S, Sivanathan L, et al. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer 2013;49(16):3387–95. [9] Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;13:73–80. [10] Collovà E, Sebastiani F, De Matteis E, et al. Use of metronomic chemotherapy in oncology: results from a national Italian survey. Tumori 2011;97(4):454–8. [11] Lam T, Hetherington JW, Greenman J, Maraveyas A. From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials. Anticancer Drugs 2006;17:113–21. [12] Orlando L, Cardillo A, Rocca A, et al. Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 2006;17:961–7. [13] Miscoria M, Tonetto F, Deroma L, et al. Exploratory predictive and prognostic factors in advanced breast cancer treated with metronomic chemotherapy. Anticancer Drugs 2012;23:326–34. [14] Gebbia V, Boussen H. Valerio MR Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. Anticancer Res 2012;32(2):529–36. [15] Smith IE, Johnston SR. O’Brien ME Low-dose oral fluorouracil with eniluracil as first-line chemotherapy against advanced breast cancer: a phase II study. J Clin Oncol 2000;18(12):2378–84. [16] M. Stockler, T. Sourjina, P. Grimison, et al. A randomized trial of capecitabine (C) given intermittently (IC) rather than continuously (CC) compared to classical CMF as first line chemotherapy for advanced breast cancer. ASCO Annual Meeting Proceedings Part I. J. Clin. Oncol. 2007; 25(18S):1031. [17] M. Martin, L. Calvo, N. Martinez, et al. Randomized, phase II trial comparing continuous versus intermittent capecitabine monotherapy for metastatic breast cancer (MBC). ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2009; 27(15S):1086.
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Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
Metronomic therapy and breast cancer: A systematic review Emilia Montagna ⇑, Giuseppe Cancello, Silvia Dellapasqua, Elisabetta Munzone, Marco Colleoni Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
a r t i c l e
i n f o
Article history: Received 8 April 2014 Received in revised form 4 June 2014 Accepted 6 June 2014
Keywords: Metronomic Chemotherapy Breast cancer
a b s t r a c t Metronomic therapy (MT) refers to repetitive, low doses of chemotherapy drugs. MT exerts an effect not only on tumour cells, but also on their microenvironment. In particular, the low-dose schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect. In addition to the anti-angiogenic effect, MT could have an immunological action through the restoration of the anticancer effect of the immune system and induction of tumour dormancy. Consequently the association of targeted therapy with anti-angiogenic properties or specific immunologic drugs could enhance the efficacy of MT. During the past 15 years, several studies have been published evaluating the metronomic strategy in breast cancer. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The analyses included the efficacy and toxicity data of MT, and the future development of this strategy in breast cancer are also discussed. The systematic review presented here suggests that MT is a treatment option for breast cancer patients, has a low toxicity profile, efficacy in most patients and has potentially significant cost-effective advantages for public health. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Metastatic breast cancer (MBC) is generally an incurable disease. The median survival rate of the patient with metastasis is within the range of 3 years [1]. However, some patients with metastatic involvement live several years after diagnosis [2]. In such a scenario, one would wish to consider a therapeutic strategy with a low toxicity profile, good tumor control and economically viable for the healthcare system. Moreover, a therapeutic program of metastatic disease must be driven by multiple considerations, including not only the heterogeneity of breast cancer subtypes but also the heterogeneity of breast cancer patients, taking into account patient age, preferences, frailty, co-morbidities and possible contraindications to more intensive regimens. Although there is as yet no universally accepted definition, the metronomic schedule refers to repetitive, low doses of chemotherapy drugs administered at close regular intervals with no extended interruption. The term ‘‘metronomic’’ was used for the first time by Hanahan et al. commenting on two papers on the use of continuous, low dose chemotherapy in cancer treatment [3–5]. Metronomic therapy (MT) has an effect not only on tumor cells, but also on their microenvironment. In particular, the low-dose ⇑ Corresponding author. Tel.: +39 02 57489439; fax: +39 02 574829212. E-mail address: [email protected] (E. Montagna). http://dx.doi.org/10.1016/j.ctrv.2014.06.002 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.
schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect [4]. In addition to the antiangiogenic effect, MT could exert an immunological action through the restoration of the anticancer effect of the immune system and induction of tumor dormancy [6]. Over the years, different drugs have been tested with a metronomic schedule in different types of tumors [7–8]. Moreover, a hybrid approach including higherdoses of chemotherapy with planned treatment breaks combined with metronomic drugs has also been evaluated. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The Medline database was searched for fully published articles using the key words ‘metronomic’ and ‘chemotherapy’ and ‘cancer’ or ‘breast’. The search was restricted to the English language. Exclusion criteria included the following: pediatric trials, studies applying MT in all tumor sites, not only the breast, editorials, case reports and review articles. For studies with multiple presentations and/or publications, only the latest versions were included in the analysis. Metronomic therapy in breast cancer patients The first study on MT in metastatic breast cancer was published in 2002 [9]. From 2002 the number of published papers has increased, especially in the most recent years, as reported in Fig. 1. Patients
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
18 16 14 12 10 8 6 4 2 0
2002-2005 2006-2009 2010-2011 2012-2014
Fig. 1. Number of published papers over the years.
included in early trials who were candidates for MT were frail or heavily pretreated while the most recent trials also included patients at the first or second line of therapy. The results from a national survey conducted in Italy indicated a significant interest in MT, with 72% of responders having been administered a regimen of MT at least once [10]. This interest is confirmed by the higher number of publications on MT reporting Italian studies, as shown in Fig. 2. The largest number of published studies are phase II trials with a relatively low of number of patients as reported in Table 1. In the development of the MT strategy, several drugs were tested, in particular those with an oral formulation. Nevertheless, the identification of the optimal dosage has yet to be established [11]. The classical metronomic drug, widely clinically tested, is cyclophosphamide. Initial studies reported the efficacy data of single or combined metronomic chemotherapy drugs. Subsequent studies evaluated how to enhance the metronomic activity by an association with hormonal therapy, biological drugs or other agents. Single or combined metronomic chemotherapy in breast cancer patients The first trial on MT for MBC patients was conducted by Colleoni et al. The authors analyzed, in 63 pretreated MBC patients, a combination of metronomic chemotherapy with low-dose oral cyclophosphamide, 50 mg daily, and methotrexate, 2.5 mg twice daily, 2 days per week. This regimen was active and well tolerated, yielding an objective response rate (ORR) of about 20% and a clinical benefit (CB) (objective response and stable disease for at least 24 weeks) of 31.7%, in the absence of serious toxicity [9]. A few years later, the same authors reported results and longterm follow-up for patients with MBC who obtained prolonged CB (for 12 months or more) with metronomic cyclophosphamide and methotrexate (CM). Of one-hundred and fifty-three patients, 15.7% achieved prolonged CB with a time to progression (TTP) of 21 months [12]. Clinical activity and the absence of severe grades of toxicity of metronomic cyclophosphamide combined or not combined with methotrexate were also confirmed by the study of Miscoria et al.
Italy Europe USA-Canada China-Japan Fig. 2. Number of published papers according to country/region.
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and by a retrospective analysis conducted on 61 MBC patients [13–14]. Continuous infusion of 5-fluorouracil (5-FU) has been developed in an attempt to improve efficacy and has been shown to exert antiangiogenic activity in preclinical models. The combination of low dose oral 5-FU with eniluracil is a simpler and convenient alternative to continuous infusion of 5-FU. In the study of Smith et al., 33 untreated MBC patients received oral 5-FU 1.0 mg/m2 with eniluracil 10 mg/m2, both administered twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity. Sixteen partial responses were seen in 29 assessable patients. Seven patients had stable disease for at least 3 months with symptom improvement. Toxicity was mild [15]. Moreover, the oral daily administration of capecitabine mimics the activity of a continuous intravenous infusion of fluorouracil and the pharmacokinetics and toxicity profile render capecitabine particularly suitable for metronomic administration. In two small randomized trials, continuous use of low dose capecitabine (650 or 800 mg/m2 b.i.d. with no drug-free breaks) proved to be just as effective in MBC patients as did the intermittent use of higher doses (1000 or 1250 mg/m2 b.i.d. days 1–14 every 21 days) [16–17]. Taguchi et al. used a low dose schedule of capecitabine (852 mg/m2 twice daily on days 1–21 of a 28-day cycle) as firstline therapy for 33 MBC patients. The authors reported a median progression-free survival (PFS) of 6.9 months with an overall survival (OS) of 24.8 months, and grade 3 toxicities which included hand and foot syndrome (15%) and neutropenia (6%) [18]. The metronomic schedule of capecitabine was also evaluated in heavily pretreated patients with MBC. Sixty patients received oral capecitabine in a single daily dose of 1500 mg. The CB was 62% and the OS was 17 months. Grade 3–4 adverse events were uncommon [19]. Other studies evaluated the efficacy and safety of an all-oral doublet combination of MT including cyclophosphamide and capecitabine. In the study of Wang et al., 68 anthracycline- and taxane-pretreated MBC patients received 21-day cycles of oral cyclophosphamide (65 mg/m2 daily) and oral capecitabine (1000 mg/m2 twice daily on days 1–14 followed by a 7-day rest period). The median time to progression was 5.2 months and the OS was 16.9 months. The ORR and CB were 30.3% and 53.0% respectively. Treatment was well tolerated, and grade 3 hand–foot syndrome was reported by the 4.4% of patients [20]. The same combination of MT with different dosages was evaluated in the study of Yoshimoto et al. Fifty-one patients received capecitabine 828 mg/m2 twice daily with cyclophosphamide 33 mg/m2 twice daily, days 1–14 every 3 weeks. ORR was 44.4% and the CB was 57.8%. Hematologic toxicity included grade 3 leucopenia (26%) and neutropenia (16%). No grade 3 hand-foot syndrome was reported [21]. Given the availability of an oral formulation and due to its pharmacokinetic profile, vinorelbine can be used with a metronomic schedule. In the Phase I trial conducted by Briasoulis et al. in advanced cancer, the vinorelbine dose of 50 mg given three times a week was identified as the optimal dose for a metronomic schedule, yielding sustainable antitumor activity without overt toxicity [22]. In 34 elderly patients not pretreated for MBC, vinorelbine was administered at 70 mg/m2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week off, every 4 weeks. The ORR was 38%. Median PFS and median OS were 7.7 and 15.9 months respectively. The treatment was well tolerated [23]. According to the synergistic activity of the vinorelbine and capecitabine combination, Saridaki et al. conducted a phase I study to identify the metronomic dosage of this doublet, using eight
Author and year
N patients
Colleoni 2002
63
Colleoni 2005
171
Orlando 2006
153
Orlando 2006
22
Bottini 2006
114 46
Garcia-Saenz 2008
24
Watanabe 2009
733
Treatment
Phase
Previous treatment and setting
ORR (%)
CB (%)
OS (months)
Reference number
Cyclophosphamide Methotrexate Cyclophosphamide Methotrexate ± thalidomide Cyclophosphamide Methotrexate Cyclophosphamide Methotrexate Trastuzumab Letrozole ± cyclophosphamide
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC
19
31.7%
/
9
20.9 vs. 11.8 /
41.5 vs 41.5
/
56
15.7% with CB>12 months 46
/
12
/
39
Cyclophosphamide Capecitabine Bevacizumab Cyclophosphamide Capecitabine Bevacizumab Oral fluorouracil and tegafur vs.CMF*
Randomized II Retrospective II
Randomized II II
Not pretreated Locally advanced Pretreated MBC
71.9 vs. 87.7 48
/
/
33
68
/
43
II
Pretreated MBC
31.8
63.6
13.9
42
Randomized III II
Early BC
/
/
/
63
Not pretreated MBC Not pretreated MBC Not pretreated MBC Pretreated MBC Pretreated MBC Pretreated-not Pretreated MBC Not pretreated Locally advanced Pretreated MBC
55
/
/
15
18
44
24.8
18
15.9
23
Smith 2010
33
Tagushi 2010
33
Oral fluorouracil Eniluracil Capecitabine
Addeo 2010
34
Vinorelbine
II
Munzone 2010
52
Liposomal doxorubicin
Retrospective
Licchetta 2010
29
II
Wong 2010
41
Cyclophosphamide Megestrol acetate dalCMP**
Dellapasqua 2011
29
Soriano 2011
21
Gebbia 2011
61
Saloustros 2011
13
Wang 2012
68
Addeo 2012
36
Fedele 2012
60
Montagna 2012
24
Saridaki 2012
36
Yoshimoto 2012
51
18
II
I/II
Liposomal doxorubicin and cyclophosphamide Cyclophosphamide Methotrexate 1E10-Alum Cyclophosphamide (22) Cyclophosphamide Methotrexate (39) Vinorelbine Bevacizumab Capecitabine Cyclophosphamide Vinorelbine Temozolomide Capecitabine
II
Cyclophosphamide Capecitabine Bevacizumab Erlotinib Vinorelbine Capecitabine Capecitabine
II
II
38 57
45
/
27
31
/
13.4
36
17
24
12
53
62
/
/
29
23.8
/
12.9
58
Retrospective
Pretreated MBC
18
/
/
14
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC Not pretreated
7.7
/
/
44
30.3
53
16.9
20
52
/
11
26
24
62
17
19
62
75
/
50
(46)
/
/
24
44
57.8
/
21
II II II
MBC I II
Pretreated MBC Pretreated
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
Dellapasqua 2008
944
Table 1 Published trials of metronomic therapy in breast cancer.
Young 2012
47
Dellapasqua 2012
69
Mayer 2012
23
Aurilio 2012
33 (22 evaluable for response) 62
Otsuka 2013
40
Manso 2013
84
Perroud 2013
15
Schwartzberg 2013 Crivellari 2013
41
Cazzaniga 2014
77 12 + 22
II
MBC Pretreated MBC
34
42
/
61
Retrospective
Pretreated and not MBC
/
/
/
70
I
Pretreated MBC
(10)
(25)
/
45
Retrospective
Pretreated MBC
/
56
43.6
35
II
Pretreated MBC Pretreated MBC Pretreated MBC Pretreated MBC
/
/
7.1
13
26
30
II ***
Cyclophosphamide Methotrexate Celecoxib Capecitabine Fulvestrant Cyclophosphamide Methotrexate vs. liposomal doxorubicin Capecitabine Vinorelbine
Retrospective II
II III I–II
Pretreated MBC Early BC Pretreated MBC
Abbreviations: ORR, overall response rate; CB, clinical benefit (defined as ORR + SD > 24 weeks); SD, stable disease; OS, overall survival. BC, breast cancer; MBC, metastatic breast cancer. * CMF cyclophosphamide, methotrexate, fluorouracil. ** Dalteparin, cyclophosphamide, methotrexate, prednisone. *** Non-pegylated liposomal doxorubicin +5 fluorouracil + vincristine + oral cyclophosphamide + prednisone.
47 45
/
21
28
6.7
46.7
/
62
24.4
58.1
28.6
34
/
/
/
64
58
25
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
Miscoria 2012
Cyclophosphamide Docetaxel Capecitabine Celecoxib Capecitabine Cyclophosphamide Bevacizumab Erlotinib Cyclophosphamide Methotrexate Vandetanib Cyclophosphamide Methotrexate Fulvestrant Cyclophosphamide Methotrexate Irinotecan Tegafur Metronomic Cooper type
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E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
escalating dose levels. The dose-limiting toxicity (DLT) level was reached at 70 mg for oral metronomic vinorelbine and at 1250 mg/m2 for capecitabine. The metronomic combination was well tolerated and feasible [24]. More recently in another phase I–II study, the maximum tolerated dose identified of vinorelbine in association with a fixed dose of capecitabine (500 mg thrice a day) was 40 mg thrice a week. With this schedule, in 31 patients evaluable for efficacy, the CB was 58.1% [25]. The activity of combination of metronomic vinorelbine and temozolomide was evaluated in a population of 36 MBC patients with brain involvement. Temozolomide was administered orally at a dose of 75 mg/m2 during whole-brain radiotherapy, followed by 4 weeks off-therapy and a subsequent administration of oral vinorelbine 70 mg/m2 fractionated in days 1, 3, and 5, weekly for three consecutive weeks plus temozolomide at 75 mg/m2 on days 1–21. The authors reported an ORR of 52 % and an OS of 11 months. The schedule was well tolerated with an improvement in quality of life in [26]. Caelyx is a pegylated liposomal doxorubicin (PLD), used as single agent in MBC at standard doses ranging from 40 to 50 mg/m2 every 3–4 weeks. The pharmacokinetic characteristics (reduced volume of distribution, long intravascular circulating half-life) supported the rationale for using PLD in a metronomic schedule. Munzone et al. in a case-series report carried out in pre-treated MBC patients, tested the efficacy and tolerability of PLD administered with a metronomic schedule of 20 mg/m2 i.v. every two weeks. Forty-four patients were assessed for either response or toxicity. The CB was 45%. Neither grade 3 nor grade 4 hematological or clinical side effects were recorded, except for 2 patients with grade 3 palmar-plantar erythrodysesthesia (PPE). No cardiac toxicity was recorded [27]. The retrospective study of Manso et al. also confirmed that a chemotherapy combination including metronomic non PLD was effective and safe in pretreated MBC patients [28]. Dellapasqua et al. reported the data on eight courses of PLD (20 mg/m2 in every two weeks) in association with low-dose metronomic cyclophosphamide (50 mg/day) as a primary treatment in 29 locally advanced breast cancer patients. The rate of breastconserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) experienced a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities [29]. In a phase II study from a Japanese group, 40 MBC patients were treated with metronomic irinotecan (60 mg/m2) on days 1, 8, and 15 every 4 weeks plus tegafur (at a dose of 80 mg/m2/day orally on days 3–7, 10–14 and 17–21 every 4 weeks). The ORR was 47 % whereas median PFS and OS were 14 and 26 months respectively. The most common grade 3–4 toxicities included neutropenia (15 %), leucopenia (12.5 %) and diarrhea (7.5 %) [30].
Metronomic chemotherapy and hormonal therapy in breast cancer patients The first studies reported no additional benefit from the combination of tamoxifen and chemotherapy [31]. However with the introduction of new hormonal drugs (aromatase inhibitors) and a better understanding of hormonal resistance, the combined hormonal and chemotherapy approach stimulated new interest [32]. The low toxicity profile of MT makes this modality feasible in combination strategies, particularly in elderly patients. In a phase II trial, 114 elderly patients with clinical T2-4 N0-1 endocrine responsive breast cancer were randomized to receive a
preoperative treatment with either letrozole or letrozole plus metronomic cyclophosphamide for six months. The ORR was 71.9% in the letrozole arm and 87.7% in the letrozole plus cyclophosphamide arm, with a significantly greater suppression of Ki67 and vascular endothelial growth factor A (VEGF-A) expression by the combination therapy [33]. In a phase II study, Schwartzberg et al. explored the activity of fulvestrant and low-dose metronomic capecitabine in 41 patients with hormone receptor-positive, HER2-negative MBC patients. The median duration of therapy was 11 months , with a median PFS of 14.98 months, and a median TTP of 26.94 months. Treatment was well tolerated [34]. The activity of fulvestrant combined with CM was also evaluated in a retrospective analysis by Aurilio et al. showing a prolonged CB in a high proportion of patients with MBC [35]. In a phase II study, the safety and antitumor activity of a combination of cyclophosphamide and megestrol acetate were evaluated. Twenty-nine pretreated post-menopausal MBC patients received treatment with cyclophosphamide (50 mg/daily, day 1–21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall ORR was 31.0% and the mean OS was 13.4 months [36].
Metronomic chemotherapy and targeted therapy in breast cancer patients It has previously been shown that the metronomic CM combination leads to a marked decrease in circulating VEGF [9]. Moreover, experimental studies suggest that neutralizing antibodies against HER2 or epidermal growth factor receptor (EGFR) result in down-regulation of angiogenesis, through VEGF gene suppression [37]. Trastuzumab, a humanized anti-HER-2 monoclonal antibody, can modulate the effects of different pro and anti-angiogenic factors [38]. Given these considerations, Orlando et al. reported the data of the combination of trastuzumab plus metronomic CM in 22 metastatic breast cancer patients with overexpressed or amplified HER2, who were pre-treated with trastuzumab. The authors reported a CB of 46%; the median TTP was 6 months and the toxicity was generally mild [39]. Moreover in preclinical models, the combination of metronomic chemotherapy with a VEGFR2 antibody resulted in sustained regressions of large tumors [40]. Bevacizumab is a recombinant humanized monoclonal antibody against human VEGF and may enhance the antiangiogenic activity of MT. In a randomized phase II trial comparing metronomic CM with the same regimen plus bevacizumab in pretreated MBC patients, a planned interim analysis revealed a significant advantage in favor of the combination arm in terms of objective responses (41%)[41]. A similar trial explored the activity of CM and bevacizumab 10 mg/kg i.v. every 14 days in an anthracycline and taxane refractory MBC population. Trastuzumab was added in HER2-overexpressing tumors. Among the 22 patients evaluable for response, the CB was 63.6% and the OS was 13.6 months [42]. In another phase II trial, bevacizumab was added to a metronomic regimen with cyclophosphamide and capecitabine. The authors reported in 46 assessable patients an ORR of 48% and an overall CB of 68%. The toxicity was generally mild [43]. On the other hand, in a very small study the combination of oral metronomic vinorelbine and bevacizumab showed good tolerance but minimal activity in terms of ORR in pretreated patients with MBC [44].
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
In a phase I study the safety and tolerability of a new antiangiogenic therapy and MT were evaluated. The authors used vandetanib, an oral drug that inhibits the tyrosine kinase activity of VEGFR2, EGFR and rearranged during transfection (RET) receptor, in three dose-escalation doses in association with metronomic CM in MBC patients. Of the 20 patients evaluable for response, 10% demonstrated partial response and 15 % a stable disease.[45] Preclinical evidence also suggests that the pathways mediated by EGFR may be involved in angiogenesis control [46,47]. EGFR is also a target for several developed drugs, including therapeutic antibodies (cetuximab) and small-molecule tyrosine kinase inhibitors such as erlotinib. The combination of erlotinib with bevacizumab has shown promising activity in lung cancer and limited activity in unselected patients with previously treated MBC [48,49]. In a phase II trial, the safety and efficacy of metronomic chemotherapy with cyclophosphamide and capecitabine in combination with erlotinib and bevacizumab were explored in patients with advanced triple-negative or estrogen (ER)- and progesterone (PR) receptor-poor HER2-negative breast cancer. In 24 patients assessable for response, the authors reported an ORR of 62% and a CB of 75%. Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2) [50]. In a phase I–II study by Wong et al., the combination of MT and other agents with anti-angiogenic properties, such as corticosteroids [51] and low-molecular-weight heparins [52] was evaluated. The study treatment was daily dalteparin, cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP) for 41 MBC patients. The CB, the primary end point of the study, was 24%. The median TTP was 10 weeks and median OS was 48 weeks. The toxicities included transient grade 3 elevation of liver transaminases in 27% of patients and vomiting in 2% of patients [53].
Metronomic chemotherapy and immunologic agents in breast cancer patients The mechanism of action of MT may also have an immunologic component and consequently the association of specific immunologic drugs could enhance its efficacy. Thalidomide, a derivative of glutamic acid, inhibits angiogenesis [54] and also has an immune-modulating activity secondary to inhibition of lymphocyte proliferation [55]. Colleoni et al. investigated the association of thalidomide with a metronomic chemotherapy (CM regimen). Patients with MBC were randomized to receive CM (arm A) or the same regimen plus thalidomide (200 mg daily) (arm B). In 171 evaluable patients the ORR was 20.9% in arm A and 11.8% in arm B. The CB was 41.5% in both arms. Higher neurological toxicity and constipation were observed in arm B [56]. Moreover, during MT therapy, several immunological effects have been reported. Generali et al. showed that the combination of hormonal therapy with metronomic cyclophosphamide induced a significant reduction in the number of a specific subpopulation of CD4+ CD25+ regulatory T cells (Treg) in elderly breast cancer patients [57]. Given these results, the combination of MT and vaccines might increase the efficacy of the treatment. Soriano et al., in an exploratory study in MBC patients, evaluated the safety and efficacy of metronomic chemotherapy with CM in combination with 1E10Alum vaccine (racotumomab). Twenty-one patients were enrolled. Five patients achieved an objective response, eight showed stable disease and eight had disease progression. Overall toxicity was generally mild [58].
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Metronomic chemotherapy and anti COX2 drugs in breast cancer patients Another strategy to increase the efficacy of MT is to evaluate the combination of anti- cyclooxygenase 2 drugs. Cyclooxygenase 2 is a prostaglandin synthase enzyme implicated in the malignancy process [59]. Celecoxib, a selective inhibitor of cyclooxygenase 2 has shown an anti-angiogenic effect in breast cancer cell lines [60]. Young et al. used a combination of docetaxel and capecitabine plus concurrent treatment with celecoxib (200 mg twice daily) in MBC patients with prior anthracycline exposure. Of the 47 patients enrolled, none achieved a complete response and 34% of patients experienced a partial response. The most common non-hematologic toxicities were diarrhea, palmar-plantar erythrodysesthesia, fatigue, and mucositis [61]. Perroud et al. added celecoxib to metronomic chemotherapy with cyclophosphamide in advanced breast cancer patients. In 15 patients the CB was 46.7% and the one-year OS rate was 46.7%. No grade 3 or 4 toxicity was reported. [62] Adjuvant metronomic chemotherapy in breast cancer patients There is a rationale for the development of metronomic strategies in the adjuvant treatment of early breast cancer. The lack of targeted therapies in triple-negative disease renders this subtype of breast cancer suitable for studies with MT. Moreover, the toxicity profile of MT permits consideration of an adjuvant chemotherapy in frail patients. MT could also be used in combination with other targeted agents (such as endocrine and anti-HER2). Given these considerations, in recent years, the role of MT has been evaluated in the adjuvant setting. Metronomic chemotherapy using tegafur/uracil (UFT), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in the preclinical model. Watanabe T et al. in a phase III trial showed that oral UFT was as effective as classical CMF as adjuvant treatment, in women with nodenegative, high-risk breast cancer. The quality of life scores were better for patients who were given UFT than for those who were given CMF. The outcome with oral UFT was similar to that with classical CMF [63]. In a phase III trial, the adjuvant metronomic CM regimen was compared to adjuvant pegylated liposomal doxorubicin in older breast cancer patients with endocrine non-responsive disease who were not candidates for standard chemotherapy. Definitive results are not available from this trial because of its early closure due to slow and inadequate accrual. After two years, only 77 patients were enrolled (38 in the PLD and 36 in the metronomic arm). The metronomic regimen was associated with better quality of life and cognitive function as compared to the PLD regimen [64]. The maintenance trial (IBCSG 22–00) investigated a tailored chemotherapy approach aimed at reducing the risk of relapse and improving survival of patients with endocrine non-responsive tumors. In this trial, one year of CM was compared with no further therapy after the standard adjuvant chemotherapy program. The trial was recently terminated with the enrolment of 1086 patients, and its results are eagerly awaited. Discussion To the best of our knowledge, this is the first systematic review of MT in breast cancer. However, even though interest in the metronomic strategy has increased in recent years, the data now available are unlikely to provide definitive answers to several questions on MT. The reported data are extracted from relatively small phase II trials with a minimum of 13 and a maximum of 171 patients
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enrolled. In addition, the study patients were often very heterogeneous at both an individual trial level, as well as in terms of the number and type of prior therapies. Moreover, the primary endpoint, the type and dosage of metronomic drugs differ among the studies. A hybrid approach including higher doses of chemotherapy with planned treatment breaks combined with metronomic drugs has also been evaluated, but the results are not comparable with those achieved with a ‘‘pure’’ metronomic strategy. Another aspect is the need to identify predictive and dynamic biomarkers of benefit from MT. Bertolini et al. reported that metronomic cyclophosphamide acts by reducing the circulating endothelial progenitor cells (CEP) while the same drug, at the maximum tolerated dose (MTD) of drugs, causes an opposite effect with a marked drop followed by a rapid rebound of CEP [65]. Similarly, Shaked et al. found that the maximum angiogenic activity of MT is strikingly correlated with the maximum reduction of circulating VEGFR-2+ and CEP in viable peripheral blood [66]. Different studies also reported a predictive potential role of baseline values of CEP in patients with advanced breast cancer treated with metronomic chemotherapy and bevacizumab [43]. Circulating endothelial cells (CEC) and CEC kinetics correlate well with more invasive biomarkers of angiogenesis [67]. CEC were found to be dynamic markers of clinical response in breast cancer patients receiving a CM regimen [68]. However no standardization of CEC and CEP dosage is available and the role of CEC and CEP needs to be confirmed in larger clinical trials. Moreover, Bocci et al. characterized the role in MT of thrombospondin-1 (TSP-1), a potent and endothelial-specific inhibitor of angiogenesis. The authors reported that protracted exposure of endothelial cells in vitro to metronomic chemotherapy caused marked induction of gene and protein expression of TSP-1 [69]. However the clinical evidence did not confirm the role of TSP-1 as a secondary mediator of the antiangiogenic effects of MT. Recently, Dellapasqua et al. showed that in advanced breast cancer patients an increase in the mean corpuscular volume of red blood cells may predict response to metronomic capecitabine
and cyclophosphamide in combination with bevacizumab. This finding awaits future confirmation [70]. As shown in Table 2, there are still several ongoing trials of MT in breast cancer. The aims are to identify the optimal regimen and schedule of MT in different patient settings, particularly the metastatic setting. Generally the toxicity profile of MT is lower compared to the classical approach considering the MTD. Results were recently presented of a multicenter, randomized phase III trial of bevacizumab therapy with either a weekly paclitaxel (arm A) or daily oral metronomic capecitabine and cyclophosphamide as first-line treatment in 147 patients with HER2-negative MBC. The incidence rates of grade 3–5 adverse events were 25% for arm A and 24% for arm B. ORR were 58% and 50% in arms A and B, respectively (p = 0.45). Less hair loss in arm B was the only clinically and statistically significant difference in quality of life [71]. Oral administration is generally appreciated by patients and reduces the cost of hospitalization. This aspect is critical, particularly in breast cancer where the number of long-term survivors is growing dramatically. New targeted treatments often incur very high public health costs. Therefore, therapies such as metronomic CM and similar regimens position themselves as potentially significant cost-effective palliative treatments for metastatic breast cancer when compared with other novel therapeutic strategies [72].
Future approaches and conclusion The systematic review presented here suggests that MT is a treatment option for breast cancer patients. In fact, the low burden of personal costs for the patient and the possibility to continue the treatment for several months, supports the use of metronomic chemotherapy as an additional therapeutic tool for metastatic and pre-treated patients with breast cancer, particularly with indolent disease. Moreover most ongoing clinical trials with MT are aimed at patients with triple-negative disease, since in this setting chemotherapy still represents one of the most reliable options.
Table 2 Ongoing trials with metronomic chemotherapy in breast cancer. Schedule
Phase
Setting
Ref.
Capecitabine 1000 m/m2 d1 – 14 + VNB 60 mg/m2 d1 – 8 q21d vs. VNB 50 mg/d d1,3,5/wk
II Randomized III II
M+, 2 cm any N TN or inflammatory M+, TN M+
NCT01112826 NCT01329627
M+, HER-2 neg M+, ER+, postmenopausal
Standard ADJ CT + capecitabine 650 mg/m2 bid PTX 100 mg/m2/wk x 8 ? DOX 24 mg/m2/wk + CTX 100 mg/d os 9 wks CDDP 25 mg/m2 d1 – 3 q3w + CTX 150 mg/d os d1 – 14 TXT 75 mg/m2 + CTX 50 mg/d 21 d, q3w Capecitabine 1500 mg/d + CTX 50 mg/d Capecitabine 1500 mg/d + AI Pertuzumab + Trastuzumab + CTX 50 mg/d ? T-DM1 (if PD) DOX 24 mg/m2 + CTX 60 mg/m2 os/wk 12 ? PTX 80 mg/m2 + CBDCA AUC 2/wk 12 Capecitabine 1000 mg/d + digoxin TXT 75 mg/m2 + capecitbine 1000 mg/m2 bid d1–14 6 cycles ? capecitabine 500 mg/m2 tid d1–21 vs. 1000 mg/m2 bid d1 – 14 Aflibercept 6 mg/kg iv q3w + Capecitabine 1100 – 1600 mg/m2/d vs. 1700 – 2500 mg/m2/ d 2 wks q3w Bevacizumab 10 mg/kg q2wks + PTX 90 mg/m2 d1,8,15 vs. Bevacizumab 10 mg/kg q2wks + CTX 50 mg/d + capecitabine 1500 mg/d CM + ASA 325 mg/d (cyc 3 – 4) 4 cycles Capecitabine 700 mg/m2 bid, d1 – 14 + etoposide 30 mg/m2/d, d1 – 7 q3w AI + CM + PDN vs. CM + PDN CTX 50 mg/d po + veliparib/placebo
II II Randomized II II II Randomized II II III
NCT01910870 NCT01526499
M+, HER-2 pos, >60 yrs
NCT01526512 NCT01924078 NCT01597414
NeoADJ, TN M+ M+
NCT00542191 NCT01887288 NCT01917279
I
M+
NCT01843725
III
M+, locally advanced
NCT01131195
II II II I/II Randomized
Post-neoADJ (no pCR) M+ M+, ER+, postmenopausal M+
NCT01612247 NCT01589159 NCT00687648 NCT01351909
Abbreviations: VNB: vinorelbine; M: metastatic; ADJ: adjuvant; PTX: paclitaxel; CTX: cyclophosphamide; DOX: doxorubicin; TN: triple negative; CDDP: cisplatin; CBDCA: carboplatin; ER: estrogen receptor; pCR: pathologic complete response; TXT: taxotere; ASA: acetylsalicilic acid; PDN: prednisone.
E. Montagna et al. / Cancer Treatment Reviews 40 (2014) 942–950
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