Metronomic Chemotherapy for Advanced Breast Cancer Patients

Cancer Letters 400 (2017) 252e258

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Cancer Letters

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Mini-review Metronomic chemotherapy for advanced breast cancer patients

* Marina Elena Cazzaniga a, , Maria Rita Dionisio b, c, d, Francesca Riva a a Department of Medical Oncology, ASST-Monza, Ospedale San Gerardo, 20900 Monza, MB, Italy b Hospital de Santa Maria, CHLN, Lisbon, Portugal c Hospital Cuf Cascais, Cascais, Portugal d I3s-Instituto de Investigaçao~ e Inovaçao~ em Saúde da Universidade do Porto: Research Institute on Cancer, Host Response Interaction, Neurobiology and Neurological Disorders, Porto, Portugal article info abstract

Article history: Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent Received 5 October 2016 given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor ac- Received in revised form tivity. This schedule seems to have not only a direct cytotoxicity on cancer cells but also an effect on the 15 December 2016 tumor microenvironment by inhibiting tumor angiogenesis and modulating immune response. Accepted 15 December 2016 Metronomic chemotherapy was widely investigated in patients with breast cancer. The results of these studies showed that this strategy is not only effective but has a low toxicity proﬁle too, proposing as a Keywords: promising strategy for breast cancer patients. In this review we summarize the results of Phase II and III Metronomic chemotherapy Metastatic breast cancer studies evaluating metronomic therapy in metastatic breast cancer. © Oral vinorelbine 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction the Maximum Tolerated Dose (MTD), without significant bone marrow toxicity and for this reason the ideal therapy to be Metastatic breast cancer (MBC) is an incurable disease and pa- administered for a long period of time. tients are expected to have a life-span/expectancy ranging between The present article presents an overview of the literature data 6 months and 2 years according to the different expression of available as of today relatively to metronomic chemotherapy used hormone receptors and Human Epidermal Growth Factor Receptor as single agent or in combination with other chemotherapy drugs, 2 (HER2) [1]. endocrine treatments or target agents, in order to offer an updated Different strategies can be efficaciously used to reach disease scenario to clinicians and allow them to better identify potential control, such as chemotherapy, endocrine therapy and more patients for this kind of treatment. recently therapy with target agents. Nevertheless, despite the unequivocal improvement in overall Metronomic chemotherapy: a long way to define the right survival (OS) observed in the last decades, mainly related to the dose contributions of various therapies rather than to a single drug or regimen, metastatic disease remains the primary cause of death in The emergence of molecular targeted agents in oncology has not the majority of patients with breast cancer. only revolutionized the care of cancer patients, but also changed So far, in the last years the focus of clinicians and researchers has the daily practice of medical oncologists. Molecular targeted agents moved to the aim of prolonging disease control, which ultimately indeed often differ from traditional cytotoxic agents due to their translates into an improvement in overall survival [2]. administration schedules and routes, their toxicity profiles and In this context, metronomic chemotherapy could represent one their antitumor activity [3]. For some aspects, the development of of the most promising strategies to reach this goal, considering that metronomic chemotherapy is quite similar to the one of targeted the main peculiarity of this treatment is the use of doses well below agents: rather than a direct antitumor effect, metronomic chemotherapy mainly exerts indirect effects on tumor cells but also on their microenvironment by inhibiting tumor angiogenesis, stimu- * Corresponding author. Department of Medical Oncology, ASST Monza, Osp. San lating anticancer immune response and acting on stromal tissue [4] Gerardo & Milano Bicocca University, Via Pergolesi 33, 20900 Monza, MB, Italy. Fax: þ39 0392332284. and could therefore be considered a multi-target therapy itself. In E-mail address: [email protected] (M.E. Cazzaniga). contrast to conventional, pulsatile, maximum tolerated dose (MTD) http://dx.doi.org/10.1016/j.canlet.2016.12.019 0304-3835/© 2016 Elsevier Ireland Ltd. All rights reserved.

Downloaded for Anonymous User (n/a) at ASST di Monza from ClinicalKey.com by Elsevier on June 12, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. M.E. Cazzaniga et al. / Cancer Letters 400 (2017) 252e258 253 chemotherapy, the main primary target of metronomic chemo- association between DCR and Relative Dose Intensity (p ¼ 0.68), therapy is the tumor's neovasculature [5]. This is the main reason Dosing Density (p ¼ 0.73), regimen type (p ¼ 0.73), cancer type why the selection of the right dose cannot be done in the classical (p ¼ 0.88) or metronomic drug(s) used (p ¼ 0.37). way, but requires the identification of a biomarker. Despite prom- What stands out for its absence in the recent literature is the ising preliminary results presented in different clinical studies us- complete lack of randomized Phase III trials, which are now ing mostly oral metronomic chemotherapy-based regimens [6e8], strongly recommended before adopting metronomic strategy in few data were available for a long time regarding the right dose of the daily practice. the different drugs to be used in the metronomic administration. So far, the undeniable advantages of metronomic chemotherapy Metronomic chemotherapy and endocrine treatment: what observed in clinical trials, such as the low toxicity, the high efficacy evidence? and the possibility to enhance some mechanisms of specific target agents, have been compromised by the empiricism associated with One of the first and more interesting trials, which studied the the determination of the optimal biologic dose (OBD). In a mile- combination of a metronomic chemotherapy regimen in combi- stone paper, Shaked et al. [9], using 4 distinct metronomic nation with an endocrine drug was the randomized Phase II study chemotherapy regimens in 4 different preclinical tumor models, done by Bottini et al., in 2006 [13]: the trial aimed to investigate the have defined OBD as the dose able to cause maximum reduction in activity of letrozole, in combination or not with oral metronomic the tumor volume with no or minimal toxicity. The authors further CTX, as primary systemic treatment in a group of 114 elderly breast assessed that OBD were 20 mg/kg for cyclophosphamide (CTX) cancer patients. Patients received letrozole (2.5 mg daily for 6 daily, 0.33 mg/kg for vinblastine, 9 mg/kg for vinorelbine (VNR) and months) or a combination of letrozole plus oral CTX (50 mg/daily 1 mg/kg for cisplatin. They further established that each OBD was for 6 months). Overall response rates (ORRs) were 71.9% (95% CI, strikingly correlated with the maximum reduction in viable pe- 60.0e83.8) and 87.7% (95% CI, 78.6e96.2), respectively. The authors ripheral blood circulating vascular endothelial growth factor re- concluded that both letrozole and letrozole plus CTX treatments þ ceptor 2-positive (VEGFR-2 ) endothelial precursors. Thanks to the appeared active as primary therapy in elderly breast cancer pa- results of this study and the possibility to convert the drug dosage tients. Considering the potential antiangiogenic effect of metro- from one animal species to another by using the body surface area nomic schedule of CTX, they warranted a further testing in a normalization method [10], it is now possible to design metro- randomized Phase III trial, at the moment never conducted. nomic chemotherapy trials, being sure to use the right dose based In a Phase II trial, Licchetta et al. [14] evaluated the safety and on the specific biological effect. the antitumor activity of the metronomic chemo-hormonal therapy The most favorite compounds for metronomic administration with CTX (50 mg/daily day 1e21 q28) and megestrol acetate (80 mg are those administered orally, due to the potential long-term use of twice a day) in patients with metastatic pretreated breast cancer. this treatment. ORR was 31.0%, DCR 41.3%, median time to progression (TTP) 7.4 In this context, the most studied drugs for metronomic months (CI 95%, 3.8e10.88, range 1e48 months) and median OS chemotherapy in advanced breast cancer are CTX, methotrexate 13.4 months (CI 95%, 7.24e17.18, range 1e53 months). The regimen (MTX), capecitabine (CAPE) and oral VNR. was active and well tolerated. Different metronomic drug concentrations and schedules might More recently, Schwartzberg et al. investigated the efficacy and affect different prevalent mechanisms of antitumor action, which toxicity of the combination of fulvestrant and low dose metronomic suggest that therapy protocols could be selected on the basis of CAPE depending on the patient's weight (1500 mg/daily if the different prevalent effects. weight was less than 80 kg or 2000 mg/daily if it was more than However, the lack of well-established pharmacokinetic profiles 80 kg) in 41 hormone receptors positive (HR þve), metastatic breast represents now the most serious clinical limitation when adopting cancer patients [15]. They received fulvestrant loading dose 500 mg metronomic chemotherapy regimens. Key aspects for future on day 1, 250 mg on days 15 and 29 followed by 250 mg every 28 development of these regimens include for example the optimal days along with continuous oral CAPE. Median PFS was 14.9 months steady-state Concentration (CSS), at which both the antiangiogenic (95% confidence interval [CI], 7.26 e upper limit [UL] not estimated) and the immunologically mediated mechanisms prevail with a and median TTP was 26.9 months (95% CI, 7.26 e UL not estimated). minimal level of low-grade adverse drug reactions [11]. Median OS was 28.65 months (95% CI, 23.95 e UL not estimated). Treatment was well tolerated with <10% Grade 3 palmar-plantar Metronomic chemotherapy for advanced breast cancer: erythrodysesthesia. Overall, the most frequent adverse events overview of the last ten years of publication were palmar-plantar erythrodysesthesia, fatigue, and nausea. The combination of fulvestrant with metronomic CAPE demonstrated A great number of Phase II studies have been published starting substantial activity in HR þve MBC and was well tolerated. from mid-2000s, showing an increasing interest of clinicians on this Data regarding the combination of endocrine therapy and topic [12]. Among the 80 publications selected for the systematic metronomic strategies are summarized in Table 1. literature analysis by Lien and colleagues, 21 trials covered the topic Are there sufficient data at the moment to suggest the use of of breast cancer involving 1135 patients. The authors identified 107 endocrine therapy in combination with metronomic chemotherapy treatment regimens with at least one metronomic drug, being CTX, in the clinical practice? CAPE, etoposide and VNR the most frequently used. The mean It is our opinion that this strategy could not be adopted as Response Rate (RR) of the pooled treatment regimens was 26%, with routine clinical practice in the daily treatment of metastatic breast a mean Disease Control Rate (DCR) of 56.3%. Median duration of cancer patients, due to the following considerations: 1) there is no response was 4.6 months on average. This systematic literature re- evidence that the addition of chemotherapy to endocrine therapy, view, even if not focused on breast cancer patients, confirmed that when patients are still considered endocrine-sensitive, could severe side-effects are rare, being observed in less than 5% of pa- induce a substantial benefit in terms of clinical activity; 2) as long tients and the treatment-associated fatalities are very rare (0.4%) as HR þve breast cancers are endocrine sensitive, patients should too, despite the fact that most study patients had an advanced dis- be treated with endocrine treatment alone, or at least in combi- ease, refractory to often multiple prior conventional systemic ther- nation with targeted agents, as stated in various consensus con- apies. Regarding efficacy, the authors did not observe any statistical ferences [16].

Table 1 Metronomic chemotherapy and endocrine therapy.

Author and year Ref. Phase Patients Type of treatment Setting Results

Bottini et al. (2006) [13] II-R N 114 Letrozole ± CTX 50 mg/day Neoadjuvant TTP not evaluated ORR 71.9% (L) ORR 87.7% (L þ CTX) Licchetta et al. (2010) [14] II N 22 CTX 50 mg/day þ megestrol acetate 2nd-line or later TTP 7.4 80 mg twice a day ORR 31% CBR 41.3% Schwartzberg et al. (2014) [15] II N 41 Fulvestrant 500 mg / 250 mg 1st-line or 2nd line TTP 26.94 every 28 days þ CAPE 1.500e2.000 mg/day ORR: 24.4% CBR: 58.5%

R ¼ randomized study; CTX ¼ cyclophopshamide; TTP ¼ time to progression (months); ORR ¼ overall response rate; CBR ¼ Clinical Beneﬁt Rate.

Metronomic chemotherapy: monotherapy or combination? Details regarding single agent metronomic therapy are summarized in Table 2. Single agent therapy Combination therapy The most widely evaluated drugs as single agent are CAPE and VNR. A meta-analysis of 11 randomized trials showed that longer CAPE is an orally administered fluoropyrimidine carbamate, first-line chemotherapy is associated with longer OS and substan- which was approved by FDA as a single agent for MBC patients. tially longer PFS, suggesting that treatment should be given until In 323 metastatic breast cancer patients, Stockler and colleagues disease progression or unacceptable toxic effects [2]. The prefer- compared three different regimens, in terms of quality-adjusted ence is for sequential single agent chemotherapy rather than progression-free survival (PFS): CAPE administered intermittently combination [23,24] with the exception of some particular clinical 2 (1000 mg/m twice daily for 14 of every 21 days), or continuously situations, such as presence of visceral crisis and rapidly pro- 2 2 650 mg/m twice daily or to classical CMF (oral CTX 100 mg/m gressing or life-threatening disease, or some special subtypes as 2 days 1e14, intravenous methotrexate 40 mg/m and 5 fluorouracil triple-negative breast cancers, considering that toxicity is often 2 600 mg/m on days 1 and 8 every 28 days). This study showed that increased when using a combination treatment [25,26]. both schedules of CAPE were as effective as classical CMF. Febrile A recent Cochrane report [27] concluded that combination neutropenia, infection, stomatitis, and serious adverse events were chemotherapy regimens yielded statistically significant improve- more common with CMF; hand-foot syndrome was more common ments in OS, TTP, and RR yet greater toxicity. with CAPE [17]. The scenario and the rational are completely different with Another Phase II trial evaluated the efficacy of low dose single- metronomic schedules: most of the studies conducted with 2 agent CAPE (825 mg/m twice daily, for 21 out of 28 days) as first metronomic regimens investigated the association of two or more line treatment in 33 metastatic breast cancer patients. Median PFS drugs [28e32], both in the adjuvant and the metastatic setting and and OS were 6.9 and 24.8 months, respectively; aside from being an all this has been made possible due to the use of very low doses of active treatment, CAPE was also well tolerated [18]. the different drugs [33]. Fedele et al. tested metronomic CAPE (1500 mg once a day) in 60 Data emerging from pre-clinical studies and in vitro models heavily pretreated advanced breast cancer patients, reporting a suggest that the metronomic combination of two different drugs clinical benefit rate (CBR) of 62%; median TTP and OS were 7 and 17 allows the use of doses of the single drug lower than those required months, respectively. On and off metronomic VNR oral adminis- both by the standard schedule or the single-agent metronomic tration resulted in good tolerability and safe profile in our selected administration as well: so far, the anti-tumor effect is reached by elderly population, and improved patient adherence to therapy using altogether lower drug concentrations. [19]. Which drugs and schedules are available at the moment when a VNR is a semi-synthetic vinca alkaloid, active in a variety of metronomic combination is the choice? cancers. In breast cancer, oral VNR has been widely studied in CTX, MTX, CAPE and VNR, having oral formulations, are excel- metronomic regimens. lent partners to be combined. 2 Addeo et al. evaluated VNR at the dose of 70 mg/m thrice a Different Phase II studies have tested the metronomic admin- week for 3 weeks and one week off in 34 elderly patients, istration of MTX and/or CTX [7,31] and CTX þ CAPE [32], reporting demonstrating a good safety profile with a median PFS of 7.7 percentages of CBR of 31e53% and ORRs of 19e30%. Most of these months and a median OS of 15.9 months. The only grade 3 events studies had small sample sizes and were conducted in heavily were neutropenia (6%) and hand-foot syndrome (15%). The Authors pretreated breast cancer patients. In some cases, the schedule concluded that this fractionated administration of oral VNB is well chosen could not precisely be defined as metronomic, at least as tolerated showing promising activity in elderly patients with actually defined, making comparison very difficult. metastatic cancer [20]. More recent trials, some of them conducted as single Institution Briasoulis et al. carried out a Phase I trial in order to determine pilot experiences, tested different and more active drugs, mainly the optimal dose for metronomic oral VNR. The authors suggested VNR and CAPE reporting percentages of ORRs of approximately 50% that 50 mg three times weekly is the best schedule in terms of and CBRs of 77e80%. efficacy and acceptable toxicity [21]. Table 3 summarizes details regarding efficacy and toxicity of A more recent Phase II study tested 30 mg of oral VNR every combination metronomic schedules. other day in 32 elderly patients: CBR was 50% and no major adverse The majority of trials evaluating the combination of two or more events (grade 3 or 4) were recorded [22]. These results confirm the drugs administered with a metronomic schedule are Phase II, not tolerability and the optimal safety profile of the metronomic randomized trials and this actually represents the main limit of this schedule of both drugs. new strategy.

Table 2 Metronomic chemotherapy in metastatic breast cancer: single agent trial.

Author and year Reference Phase Patients Type of treatment Setting Results

Capecitabine Taguchi et al. (2010) [18] II N 33 CAPE 825 mg/m2 twice daily 1e21 q28 1 line CBR 42% PFS 6.9 OS 24.8 Stockler et al. (2011) [17] III N 323 CAPE 1000 mg/m2 twice daily, 1e14 q21 1 line OS 22 vs CAPE groups CAPE 650 mg/m2 twice daily continuously vs vs OS 18 classical CMF CMF group Fedele et al. (2012) [19] II N 60 CAPE 1500 mg daily continuously Heavily pretreated CBR 62% patients TTP 7 OS 17 Vinorelbine Addeo et al. (2010) [20] II N 34 oVNR 70 mg/m2 thrice a week, 1e21 q28 1 line ORR 38% PFS 7.7 OS 15.9 De Iuliis et al. (2015) [22] II N 32 oVNR 30 mg every other day continuously All CBR 50% Elderly

CAPE ¼ capecitabine; oVNR ¼ oral vinorelbine; PFS Progression Free Survival (Months); OS Overall Survival (Months); TTP Time To Progression (Months); CBR Clinical Beneﬁt Rate (deﬁne as overall response rate þ stable disease 24 weeks); CMF CTX, MTX, Fluorouracil.

Table 3 Efﬁcacy and toxicity of combination metronomic schedules.

Author and year Reference Phase Patients Type of treatment Setting Results

CTX/MTX Colleoni et al. (2002) [7] II N 63 CTX 50 mg/day All TTP 2.8 continuously þ MTX 2.5 mg bid ORR 19% days 1 and 2 weekly CBR 31.7% Wang et al. (2012) [32] II N 66 CTX 65 mg/m2/day d1e14 q21 2nd or later PFS 5.2 CAPE 1000 mg/m2 twice daily TTP 5.2 d1e14 q21 OS 16.9 ORR 30.3% CBR 53% VNR þ CAPE Cazzaniga et al. (2014) [28] I/II N 34 oVNR 20e40 mg daily, d1,3,5 All TTP 18.5 weekly þ CAPE 500 mg tid CBR 58.1% continuously Cazzaniga et al. (2016) [47] II N 80 oVNR 20e40 mg daily, d1,3,5 All TTP 7.5 weekly þ CAPE 500 mg tid CBR 48.8% continuously VNR þ CAPE þ CTX Montagna et al. (2015) [29] II N 69 oVNR 40 mg daily, d1,3,5 All PFS weekly þ CAPE 500 mg tid 22 (untreated pts) continuously þ CTX 50 mg daily 14 (treated pts) CBR 78.3% CTX þ OTHER DRUGS Yoshimoto et al. (2012) [33] II N 45 CAPE 828 mg/m2 bid þ CTX 1st or 2nd PFS 12.3 33 mg/m2 bid Addeo et al. (2012) [30] II N 32 TMZ 75 mg/ 2nd/1st CBR 57.8% m2 þ WBRT / oVNR 70 mg/m2 (brain metastases) TTP 8 d 1,3,5 þ TMZ 75 mg/m2 d1e21 OS 11 q28 ORR 52% CBR 77%

CAPE ¼ capecitabine; oVNR ¼ oral vinorelbine; CTX ¼ cyclophopshamide; TMZ ¼ temozolomide; WBRT ¼ whole brain radiotherapy; PFS Progression Free Survival (Months); OS Overall Survival (Months); TTP Time To Progression (Months); CBR Clinical Beneﬁt Rate (deﬁne as overall response rate þ stable disease 24 weeks).

Despite the lack of randomized Phase III trials, but considering Bevacizumab is a humanized anti-VEGF monoclonal antibody, the great literature production of these last years and the indis- which was approved by FDA for first-line treatment of HER2 putable results in terms of toxicity, metronomic chemotherapy has negative MBC in combination with paclitaxel [35]. been endorsed as a reasonable treatment option for patients not Dellapasqua et al. evaluated the combination of bevacizumab requiring a rapid tumour response by the 2015 ABC3 Consensus with metronomic CAPE and CTX in a Phase II trial including 46 Conference. patients. The treatment was well tolerated; CBR was 68% and median TTP was 42 weeks [36]. Metronomic chemotherapy and target agents Similar results were obtained by García-Saenz and colleagues. They assessed the activity of metronomic CTX and MTX plus bev- fi Several studies evaluated the ef cacy of metronomic chemo- acizumab in 22 anthracycline and taxane-refractory metastatic therapy in association with targeted therapies. Antibodies against breast cancer patients. The authors reported CBR in 63.6% of the VEGF are the most widely studied, since metronomic schedule may patients, whereas median PFS and OS were 7.5 months and 13.6 enhance their anti-angiogenic effect. Moreover, xenograft models months respectively, associated with a mild toxicity [37]. showed that the combination of metronomic chemotherapy with Bevacizumab was also tested in association with metronomic fi VEGF receptor 2 antibody leads to an increase in ef cacy without an VNR alone. In this setting, however, only a minimal efficacy in terms aggravation of side effects [34].

For a long time, clinicians and researchers have chased the 1. Role of metronomic chemotherapy in triple-negative disease e dream of improving OS in advanced breast cancer patients. different trials are on the way in this setting of patients. The

Table 4 Published trial of metronomic chemotherapy in association with targeted therapy.

Author and year Reference Phase Patients Type of treatment Setting Results

Orlando et al. (2006) [31] II N 22 oCTX 50 mg/die þ MTX 5 mg twice Pretreated ORR 18% weekly þ trastuzumab 6 mg/kg q21 CBR 46% Dellapasqua et al. (2008) [36] II N 46 oCTX 50 mg/die þ CAPE 1500 mg/ 1 line and pretreated ORR 48% die þ bevacizumab 10 mg/kg q14 patients CBR 68% TTP 42 ws García-Saenz et al. (2008) [37] III N 22 oCTX 50 mg/die þ MTX 1 mg/kg i.v. Pretreated patients ORR 31.8% q14 þ bevacizumab 10 mg/kg q14 CBR 63.6% OS 13.9 Saloustros et al. (2011) [38] II N 13 oVNR 50 mg thrice Pretreated patients ORR 7.7% weekly þ bevacizumab 10 mg/kg q14 Montagna et al. (2012) [39] II N 24 Oral CTX 50 mg/die þ CAPE 1500 mg/ 1st-line ORR 62% die þ bevacizumab 15 mg/kg CBR 75% q21 þ erlotinib 100 mg/die TTP 43 ws Mayer et al. (2012) [40] I N 20 oCTX 50 mg/die þ MTX 5 mg twice Pretreated ORR 10% weekly þ vandetanib 3 dose-escalation CBR 25% cohorts Kummar et al. (2015) [43] II N 39 oCTX 50 mg/die ± veliparib 60 mg/die Pretreated No benefit oCTX ¼ oral CTX; CAPE ¼ capecitabine; MTX ¼ methotrexate; ORR ¼ Overall Response Rate; CBR ¼ Clinical Benefit Rate(define as overall response rate þ stable disease 24 weeks); TTP ¼ Time To Progression; OS ¼ Overall Survival (Months); ws ¼ weeks.

VICTOR-2 trial is a Phase II study designed to evaluate the ef- References ficacy of a full-oral metronomic combination of VNR and CTX in both HR þve and triple negative breast cancer (TNBC) patients. [1] A. Hennigs, F. Riedel, A. Gondos, P. Sinn, P. Schirmacher, F. Marme, et al., Prognosis of breast cancer molecular subtypes in routine clinical care: a large Preliminary data suggest a slight activity in the TNBC subgroup, prospective cohort study, BMC Cancer 16 (2016) 734, http://dx.doi.org/ but no definitive results are available. Results of the VEX trial 10.1186/s12885-016-2766-3. (VNR þ CTX þ CAPE) in the TNBC population are still pending. [2] A. Gennari, M. Stockler, M. Puntoni, M. Sormani, O. Nanni, D. Amadori, et al., Duration of chemotherapy for metastatic breast cancer: a systematic review An international, randomized Phase II study (VICTOR-3) is and meta-analysis of randomized clinical trials, J. Clin. 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