Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

Cem Simsek; Ece Esin; Suayib Yalcin

doi:10.1155/2019/5483791

Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

Simsek, Cem;Esin, Ece;Yalcin, Suayib 2019-03-20 00:00:00 Hindawi Journal of Oncology Volume 2019, Article ID 5483791, 31 pages https://doi.org/10.1155/2019/5483791 Review Article Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience 1 2 3 Cem Simsek , Ece Esin , and Suayib Yalcin Department of Internal Medicine, Hacettepe University, Ankara, Turkey Department of Medical Oncology, A.Y. Ankara Training Hospital, Ankara, Turkey Department of Medical Oncology, Hacettepe University, Ankara, Turkey Correspondence should be addressed to Cem Simsek; cemsimsek111@gmail.com Received 27 April 2018; Revised 24 December 2018; Accepted 5 February 2019; Published 20 March 2019 Academic Editor: Akira Iyoda Copyright © 2019 Cem Simsek et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. eTh literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management. 1. Introduction (ASCO) Annual Meetings (2005 to 2017), and European Society for Medical Oncology (ESMO) Congresses (2005 to While our understanding about the biology of cancer and the 2017) were performed. The reviewing process was done in interaction of malignant cell with their microenvironment compliance with the Preferred Reporting Items for Systematic has improved, the research revealed that, apart from the Reviews and Meta-Analyses statement (PRISMA) [4]. Arti- molecule administered per se´, thedoseand schemeof admin- cles were also screened manually and related citations were istration are important for therapeutic efficacy [1]. The idea of included into the systematic review to increase the sensitivity. metronomic chemotherapy, the term rfi st used by Hanahan, Studies conducted in adult patients in English language, was rfi st revealed with this standpoint [2]. Preclinical and published in peer-reviewed journals as phase II or III clinical studies have been investigating the use of metronomic randomized controlled trials (RCTs) comparing continuous therapy as an augmentation or as a substitute for conventional chemotherapy to an intermittent strategy of chemotherapy, regimens [3]. However, there is still ongoing debate about with or without maintenance therapy including at least one the current role of metronomic regimens in the treatment of of the outcomes of interest, were included. The ASCO and cancer. The purpose of this systematic review is to reevaluate ESMO meeting abstracts as well as systematic reviews and the position of metronomic chemotherapy in modern cancer meta-analyses were also accepted for inclusion. management and make a projection about the future role in the treatment of malignancies. 3. Results 2. Materials and Methods .. Literature Search Results. Entire literature search re- Literature searches of PubMed (2005 to November 2017), trieved 5285 results. 1263 were regarded as potentially rele- ISIS (2005 to 2017), American Society of Clinical Oncology vant and fully reviewed. 266 of them were retained in the 2 Journal of Oncology NK Ｌ？Ａ Interactions Increased Decreased cytotoxic response immune tolerance MDSC ４ Decreased cancer stem cells CSC Decreased Increased Tumor endothelial progenitors endothelial toxicity microenvironment Endothelium Endothelial progenitor cells Decreased Increased anti-angiogenic cytokines angiogenic cytokines TSP-1 Figure 1: Proposed mechanisms for actions of metronomic chemotherapy regimens. study. Twelve abstracts from ASCO meeting abstracts were which is selectively sensitive to metronomic administration of certain types of drugs [7–12]. The endothelial progenitor retrieved and 4 of them were retained. Two ESMO meeting abstracts were also included. cell (EPC) is another major player in tumor vasculogenesis, which is another target of MTC [13, 14]. Apart from toxi- .. e Deﬁnition of Metronomic erapy. The term “metro- city to endothelial cells, MTC also induces antiangiogenic nomic chemotherapy” (MTC) is currently used for frequent protein Thrombospondin-1, inhibits angiogenic HIF-1 𝛼 ,and and regular administration of lower doses of chemotherapeu- decreases circulating VEGF levels [15–18]. tic drugs with minimal drug free time intervals, or simply Secondly, as the tumor transforms its surroundings to cre- “lower doses, longer times”, in order to establish a prolonged ate a viable microenvironment, it modifies the hosts’ immune and lower albeit an active range of plasma concentration system and establishes a conciliatory climate. Restoring and enabling a favorable side-eeff ct profile [5]. In the opposite enhancing the antitumor immune response is another aspect way, conventional regimens are used as maximum tolerated of metronomic regimens (Figure 1) [19]. Regulatory T cell (Treg) as one of the key players “locks down” cytotoxic dose (MTD), in which relatively high doses are given with 2- 3-week intervals [6]. response and thus maintains the tumor immune-tolerance [20]. MTC selectively depletes Treg and thus restores the .. e Mechanisms of Metronomic Action. The preliminary natural killer (NK) and T cell functions [21, 22]. Repression role of MTC is derived from its antiangiogenic mode of of the myeloid derived stem cell, another immune suppressor, was also demonstrated in clinical trials [23, 24]. Besides, MTC action (Figure 1). Thismodeofaction isshared bytwo classes of therapies, metronomic chemotherapy and anti- enhances the cytotoxic response by inducing the antigen VEGF monoclonal antibodies. However, they have several presenting dendritic cell maturation, augmenting its function and increasing tumorigenic antigen presentation that assem- dieff rent aspects. The antiangiogenic drugs directly impair the action of vascular endothelial growth factor (VEGF) and bles the immunogenic cancer death. Immunogenic cancer the metronomic chemotherapy disables the cells enrolled death is the process in which the dendritic cell recognizes the immune-adjuvant damage associated molecular patterns in the angiogenic mechanisms, suggesting that the tumoral endothelial cells could be a better target to overcome the (DAMPs) like HGMB-1, calreticulin, and ATP and comple- drug resistance (Tan et al.). Tumor endothelial cells (TEC) ments the cytotoxic cell death [25–33]. With its immune are distinguishable from typical endothelial cells as they have modulatory aspects, MTC was shown to increase potency of dieff rent characteristics of proliferation, migration, genetic other immune stimulatory modalities like vaccines [33, 34]. Another resident in the cancer microenvironment are outline, and discrete reactions to growth factors. TEC is a major target for the antiangiogenetic action of MTC, cancer stem cells, which were discovered to take part in Journal of Oncology 3 cellular dedieff rentiation, tumoral heterogeneity, invasion, In another study with metastatic hormone receptor positive metastasis, and drug resistance [35, 36]. MTC was shown patients, metronomic combination of CP with vinorelbine to decrease the number of triple positive CD133+/CD44+/ and capecitabine was evaluated for both na¨ıve and pretreated patients. Na¨ıve patients had a TTP of 25.1 months, while pre- CD24+ and CD44+ stem cells; however, its therapeutic impli- cation has not been well defined yet [37, 38]. Heterogeneity of treated patients’ median TTP was 11.2 months [57]. Zhang et cancer cells can stem from the positive selection of resistant al. evaluated addition of metronomic CP to docetaxel in non- triple-negative patients as a rfi st-line treatment compared to cancer clones aer ft chemotherapy. With this perspective, the “chemo-switch” protocol, studied by Pietars et al, to control docetaxel alone. There were no differences between groups the tumoral stromal cells was also suggested to surpass this with respect to the ORR, PFS, and OS; the authors concluded evolutionary process [39, 40]. that the combination was not effective in this setting [58]. Tumoral dormancy arises when proliferation of cancer CP and MTX have a diverse combination schedules with cells is countervailed by their apoptosis [41]. The major targeted agents. Bevacizumab and trastuzumab (in HER- factors hypothesized to maintain this balance are inu fl ence of 2 positive patients) with CM combination were tested by microenvironment, impediment vascularization (angiogenic Garcai-Sanex et al. in a population of taxane and anthra- dormancy), and immune surveillance [42]. There are plen- cycline refractory patients. An overall survival (OS) of tiful data that demonstrate that MTC particularly induces 13,6 months was achieved [59]. The highest clinical benefit angiogenic dormancy by upregulating and downregulating rate (68%) was reported with the combination of CP with antiangiogenic factors such as TSP-1 and proangiogenic bevacizumab and capecitabine in pretreated breast cancer factors such as VEGF, respectively [43]. patients. Vandetanib was also integrated with CM based Another demonstrated mechanism of action is selective metronomic therapy in a phase I dose escalation study. modulation of certain gene and protein functions in tumor Adverse events resulted in loss of chemotherapy adherence in cells, which can be used as a means of an antiproliferative 1/3 of patients yielding a 10% partial response of the remain- effect on tumor cells or to sensitize the tumor to certain ing 20 patients [60]. Perraud et al. experimented CM plus a chemotherapy actions [44]. selective cyclooxygenase-2 inhibitor celecoxib in 15 patients; With its aforementioned interaction of these factors, clinical benefit (CB) rate was 46.7% with no serious toxicities MTC has been deduced to have a role in induction of tumor [61]. Aurilio et al. used CM with fulvestrant, which resulted dormancy (Figure 1) [45]. Additionally, MTC has been shown with prolonged CB [62]. to decrease metastasis; however, the mechanism of this effect The aim of metronomic treatment is not solely palliative has not been established [46, 47]. treatment; neoadjuvant setting is an active area of investi- gation. Dellapasqua et al. reported the results of CP plus .. Clinical Experience in Breast Cancer. Breast cancer is one liposomal doxorubicin (PLD) as an initial therapy in locally of the broadest tracks for the “metronomic march.” The grow- advanced breast cancer patients; the rate of breast conserving ing number of patients with incurable metastatic disease who surgery was found to be 44.8%. Additionally, 62.1% of patients need palliative treatment, the cumulative toxicity of cytotoxic were reported to have a PR, importantly without grade 4 therapy, and lastly the economic burden led a concerted effort toxicity [63]. An immunogenic mechanism was also explored to find alternatives for conventional regimens including tax- with CM and an immunogenic vaccine; ORR was 23.8% [64]. anes, anthracyclines, pyrimidine antimetabolites, and tubulin A metronomic based chemohormonal scheme, CP plus inhibitors [48]. megestrol acetate was used in 29 patients, ORR was 31.0%, Cyclophosphamide (CP) and methotrexate (MTX) were and CBR was not reported [65]. An all oral scheme of CP on the top of the list to be tested in metronomic scheme in 2 2 (65 mg/m daily on days 1-14) plus capecitabine (1,000 mg/m breast cancer [49–51]. The earlier studies investigated the oral twice daily on days 1-14 repeating every 28 days) treatment metronomic use of CP and MTX together (CM) in pretreated was evaluated in 68 pretreated patients. After median follow- metastatic breast cancer patients (Table 1). Colleoni tested up of 26 months, a CB was 53%; grade 4 toxicity occurred the combination of CP 50 mg daily with MTX 2.5 mg twice in 5% of patients [66]. Another CP (33 mg/m twice daily, daily 2 days per week, obtaining objective response rate days 1-14) and capecitabine (capecitabine 828 mg/m twice (ORR) of 20.9% and a clinical benefit [18] (at least 24 weeks daily) treatment repeating every three weeks by Yoshimoto of objective response and stable disease) of 31.7% [49]. In et al. resulted in a clinical benefit of 57.8% without any grade the long-term follow-up, those patients yielded a 15.7% pro- 4toxicity [67]. longed clinical benefit (longer than 12 months) [52]. Miscoria As an extensively experienced drug for about 5 decades, 5- et al. and Gebbia et al. showed similar disease control and FU is still being used for breast cancer. With the discovery of tolerable toxicity profiles in trials tested for CP alone or capecitabine, an oral prodrug of 5-FU, thymidylate synthase in combination with MTX [53, 54]. Metronomic CP and inhibitors have been extensively researched for metronomic MTD liposomal doxorubicin combination were evaluated in metastatic patients; CB was 75% with a median OS of 6.4 use [68]. Oral capecitabine (828 mg/m twice daily) with months [55]. weekly paclitaxel was evaluated by Taguchi et al. PFS and OS A more recent study in pretreated metastatic breast were reported to be 8.3 months and 22.9 months, respectively cancer combination of metronomic CP with MTX was tested; [69]. First phase III study was published by Watanabe et medians of PFS and OS were 5 and 7 months, respectively. al. comparing the adjuvant activity of oral uracil-tegafur Out of 48 patients, 1 patient had complete response [56]. with conventional CMF (cyclophosphamide, methotrexate, 4 Journal of Oncology Th Table 1: Table showing the studies using metronomic regimens in breast cancer. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS CP 50 mg qd po Metastatic Colleoni, 2002 MTX 2.5 mg bd 2 days of 1 63 - 16% 3% 19.0% - 31.7% - - pretreated week po CP 50 mg qd po Metastatic, Colleoni, 2006 MTX 2.5 mg bd on 1st and 86 pretreated and -17% 3 20.9% - 41.5% - - 4th days po untreated CP 50 mg qd po Metastatic, MTX 2.5 mg bd on 1st and Colleoni, 2006 85 - 8% 3 11.8% - 41.5% - - pretreated or 4th days po untreated alidomide 200 mg qd po MTX 2.5 mg bid on 1st and Metastatic, 15.7% (12 Orlando, 2006 2nd or 4th days po 153 pretreated or -16% 5 - - -- months ) CP 50 mg qd po untreated CP 50 mg qd po MTX 2.5 mg bid days 1, 4 Metastatic, Orlando, 2006 22 46% 18% --- 6m q1w pretreated, HER2 + Trastuzumab 6 mg/kg q3w CP 50 mg qd po Metastatic Miscoria, 2012 MTX 2.5 mg bid days 1, 4 62 -- - - 2.6m 7.1m pretreated q1w CP 50 mg qd po 22 9% 3% 0% - 3.8 m ? - 12.8 m Metastatic vs. Vs. Vs. Vs. Vs. Vs. Vs. pretreated Gebbia, 2012 CP 50 mg qd po with MTX 39 12% 8% 0% 4.2 m 14 m hormone resistant 2.5 mg bid 2 days per week CP 50 mg qd po Metastatic, MTX 2.5 mg bid po two Wong, 2010 41 pretreated or 7% 2% 15% 24% 10 w 24% 48 w days q1w Prednisone 5 mg untreated qd CP 50 mg qd MTX 1 mg/kg iv q14d Metastatic, Garcia-Saenz, 32% Bevacizumab 10 mg/kg iv 22 pretreated, HER2 32% - - - 63.6% 7.5 m 13.6 m 2008 (24 w) q14d +/- Trastuzumab (in HER2 +) CP 50 mg qd MTX 2.5 mg qd 2 days per Metastatic, 15% Mayer, 2012 week 20 pretreated or 10% - ---- - (24 w) Vandetanib 100 mg / 200 untreated mg / 300 mg qd CP 50 mg qd po 3% 24 w 12 m Perroud, 2013 155 !! 1patient - - 14 w 46.7% Celecoxib 200 mg bid po (24 w) (40%) (46.7%) CP 50 mg qd po MTX 2.5 mg bd on 1st and Metastatic, Aurilio, 2012 32 !! !! !! !! !! 56% - - 4th days per week po pretreated, HR + Fulvestrant 250 mg im q28d Journal of Oncology 5 Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS CP 50 mg qd po Non-metastatic, 42 w Crivellari, 2013 MTX 2.5 mg bd on 1st and 36 >65 y, untreatable, - Closedearly - --- - (81%) 4th days per week po HR- CP 50 mg qd po Non-metastatic, Dellapasque, Liposomal Doxorubicin 29 untreatable, 34.5% 62.1% - ---- - 20mg/m2 preoperatively CP 50 mg qd po Soriano, 2011 MTX 2.5 mg bid 21 Metastatic, 4% - - - 9.8 m - - 12.9 m 1E10-Alum CP 50 mg qd po Dellapasque, Capecitabine 500 mg tid po 46 Metastatic 17% 46% 2% 42 w 68% - - Bevacizumab 10 mg/kg q2w CP 50 mg day 1-21 q28d po Metastatic, Licchetta, 2010 Megestrol acetate 80 mg bid 29 pretreated, 31% 7.4 m 13.4 m po HR +/-, HER2 +/- CP 65 mg /m2 iv days 1-14 q3w Metastatic, Wang, 2012 68 - - - 30.3% 5.2 m 53.0% - 16.9 m Capecitabine 1000 mg/m2 pretreated bid days 1-14 q3w CP 33 mg/m2 bid days 1-14 q3w Metastatic, HER2- 1y (86%) Yoshimoto, 2012 51 13% - - 44.4% - - 10.7/13.2 Capecitabine 828 mg/m2 ER-/ER+ 2y (71%) bid days 1-14 q3w 5-FU 1 mg/m2 days 1-28 q35d po 24% Smith, 2000 29 Metastatic 55% Eniluracil 10 mg/m2 days (3 m) 1-28 q35d po Capecitabine 825 mg/m2 Metastatic, 24% Taguchi, 2010 33 -- 18% - - 6.9m 24.8m bid days 1-21 q 28d untreated recurrent (> 6m) 2 7 Metastatic, (pretreated with (pretreated Fedele, 2012 Capecitabine 1500 mg qd 58 7m 62% 17m pretreated Standard with Standard Capecitabine) Capecitabine) T0, high risk, (RFS) 5 y Watanabe, 2009 UFT 300 mg tid --- - - - 5y(96.2 %) adjuvant (87.8 %) 6 Journal of Oncology Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Capecitabine 500 mg tid Metastatic, Cazzaniga, 2014 Vinorelbine 20-30-40 31 --- - - 58.1% - - pretreated, mg/tot Capecitabine 1250 mg/m2 qd Metastatic, 8% Young, 2012 38 34% - - 3.6 m 42% - - Docetaxel 15mg/m2 pretreated (6 m) Celecoxib 200 mg bid Capecitabine 1500/2000 mg daily in divided doses Schwartzberg, Metastatic, HR+, Fulvestrant 500 mg day 1, 41 - - - - 26.94 m - 14.98 m 28.65 m 2014 HER2- 250 mg day 1, 15, 28 followed by 250 mg q28d Irinotecan 60 mg/m2 days 1, 8, 15 q4w Metastatic, Otsuka, 2015 34 3% 44% - - - TS-1 80 mg/m2 days 3-7, recurrent 10-14, 17-21 q4w Operated, neoadjuvant -DFS- 44.34 m Alagizy, 2015 Capecitabine 500 mg bid po 41 FEC100+, +/- --- - - - 42.4 m (estimated) Postoperative RT, HR-, HER2- Temozolomide with radiotherapy and following 4w Temozolomide 75 mg/m2 Untreated brain Addeo, 2012 36 44% 8% 52% - - 8 m 11 m days 1-21 q4w metastasis, Vinorelbine 70 mg/m2 1,3,5 weekly for 3 w q4w, max 12 cycles Vinorelbine 70 mg/m2 1,3,5 Addeo, 2013 weekly for 3 w q4w, max 12 34 Metastatic - 32% 6% --- 7.7m 15.9m cycles Vinorelbine 50 mg 3 times per week Metastatic, Saloustros, 2011 13 46% 8% Closedearly ---- - Bevacizumab 10 mg/kg 2 pretreated times per week q28d De Iuliis, 2015 Vinorelbine 30 mg q2d 32 Metastatic - - - - 50% - - Journal of Oncology 7 Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Letrozole 2.5 mg qd 57 71.9% Letrozole 2.5 mg qd and CP Bottini, 2006 HR+, - - - 57 87.7% 50 mg qd 6 months NP-Liposomal Doxorubicin 30 mg iv 5-FU 500 mg iv Metastatic, Manso, 2013 38 27% - - 281 d 8.4 m 21 m Vincristine 0.25 mg iv pretreated CP 50 mg qd po Prednisone 20 mg Paclitaxel 80 mg/m2 days 1. 8. 15, 4 cycles Cyclophosphamide 50 mg qd po 4 cycles Capecitabine 1200 mg/m2 qd 4 cycles HR-, ER-, 31 Masuda, 2014 33 -54.5% - - - -- 5-FU 500 mg/m2 q3w, 4 preoperative (93.9%) cycles Epirubicin 100 mg/m2 q3w, 4cycles CP 500 mg/m2 q3w, 4 cycles Capecitabine 500 mg tid Metastatic, CP 50 mg qd 21% Montagna, 2012 24 untreated, HR -, 58% 4% - - 75% 43 w - Bevacizumab 15mg/kg q3w (9 w) HER2- Erlotinib 100 mg qd Metastatic, Munzone, 2010 P Liposomal-Doxorubicin 45 untreated, 39% 18% -- - 45% -- pretreated CP 50 mg qd po Metastatic, Mutlu, 2015 Etoposide 50 mg bid 2 days - - - - 7.03 m 32.5 m pretreated per week Capecitabine 828 mg/m2 bid po days 1-21 q28d Metastatic, Taguchi, 2013 43 46.5% 8.3 m 22.9 m Paclitaxel 80 mg/m2 days 1, pretreated 8, 15 q28d Capecitabine 1000 m2 bid Metastatic, Ambros, 2014 po days 1-14 q21d 86 24.3% 7 m 55.8% 24.0 m pretreated, HER2- Metastatic, Etoposide 50 mg/m2 po Neskovic, 1996 18 untreated, 28% 6% days 1-14 q 28d pretreated Etoposide 60 mg/m2 po Metastatic, Yuan, 2015 75 39% 9% 4.5 m days 1-10 q 21d pretreated 8 Journal of Oncology and uo fl rouracil) in node negative high-risk breast cancer Antiangiogenic action of microtubule inhibitors is impor- patients. With 733 patients and 6.2 years of median follow- tant as a means to metronomic therapy. Oral form of vinorel- up, relapse free survival and overall survival rates of two com- bine has been experimented in 34 elderly metastatic breast cancer patients; an OR of 38% was reported [84]. The same binations were similar, and uracil-tegafur group expressed a better quality of life [70]. Capecitabine was also combined author used temozolomide during whole-brain radiotherapy with an oral tubulin inhibitor, vinorelbine. Cazzaniga et and metronomic vinorelbine aer ft wards in 36 patients with cerebral metastasis; OR was 52%. [85]. Vinorelbine was added al. used the metronomic combination of vinorelbine with capecitabine with CB of 58% in 34 patients [71–73]. Same to bevacizumab in a trial by Saloustras et al. but study was team conducted another study using the same combina- closed prematurely due to lack of efficacy (OR was 7.7%) [86]. tion; CB was 45.7% and 51.1% in rfi st-line and second-line Another study with an alternative on and off metronomic therapies, respectively. [74] Young et al. investigated the regimen of vinorelbine was dosed every other day for 4 years with a cumulative dose of 30 mgs; a 50% CB was reported, capecitabine with weekly docetaxel to low dose of taxane therapy to induce thymidine phosphorylase expression with without grade 3 or 4 toxicity [87]. addition of daily celecoxib; a 42% of CB was observed with Oral etoposide is a well-tolerated and effective drug for metastatic breast cancer. Two decades ago, Calvert et al. used median time of disease progression (TTP) of 3.6 months [75]. In hormone receptor positive tumors, conventional scheme oral etoposide of 50 mg/m2 for rfi st 14 days of 28-day cycles of fulvestrant was added to capecitabine in 41 patients; CB in 38 pretreated metastatic breast cancer patients. Eight of the patients had a partial response with median TTP of 16 weeks of 58.1% was obtained with 14.9 months’ median PFS [76]. A newer study by Otsuka et al. demonstrated an OR rate of [88]. Bontenbal also used etoposide with 50 mg/m2 orally 47% with metronomic tegafur-gimeracil-oteracil and MTD for rfi st 21 days of 28 days in 27 pretreated metastatic breast irinotecan [77]. cancer patients, achieving a CBR of 43% [89]. Another two- Triple negative breast cancer (TNBC) is another area phase II trial used the same scheme in 43 and 18 pretreated metastatic breast cancer patients; ORR of 35% and PR of 21% where we have a significant shortage of viable treatment strategies; metronomic chemotherapy can be employed in were reported, respectively [90, 91]. The same regimen was multiple settings. An elegant preclinical study demonstrated used as a rst- fi line drug in metastatic patients; one CR and vfi e PR were obtained [92]. In a recent multicenter phase II trial, the action of metronomic chemotherapy in TNBC. In this study, metronomic topotecan was combined with pazopanib oral etoposide of 60 mg/m2 in rfi st 10 days of 21-day cycles was in an orthotopic metastatic breast cancer model to eval- used in 75 patients. A CB of 21.3% was achieved with median uate its potential mechanism of actions and the thera- PFS of 4.5 months [93]. peutic efficacy. The combination was shown to modulate Metastatic breast cancer is a diverse and heterogenous angiogenesis, drug resistance, apoptosis, and proliferation disease with specific targets in which stepwise and sequen- and subsequently prolonged the survival [78]. For neoadju- tial treatment can add survival benefit at the end. Hence, vant regimens, metronomic CP was recruited with weekly metronomic treatments are well known and extensively studied for these types of tumors. In metastatic setting, for paclitaxel aer ft epidoxorubicin-cisplatin-uo fl rouracil (ECF). Pathological response rates were evaluated; posttreatment hormone-receptor expressing tumor types, weekly paclitaxel, Ki-67 was found to be decreased by 41% and 91% of the oral vinorelbine, capecitabine, and ixabepilone have proven efficacy with different side effect profiles. In triple negative patients had complete pathological response [79]. Metro- nomic chemotherapy has also been evaluated for first-line tumor type, capecitabine is now a standard approach aer ft therapy in metastatic TNBC; a multicenter phase III study neoadjuvant setting for patients with residual disease. In compared the toxicity and efficacy of bevacizumab combined heavily pretreated patients, for palliative purpose, oral CYP with metronomic CP versus bevacizumab with paclitaxel; and etoposide were used either as single agents or alterna- there were no differences in ORR or PFS. A novel poly-ADP- tively. ribose-polymerase inhibitor drug veliparib was evaluated in BRCA associated metastatic pretreated TNBC; objective .. Clinical Experience in Castration-Resistant Prostate Can- response occurred in 43% of BRCA associated patients and cer. Castration-resistant prostate cancer (CRPC) is an area 11% of BRCA negative/unknown patients [80]. Metronomic in which there are significant gaps in therapy with cur- chemotherapy was also evaluated as maintenance therapy in rent strategies; for now progressive disease is inescapable TNBC patients. In a prospective controlled study with 158 eventually. But frailty of patients makes the management of stage II-III TNBC patients, group treated with additional this disease more difficult. There has been a comprehensive maintenance metronomic after adjuvant FEC-100 and doc- research for treatment CRPC. Hence, the research continues etaxel was compared to control group without maintenance for possible treatment options for docetaxel-resistant tumors therapy; metronomic group’s DFS and OS were 28 and 37 (i.e., androgen synthesis inhibitors, specific or nonspecific months, respectively, compared to control groups’ DFS of 24 immunotherapy, mitoxantrone, and targeted therapy), and months and OS of 29 months [81]. For advanced pretreated when the frailty of the patients is taken into consideration, TNBC, Viale et al. tested the combination of metronomic CP metronomic therapies were repeatedly tested (Table 2) [94]. with cisplatin yielding a 23.3% clinical benefit at 6 months For CRPC, metronomic CP was an early drug to be after treatment [82]. A different paper evaluated postadjuvant tested and, combined or alone, is still a favored choice. A (FEC100 + radiotherapy) metronomic capecitabine of 6 study investigating CP in CRPC was by Raghavan in 1993; months; mean disease free survival was 42.4 months [83]. of 30 HRPC patients, 18 had a CB and improvement of Journal of Oncology 9 Table 2: Table showing the studies using metronomic regimens in prostate cancer. Duration of Author Treatment N Patient type PSA PR TTP PFS OS Response CP 2 mg/kg qd days 1-14 q28 d Hormone Bracarda, 2000 32 43.7% - - - - - Estramustine 10 mg/kg/day refractory days 1-14 q28d Etoposide 50mg/m2 qd days 1-21 q28d Hormone Pienta, 2001 55 22% Estramustine 15 mg/kg qd refractory days 1-21 q28d CP 100 mg qd Hormone Nishimura, 2001 UFT 400 mg qd 21 57% 7 m - - - - refractory Estramustine 560 mg qd Vinorelbine 25 mg/m2 iv Hormone Robles, 2003 q7d 12 weeks than q14d 14 refractory, 36% Prednisone 10 mg qd po metastatic CP 50 mg qd Hormone Glode, 2003 34 58% 8 m - - - - Dexamethasone 1m g qd refractory CP 100 mg days 1-20 q30d Hellerstedt, Hormone Prednisone 10 mg qd 36 42% 4.5 m - - - 16.4 m 2003 refractory DES 1 mg qd Hormone Lord, 2007 CP 50 mg qd 58 34.5% 7.5 m - - - - refractory Venkirataman, Dexamethasone 0.5 mg qd 102 Castration resistant 49% CP 500 mg/ m bolus than 50 mg qd po Hormone Fontana, 2009 Celecoxib 200 mg bid 28 32% - - - 3 m 21 m refractory Dexamethasone 1 mg/day po CP 50 mg qd Hormone Ladoire, 2010 23 26% - - - 6 m 11 m Prednisolone 10 mg qd refractory CP 50 mg qd Hormone Nelius, 2010 Dexamethasone 1 mg/day 17 23.5% - - - - 24 m refractory po CP 50 mg qd MTX 2.4 mg po two times a Castration Gebbia, 2011 58 25% 24% 28% - - - week resistant, LHRH analogue CP 100 mg qd Hormone Hatano, 2011 UFT 400 mg qd 57 63% - - 13.3 m - - refractory Dexamethasone 10 mg/day 10 Journal of Oncology Th Table 2: Continued. Duration of Author Treatment N Patient type PSA PR TTP PFS OS Response CP 50 mg bid weeks 1,3,5 Ketoconazole 200 mg tid weeks 1,3,5 Castration Jellvert, 2011 Etoposide 50 mg bid weeks 17 59% - - - - - resistant, 2,4,6 Estramustine 140 mg bid weeks 2,4,6 CP 50 mg qd MTX 2.5 mg bid two times Hormone Khan, 2011 69 N/A 57 days a week refractory Celecoxib 400 mg bid CP 50 mg qd Meng, 2012 Capecitabine 1000 mg bid Castration 28 35.7% - - - 4.7 m 19.5 m alidomide 100 mg qd resistant, Prednisone 5 mg bid CP 50 mg qd 634CC 2.2 m Castration Orlandi, 2013 Cetuximab 200 mg bid po 43 32% - - - 634CG/GG - resistant, Dexamethasone 1 mg qd po 6.25 m CP 50 mg qd po Docetaxel 06 mg/ m in q21d Castration Derosa, 2014 41 82% - - - - - Prednisone 10 mg qd from resistant, untreated day 2 Celecoxib 400 mg qd Castration CP 50 mg qd po Yashi, 2014 24 33.3% - - - 5.0 m 19.0 m resistant, Dexamethasone 1 mg qd po metastatic Etoposide 25mg/m2 bid days 1-21, q28d Castration 39 41% 5.9 m Zhu, 2014 Prednisone 5 mg bid days resistant, 1-21, q28d Castration Barroso-Sousa, CP 50 mg qd or CP 150 mg resistant, 2015 days 1-14, q21d 40 20% - - - - - pretreated, Prednisone 10 mg po metastatic CP 50 mg qd po Castration Wang, 2015 Lenalidomide 25 mg qd 6 resistant, 31.7% - - - - - days 1-21 q28d metastatic Abiraterone 25 mg qd po Petrioli, 2015 26 Castration resistant 69.2% 6.4 m 14.3 m Prednisone 5 mg qd po Journal of Oncology 11 the symptoms [95]. After a decade, Nicolini et al. used CP the progression rate was 65.7% and there were no objective in eight metastatic HRPC patients; a CB of 62.5% and a responses [113]. In a phase I trial, adding thalidomide to CP, greater than 50% PSA response in 2 patients were reported 10 out of 13 patients (76.9%) had a progression of PSA> 25%, [96]. Of 80 other patients in whom CP was tested, rate of with 2 (15%) having a>50 reduction [114]. CP, corticosteroid, response was 34.5% including both objective and prostate capecitabine, and thalidomide were evaluated in 8 patients for specific antigen response [97]. Glode et al. tested CP with a median time of 6 months; overall survival was 19.5 months corticosteroids, as both drugs have been used for CRPC and [115]. Another study by Bracarda et al. used estramustine and both were shown to have antiangiogenic properties. Of 34 CP in docetaxel naive patients; the 50% reduction was seen patients, 26% experienced disease progression and 6% were in 14 (43.7%) of 32 patients [116]. Nishimura et al. added found to have a <50% decrease in PSA; 29% of patients tegafur to the estramustine and CP combination; 12 (57.1%) were found to have a greater than or equal to 80% and of 21 patients showed a PSA decline of 50% or greater [117]. 39% were found to have a 50-79% reduction in PSA [98]. Hatano et al. retrospectively evaluated oral UFT and CP Another study with 18 patients and a shorter follow-up of with dexamethasone in 57 patients. 63% of PSA response 12 weeks reported a decrease in PSA of greater than 50% in was achieved; in the PSA responder group, median time to 23.5% and stable disease corresponding to a PSA response progression was 13.3 months [118]. Derosa et al. combined of less than 50% was seen in 29% of the patients [99]. In a first- and second-line drugs in metastatic chemotherapy- retrospective analysis of 40 patients, PSA response rate was naive CRPC patients and used CP and prednisone together achieved in 20.0% of patients [100]. A retrospective analysis with docetaxel; of 41 patients, 87% were free of progression of CP plus prednisolone regimen reported a more than 50% at 6 months, and a decrease in PSA 50% was observed PSA decrease in 26%of patients [101]. Additionally, in a study in 82%. No grade 4 toxicities were reported, with grade 3 of 24 patients, the median PSA progression-free survival was toxicities being neutropenia (5%), thrombocytopenia, diar- 5.0 months and a PSA decrease of 50% was observed in 8 rhea, and stomatitis (2.5%) [119]. Another modiefi d scheme patients (33.3%) [102]. In a multicenter retrospective study consisting of ketoconazole in combination with estramustine, with 48 patients pretreated with docetaxel and another drug, cyclophosphamide, or etoposide administered on alternate ecffi acy of metronomic CPA was retrospectively evaluated. weeks, suggested by Jellvert et al, achieved a 59% decrease 14% of patients had a biochemical response (PSA decrease in PSA>50% [120]. In another multicenter trial with oral greater than 50%); median PFS and OS were reported as etoposide and estramustine 15 mg/kg daily in 55 patients, 22% 3,5 and 6,9 months, respectively [103]. Another study eval- of PSA response was reported [121]. Oral dexamethasone uating biochemical response for 18 patients with median 2 0.5 mg daily alone was evaluated in 102 castration-resistant months of metronomic CPA exposure reported a biochemical patients with 49% achieving a PSA response [122]. Daily oral response of 44% [104]. Fea et al. evaluated the efficacy of CP 100mg with 50mg etoposide (14/21 days) was evaluated in metronomic CPA with ongoing LHRH agonist therapy until 20 hormone refractory patients; an OR of 35% was reported disease progression or toxicity in pretreated patients; PSA [123]. In a retrospective evaluation of oral dexamethasone response rate was 16% without any grade 3 or 4 toxicities regimen in 99 patients, 40.4% of PSA response was found [105]. [124]. Intravenous vinorelbine 25 mg/m weekly for first 12 Thereareother possibleeeff ctive combinations of weeks and biweekly aer ft wards was used with low dose oral cyclophosphamide in pretreated CRPC. In a phase II trial prednisone in 14 patients, with a PSA response in 29% [125]. combining DES with CP and corticosteroids, with reference Oral metronomic vinorelbine was also evaluated with serum to prior shown success of DES in hormone refractory disease, markers of tumor response and activity. PSA response was 15 (42%) of 36 patients had a>50% PSA response and the 61%, and a decrease in VEGF and TSP-1 was observed in overall median survival was 16.4 months [106]. Celecoxib was responders [126]. Vinorelbine alone was compared to weekly also used with CP as it has been shown to have antiangiogenic docetaxel in frail CRPC patients for efficacy, tolerability, action [107]. In consecutive elderly 29 patients, 13 (45%) had toxicity, and compliance. Efficacy and tolerability of the a confirmed PSA decrease of 50% or greater [108]. Another two regimens were found to be similar in elderly unfit study combining celecoxib with CP, by Orlandi et al., 14 (32%) patients [127]. In another phase I/II trial, CP 50 mg daily with showed a PSA>50% decrease; the study also investigated the lenalidomide 25 mg daily in rs fi t 21 days repeating every four pharmacogenetics of VEGF-A and showed that a genotype of weeks was tried in 6 patients with PSA reduction in 31.7%, VEGF-A has impacts on FPS. In 28 advanced CRPC patients, with improved markers of neovascularization [128]. Oral Fontana et al. studied CP 50 mg daily with Celecoxib 200 mg etoposide 25 mg twice daily with oral prednisone twice daily twice daily and dexamethasone 1 mg daily. 32% of the patients was administered for 21 of 28-day cycles; 41% of biochemical had a PSA response. Median OS and PFS were 3 months response was achieved with a PFS of 5.9 months[129]. and 21 months, respectively [109]. In another phase II trial, CP 50 mg daily was combined with MTX 2.4 mg twice a Onestudy hasevaluated themetronomictherapy in week. PSA response was observed in 25% of the patients nonmetastatic prostate cancer. In this prospective single- [110, 111]. Dexamethasone combination with celecoxib and arm study, metronomic CPA was administered for 6 months metronomic CPA was tested by another group for pretreated to patients with only biochemical recurrence after curative CRPC; reported PSA response was 39% with a median OS local therapy before androgen deprivation. 38 patients were of 13,3 months for 22 patients [112]. CP and MTX joined enrolled; 37% of patients had a PSA stabilization, and 58% with celecoxib were evaluated in another phase II trial, but had PSA progression [130]. 12 Journal of Oncology In castration-resistant prostate cancer, with the invention having a partial response of 11 months [136]. In another of new class antitestosterone drugs (enzalutamide and abi- multicenter retrospective study using the same dose of raterone), the role for CYP, etoposide, estramustine, and keto- oral etoposide for 14 days of 21-day cycles regimen in 51 conazole diminished. On the other hand, in a limited number platinum-resistant patients, PFS of 3.9 months and OS of of patients who were progressed on standard approaches and 16.4 months were achieved [137]. As cyclophosphamide is still in need for treatment, oral etoposide and ketoconazole a part of conventional treatment of ovarian cancer and it may have a role. Of note, dexamethasone may have both is favorable for metronomic regimen, Samaritani et al. tried tumor-static effects and antiangiogenic effect in addition to metronomic cyclophosphamide in a 17-year-old female with blocking androgen synthesis for CRPC patients. advanced ovarian cancer with PFS of 65 months. [138] Another study experiencing oral CP alone as salvage ther- . . Clinical Experience in Ovarian Cancer. High recurrence apy in platinum-sensitive heterogeneous patients reported rates even after achievement of complete response to standard median PFS for 4 months and median OS of 13 months [139]. surgical debulking and platinum-based combination therapy Metronomic doses of CPA plus temozolomide were studied make ovarian cancer a challenging entity for clinicians; thus in 55 platinum-refractory patients; an ORR of 44.4% was newer therapeutic approaches have been under investigation. achieved with a median PFS of 5.9 months and a median OS As angiogenesis plays a prominent role in pathogenesis of 10.1 months [140]. Again in platinum-refractory patients, of ovarian cancer, metronomic chemotherapy with other CPA was combined with antiangiogenic pazopanib with antiangiogenetic agents has been a distinguished area for metronomic dosing scheme with median PFS and OS being research [131] for both first-line, maintenance and salvage 8,3 and 24.9 months, respectively [141]. CP and bevacizumab were also tested for pretreated therapy (Table 3). Bevacizumab as an antiangiogenic molecule and its platinum-resistant ovarian cancer. Two studies by Sanches synergism with metronomic chemotherapy were tested for et al. and Garcia et al. combined CP 50 mg/day with beva- ovarian cancer [132]. Bevacizumab was incorporated into cizumab 10 mg/kg intravenously every 2 weeks; the PFS was standard first-line therapy in a phase III study by Burger et al. 4.5 months and 7 months and OS was 7 and 17 months, fortifying the position of bevacizumab, comparing patients respectively [142, 143]. Barber et al. also reported an OS of having carboplatin paclitaxel in three groups. The First one 20 months in 66 patients [144]. Jurado et al. retrospectively was without bevacizumab and the second and third groups evaluated CP and bevacizumab; median progression time was 5.5 months [145]. In another study using the same combi- were with initial and throughout bevacizumab, respectively. It was reported that bevacizumab prolonged the median PFS nation with identical dosage in heavily pretreated patients by about 4 months with a median time of 14.1 months versus with a median previous chemotherapy number of 8, a total response of 53.3% was reported [146]. Bevacizumab was also control groups’ 10.3 months [133]. Two studies evaluated metronomic regimens for mainte- integrated with other conventional regimens. Topotecan in nance therapy. In a nonrandomized study enrolling ECOG cycles of 1, 8, and 15 days of 28-day administrations with 0-1 patients with complete response to standard rfi st-line biweekly bevacizumab resulted in PFS of 7.8 months and OS therapy, metronomic regimen of CPA and MTX was com- of 16.6 months [147]. Pujade-Lauraine et al. experimented pared to observation alone. Maintenance arm had a longer bevacizumab with three different combinations: pegylated PFS of 18 months versus 15 months of observation arm liposomal doxorubicin, weekly paclitaxel, and topotecan; the without any grade 3 or 4 toxicity. Another retrospective median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab [148]. Weekly administered study evaluated a group of patients who were administered a metronomic regimen for neoadjuvant therapy and also ixabepilone was retrospectively evaluated with or without 6 months as a maintenance after adjuvant standard ther- bevacizumab for 24 uterine and 36 ovarian, primary peri- toneal and fallopian tube cancers. For uterine cancers, addi- apy. Metronomic neoadjuvant plus metronomic maintenance group was reported to have a prolonged DFS of 3 months tion of bevacizumab significantly increased both PFS (3.0 without increased toxicity prole fi [134]. months versus 6.5 months) and OS (4.2 months versus 9.6 Neoadjuvant chemotherapy is standard before maxi- months); it was reported that similar results were estimated mal debulking surgery; nevertheless there is an important for ovarian cancer [149]. A meta-analysis evaluating the fraction of patient who are not suitable for eeff ctive but role of bevacizumab concluded that there is an advantage highly toxic platinum-based regimens. Dessai et al. used of PFS and OS when chemotherapy was combined with paclitaxel and carboplatin with an alternative weekly metro- bevacizumab and increased risk of non-CNS bleeding, hyper- tension, gastrointestinal perforation, thromboembolism, and nomic scheme (80 mg/m2 / AUC-2) in patients regarded as unsuitable for standard 3-week regimen. The response proteinuria [150]. The tyrosine kinase inhibitor sorafenib was to the neoadjuvant chemotherapy was 100%; two grade 3-4 also investigated for metronomic efficacy with topotecan; grade 3-4 toxicities of leukopenia/neutropenia (23%), throm- toxicities were reported [135]. Although response rates of ovarian cancer to plat- bocytopenia (17%), and anemia (10%) had occurred. Of 16 inum regimens are considerably high, platinum resistance patients, PR was reported in 5 (16.7%) and SD was reported is inevitable; thus developing treatment strategies in case in 14 (46.7%) [151]. Celecoxib was joined with carboplatin by of platinum-refractoriness is an essential area for research. Legge et al. Median PFS and OS were 5 and 13 months, respec- Oral etoposide of 50 mg/m tively [152]. A cohort comparing metronomic thalidomide for twenty days repeated every 28 days was used in 18 pretreated patients with 1 patient versus tamoxifen in only biochemically recurrent ovarian Journal of Oncology 13 ft Th Th Th Table 3: Table showing the studies using metronomic regimens in ovarian cancer. Bev, Bevacizumab; CP, Cyclophosphamide. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Bev 10 mg/kg q14d Pretreated, 3 6 2 Chura, 2007 15 53% - - - - CP 50 mg qd po recurrent (20%) (40%) (13.3%) Standard regimens 18 60% 6.7% 3.7 m Pretreated, ovarian or Gordinier, 2007 alidomide 200 mg qd 18 53.8% 5% - --- 3.8 m - primary peritoneal None 4 ? ? ? Topotecan 1.25 mg/ m days 30 - 17% 30% 47% - - - 19 m 1-5, q21d alidomide 200 mg qd Recurrent, epithelial, increasing to maximum Downs, 2008 Vs. Vs. Vs. Vs. Vs. platinum refractory tolerated Vs. Topotecan 1.25 mg/ m 39 - 3% 18% 21% - - - 15 m days 1-5, q21d Bev 10 mg/kg q14d Recurrent, 17 6m Garcia, 2008 17 - -- 7.2m - 16.9 m CP 50 mg qd po platinum refractory (24%) (56%) Bev 10 mg/kg q14d Recurrent, platinum 2 2 2 4 6m Jurado, 2008 9 5.5 m - - CP 50 mg qd po refractory (22%) (22%) (22%) (44%) (33%) alidomide 200 mg qd increasing to maximum tolerated or 400 mg Stage III/IV, disease Hurteau, 2010 138 Closed early, interim analysis showed thalidomide was inferior to tamoxifen vs free aer 1st line, Tamoxifen 20 mg qd po for 1year 14 Journal of Oncology Table 3: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Sanchez-Munoz, Bev 10 mg/kg q14d 12 3 38 Pretreated, recurrent (8.1%) --- 4.5m 10.7m 2010 CP 50 mg qd po (32.4%) (8.1%) (6 w) Carboplatin AUC5, q28d Legge, 2011 45 Pretreated, recurrent 10 3 29% - - 5 m 13 m Celecoxib 400 mg qd Bev 10 mg/kg days 1, 13 Platinum resistant, q28d 14 10 McGonigle, 2011 40 ovarian / peritoneal / - --- 7.8m 16.6m Topotecan 4 mg/ m days 1, (35%) (25%) fallopian 8, 15 q28d Sorafenib 400 mg qd Ramasubbaiah, Platinum 14 5 Topotecan 3.5 mg/ m days 14 - --- - - 2011 resistant, (46.7%) (16.7%) 1, 8, 15 q28d Etoposide 50 mg qd po Kucukoner, 2012 51 Platinum resistant, 25.5% 17.6% 3.9 m 16.4 m days 1-14 q28d Bev 10 mg/kg q14d 15 21 7 5m 20 m Barber, 2013 66 Pretreated, recurrent 42.4% CP 50 mg qd po (22.7%) (31.8%) (10.6%) responders) responders) Platinum 11 Ferrandina, 2014 CP 50 mg qd po 54 - -20.4% 4m 13m resistant/sensitive (20.4%) CP 50 mg qd po Bhattacharyya, TMZ 20 mg bid days 1-14, 55 Platinum resistant, 24 N/A 44% 5.9 m 10.1 m q21d Ixabepilone 16-20 mg/ m 8/3 - - - 41.7% - - 3.0 m/- - days 1, 8, 15, q28d Roque, 2015 Uterine/Ovarian- Vs 9.6 m fallopian-peritoneal Ixabepilone 16-20 mg/ m days 1, 8, 15, q28d 16/33 --- --- 6.5m/- - Bev 10 mg/kg q14d Journal of Oncology 15 cancer wasclosed asinterim analysis and itwas shownthat compared metronomic and standard TMZ regimens; thalidomide was not more effective in reducing the recur- although 6-month OS did not have a significant difference, rence rate relative to tamoxifen and higher toxicity rate [153]. PFS was detected to be significantly higher in metronomic Another study evaluating metronomic thalidomide versus schedules[164]. TMZ wasalsocombined withother single-agent chemotherapy in recurrent ovarian cancer and antiangiogenic agents like COX-2 inhibitors; Tuettenberg primary peritoneal cancer showed no significant difference et al. showed that the metronomic TMZ and rofecoxib [154]. Thalidomide with standard topotecan resulted in 2 combination showed antiangiogenic action [165]. A similar months’ increase in PFS in a different phase II trial [155]. study with TMZ and celecoxib in refractory GBM patients Noronha et al. evaluated weekly paclitaxel 80 of mg/m2 in resulted in a PFS of 6 months in 43% of patients [166]. platinum refractory and platinum ineligible 37 non-small cell Another current approach for treatment of GBM with lung cancer patients; the response rate was reported as 35%, bevacizumab was also evaluated by Reardon et al. using bevacizumab with metronomic etoposide for recurrent with median PFS of 4 months [156]. Temozolomide twice daily for fourteen days repeated every three weeks was com- GBM; authors reported similar activity but increased bined with daily CP in 54 patients. There were grade 3 and toxicity [167]. Same authors also tried metronomic etoposide grade 4 toxicities which were mostly hematologic. Overall or temozolomide administered with bevacizumab for response was 44.4%; median PFS was 5.9 months [140]. bevacizumab recurrent GBM but the trial was closed at In conclusion, metastatic epithelial ovarian cancer is a thefirstinterim dueto lackof activity [168]. Twenty-three long-standing malignancy with a need for further treatment high-grade glioma patients were administered bevacizumab options. In heavily pretreated patients, oral metronomic (1 mg/kg every three weeks) and TMZ (50 mg/m2 daily) until CYP has a role. Topotecan is also an effective agent for clinical or radiological progression; 6 months of PFS were platinum-resistant patients as a single agent. Bevacizumab is reported to be lower with respect to other bevacizumab- an approved agent in both platinum-sensitive relapsed and including regimens [169]. With respect to the results with bevacizumab, Zustovich et al. tried another tyrosine kinase resistant ovarian cancer patients in induction and mainte- nance period. There is a growing interest for further studies inhibitor, sorafenib, twice daily with metronomic TMZ; in metronomic, angiogenesis-targeted treatment approaches 6-month PFS was 26%, and median OS was 7.4 months [170]. in this tumor type. In a highly aggressive and resistant tumor type, in glial tumors, well-established metronomic treatment modality includes temozolomide. The addition of bevacizumab has . Clinical Experience in Glial Cancer. GBM has long been conflicting results; however, it is accepted that targeting treated with temozolomide (TMZ) but the results are dis- angiogenesis may improve progression-free survival. satisfying. The metronomic approach to TMZ and GBM has been beheld since the inhibition of O6-methylguanin-DNA- .. Clinical Experience in Renal Cell Cancer. Targeted ther- methltransferase (MGMT) by prolonged TMZ exposition apies have become the standard of care for renal carcinoma. [157]. Targeting angiogenesis, a key metabolism in oncogenesis of A trial with metronomic therapy of alternating etoposide- these tumors has led to improving the survival rate of these cyclophosphamide with daily thalidomide and celecoxib did patients. On the other hand, agent specific toxicities (quality not increase survival rates (Table 5) [158]. Several clinical of life deterioration, anorexia, weight loss, and fatigue) are trials experimented the metronomic TMZ. Clarke et al. major concerns in terms of treatment adherence. Besides, as compared six adjuvant cycles of either MTD (150 mg/m , the progression-free survival duration prolonged, the risk of days 1 to 7 and 15 to 21) or metronomic (50 mg/m daily) TMZ treatment resistance increases. following standard radiotherapy and daily temozolomide in When resistance to targeted therapies emerged, a pos- 85 patients. For MTD and LDM regimens, the 1-year survival sibility to increase the efficacy of targeted therapies with rates were 80% and 69% and the median OS was 7.1 months metronomic scheduling with reference to preclinical knowl- and 15.1 months, respectively [159]. Another study by Kong edge raised and generated further clinical studies [39]. An et al. showed that metronomic TMZ can be effective for elegant preclinical study demonstrated the efficacy of metro- the patients refractory to standard cyclic treatment, with nomic regimens. Metronomic topotecan was combined with pazopanib and tested against human RCC cell lines. The com- 15 patients, with 50 mg/m daily TMZ; 6-month PFS was 32.5 months and 6-month OS was 56.0% [160]; this rescue bination induced and maintained dormancy in metastatic approach was also supported by another study. Metronomic foci. Pazopanib was also shown to increase intracellular TMZ was experimented in similar doses until progression in topotecan levels [171]. An early study was by Bellmunt et highly pretreated patients including ones with bevacizumab al. investigating six cycles of combination therapy MTD exposure; 6-month PFS was 19% [161]. Again, another study gemcitabine combined with metronomic capecitabine and using 8 weeks of metronomic TMZ in relapsed GBM patients sorafenib for 6 cycles and followed by metronomic sorafenib. yielded a median OS of 6 months with a 6-month PFS The median PFS for these patients was 11.1 months. Of the 44 patients, a partial response was achieved in 20 patients, and of 20%. Authors also evaluated the micro vessel density in patients who needed reoperation after maintenance therapy stable disease was reported in 17 [172]. Another study used and demonstrated a decrement [162]. etoricoxib plus pioglitazone daily, with low-dose interferon three times a week and capecitabine twice daily orally for 4 Bevacizumab refractory patients were reported to have a worse response [163]. A published meta-analysis days, every 3 weeks. Median OS and PFS for the total cohort 16 Journal of Oncology were 26.9 and 7.2 months, respectively. Grade 4 toxicity was was reported in 31 patients, with progression-free survival seen in 48.8% [173]. In a recent trial by Tupikowski et al. of 9.53 months [181]. Kontopodis et al. used metronomic metronomic CP and interferon𝛼 combination resulted in a vinorelbine in 46 pretreated patients with a response rate of CB longer than 24 weeks, which was observed in 40% in 30 10.9%; median OS was 9.4 months; 23.9% of patients showed patients; median OS was 13.2 months [174]. grade 3-4 neutropenia [182]. In RCC, sunitinib, pazopanib, and axitinib and in limited Brain metastasis is a frequent progression in NSCLC patients sorafenib have antitumoral efficacy. Beyond tyrosine progression. Low dose TMZ of 75 mg/m for 21 days every kinase inhibitors and new era drugs, for immunotherapies, four weeks concomitant with whole-brain radiotherapy was there is no proven drug which has a metronomic action. administered in patients with brain metastasis. 2 complete Sunitinib in standard doses may be less tolerated in frail and and 11 partial responses were reported in 27 patients [183]. elderly patients. In such cases, 50 mg sunitinib in 14 days on/7 TMZ was also used in a study including brain-metastatic and days off schedule may be an option. non-brain-metastatic patients, with the dose of 75 mg/m , yielding median survival of 3.3 months; grade 3 and grade . . Clinical Experience in Lung Cancer. Lung cancer is the 4 toxicities were reported [184]. Another study evaluating leading cause of cancer-related death; unfortunately it is metastatic patients treated with metronomic regimens con- mostly diagnosed at an advanced stage. According to cluded that addition of radiotherapy may have a synergistic patient and disease characteristics, palliative or curative effect on overall survival [185]. treatments may be chosen. Regarding this point, metronomic Oral vinorelbine is a studied drug for front line, regarding chemotherapy has been a consideration especially for elderly that it has already been established as a front-line MTCR. Two and debilitated patients. studies combined oral vinorelbine. The rfi st one combined For non-small cell lung cancer, metronomic regimens vinorelbine with cisplatin as first line for inoperable advanced were tested as both a rfi st line in frail patients and as a salvage NSCLC; PFS and OS were 4.2 months and 12.0 months, therapy. Oral etoposide is a widely experienced drug for respectively [186]. The second study by Tan et al. used oral salvage therapies. Pfeiffer et al. compared 100 mg twice daily vinorelbine with three different doses of 30-60-90 mg/week oral etoposide with conventional intravenous regimen for a with sorafenib; median PFS was 4.4 and median OS was palliative treatment option for small cell lung cancer (SCLC). 8.2 months; the study showed no statistically significant 1-year survival was 9.8% in etoposide group with OS of 4.8 difference among the three different doses [187]. months, which were reported to be inferior to intravenous Metronomic chemotherapy has also been used for cyclophosphamide and etoposide or cyclophosphamide dox- patients who are ineligible for standard treatment options. orubicin and vincristine regimens [175]. Sorio et al. used oral etoposide with 17 elderly patients In another trial with oral etoposide alternating doses with advanced NSCLC with 100 mg daily for first 14 days of 100 mg in non-small cell lung cancer (NSCLC) patients, of 3- or 4-week cycles; median OS was 24 weeks with one partial response and stable disease were 28% and 34%, partial response and six stable diseases [188]. Camerini et al. respectively, with median TTP of 6 months and median OS evaluated oral vinorelbine in 43 elderly chemotherapy-naive of 9 months [176]. An all oral regimen including etoposide patients, with OS of 9 months [189]. Two other studies also 50 mg/m with UFT and leucovorin was used in pretreated tested vinorelbine for frail patients. One of the studies used advanced NSCLC. Grade 3 neutropenia and thrombocytope- oral vinorelbine (30 mg, 3 per week) for 35 chemotherapy- nia were observed in 12% and 15% patients, respectively, na¨ıve patients, yielding an ORR of 26%, median PFS of 4 with rarer grade 3 nonhematologic toxicities. 14% of stable months, and a median OS of 7 months [190]. In another disease and 28% of partial response were achieved with a study applying the same regimen in a similar frail population, median TTP of 3 months [177]. Another all oral regimen median PFS and OS were 2,5 and 5,5 months, respectively with etoposide with lomustine and cyclophosphamide was [191]. Other regimens were tested for frail, advanced NSLC used in 71 pretreated SCLC patients; ORR of 38% and severe patients. A metronomic regimen of paclitaxel and gemc- but rare hematologic toxicity were reported [178]. An earlier itabine was tested with a combination of bevacizumab with trial by Correale et al. with weekly cisplatin (30 mg/m ,days additional markers of vascularization. In 39 advanced NSCLC patients, ORR was 56%, and median PFS rates at 6 and 1, 8, 14, and 28) oral etoposide (50 mg/m ,1-21 of 28 days) showed increased efficacy; overall response rate was 45.2%, 12 months were 61% and 21%, respectively, with a median grade 3 leukopenia and anemia have been seen, and 3 of OS of 25.5 months [192]. As radiotherapy is a conventional 31 patients died from pulmonary thromboembolism [179]. option in elderly patients ineligible for cytotoxic therapy, a study evaluated the addition of metronomic regimens to Goern et al. used 25 mg/m weekly docetaxel and 50 mg radiotherapy; no significant clinical efficacy was observed daily trofosfamide in 62 stage IV NSLC patients. Overall [193]. response was 19%; median OS was 9.6 months; with PFS of 2.9 months [180]. Same authors studied efficacy of cisplatin Ecffi acy of metronomic regimens as a maintenance chemotherapy was also tested. Maintenance treatment with 30 mg/m days 1-3, with bevacizumab 5 mg/kg in day 3 and oral etoposide in days 1-15 repeating every 3 weeks oral etoposide after rfi st-line docetaxel and cisplatin treat- (mPEBev regimen) in 45 stage III/IV non-small cell lung ment was evaluated in metastatic NSCLC patients, although no complete response was observed; median overall survival cancer. Patients achieving stable disease or objective response were given erlotinib until progression. A partial response was 10 months, with 1-year survival of 41% [194]. Another Journal of Oncology 17 trial evaluating oral etoposide as a maintenance treatment 28-day cycles in 28 gastric cancers; an overall response of was conducted by Li et al. in SCLC patients who responded 50% was achieved with a median TTP of 4.5 months and to etoposide cisplatin regimen. 31 of 54 etoposide cisplatin OS of 9.5 months [201]. In another phase II study by He responsive patients were evaluated; median PFS was 9 months et al. in 45 pretreated elderly patients, 1000 mg capecitabine and OS was 14 months [195]. In a recent trial, oral etoposide was administered throughout days 1–28 every 5 weeks. was combined with bevacizumab as a maintenance therapy Objective response rate was 20.9%. The median TTP was 3.6 following cisplatin, etoposide, and bevacizumab; median PFS months and median OS was 7.6 months. No grade 4 toxicity and OS were 7.8 and 13.2 months, respectively [196]. Correale was observed [202]. Weekly paclitaxel with lower doses of et al. used oral vinorelbine for>70-year-old patients. ORR 80 mg/m was retrospectively evaluated on patients with was 18.6% [197]. unresectable esophageal cancer. After a median of 11 cycles, Metronomic chemotherapy was far less studied for small 71% of 51 patients had improvement in dysphagia. Overall cell lung cancer (SCLC). One study evaluated the efficacy response was 49%, with median progression-free survival of of more ao ff rdable weekly paclitaxel over standard MTC 4.7 months [203]. A different study retrospectively evaluated topotecan for the second-line treatment. Median PFS and OS the efficacy of metronomic capecitabine in pretreated upper were reported as 145 and 168 days, respectively [198]. gastrointestinal tract cancers including patients with esopha- In the palliative setting for heavily pretreated NSCLC gogastric and pancreaticobiliary tumors with 31% of patients patients, oral etoposide is the most studied metronomic agent achieving clinical benefit [204]. which may have an efficacy. Similar approach can be accepted Metronomic regimens were also evaluated for the second- also for SCLC patients who are in need for symptom control line treatment of CRC. A phase II trial to evaluate the and treatment beyond first- and second-line approaches. In efficacy of metronomic UFT, CPA, and etoposide for rfi st-line the elderly, frail patients who are not candidates for standard therapy in metastatic or recurrent colorectal cancer patients approaches, oral metronomic etoposide and vinorelbine may reported an ORR of 70% and a median OS of 23,5 months be the options. In the first-line treatment of NSCLC, systemic [205]. In a study evaluating ecffi acy of addition of metro- bevacizumab has a role as an antiangiogenic agent in addition nomic tegafur/uracil (UFT) to 5-FU and oxaliplatin in 28 to chemotherapy. pretreated metastatic CRC patients, yielded median OS was 13.4 months [206]. Metronomic UFT was combined with . . Clinical Experience in Gastrointestinal Cancer. Antian- 2 weekly 40 mg/m irinotecan in 49 stage IIIb and stage IV giogenesis had been the area of interest in gastrointestinal patients, yielding 5-year survival of 73% and 62%, respectively malignancies for decades. Bevacizumab is the antiangio- [207]. genic agent that is approved for metastatic colorectal cancer Metronomic regimens are again an inviting option for patients. In addition to bevacizumab, pharmacokinetics of frail patients. A study by Romiti et al. retrospectively evalu- well-known chemotherapeutic agent u fl orouracil had been ated efficacy of metronomic capecitabine of 1500 mg daily in studied for better efficacy and decreased toxicity. Hence, 86 frail patients. Overall disease control rate was 26% with a lowered but prolonged doses of standard chemotherapy for 2% partial response and 23% stable disease. 19% of patients gastrointestinal malignancies have been proposed for better were progress-free for 6 months, and the median OS was 8 efficacy, decreased toxicity, and targeting angiogenesis. months. No grade 4 toxicity was observed [208]. Another Pharmacodynamic and pharmacokinetic profiles of trial also with pretreated frail elderly patients with advanced metronomic regimens in gastrointestinal cancer were colorectal cancer evaluated the efficacy and toxicity profile evaluated using a combination metronomic regimen of UFT, of a metronomic regimen of capecitabine (1000 mg twice CP, and celecoxib in pretreated cases. This study showed that 2 2 daily), oxaliplatin (65 mg/m ), and bevacizumab (7.5 mg/m ). the cases of higher 5-FU peak concentrations and area under No grade 4 toxicity was observed; progress-free survival the curves had a better treatment response, thus elegantly was 12.3 median, with 86.7% reaching six months [209]. illustrating the relation between pharmacokinetic profile Capecitabine was also used in a metronomic regimen of 1,5 g and clinical ecffi acy. Moreover, pharmacodynamic profile of daily in frail, recurrent, pretreated colorectal cancer patients. the combination was delineated by measuring the plasma Disease control rate was 26% with a median OS of 8 months levels of pro- and antiangiogenic molecules. Patients with [210]. Another study retrospectively evaluating metastatic higher proangiogenic molecules despite chemotherapy had colorectal cancer patients reported a median TTP of 6.3 more progressive diseases which proposed an antiangiogenic moths and a tolerable toxicity prole fi [211]. activity of the regimen [199]. In another study, metronomic irinotecan was tested in pretreated cases with three Metronomic maintenance strategies for RAS mutant dieff rent metronomic dosage regimens. The combination colorectal cancer were also tested. In a study, RAS mutated achieved a similar response as conventional third- or CRC was evaluated for the response to metronomic main- fourth-line chemotherapy without any significant toxicity. tenance regimens. Patients were given one of four con- Antiangiogenic molecule Thrombospondin-1 was shown to ventional regimens (capecitabine or 5-FU plus oxaliplatin decrease concomitantly with irinotecan infusion, supporting or irinotecan); then nonprogressing ones were randomized an antiangiogenic action of the regimen [200]. with their KRAS mutational status. KRAS mutant ones were An earlier study regarding metronomic chemotherapy randomized to metronomic capecitabine or bevacizumab and in gastric cancer by Colleoni et al. used oral etoposide KRAS wild types were randomized to bevacizumab alone 50 mg/m with intravenous u fl orouracil for fourteen days of or bevacizumab plus erlotinib. The addition of erlotinib 18 Journal of Oncology in KRAS wild type patients did not significantly prolong doses of 5 mg/kg or 10 mg/kg every two weeks in 43 advanced survival [212]. For stage III colorectal carcinomas, efficacy HCC patients; 16-week disease control rate was 42%. Grade of metronomic UFT was questioned in a retrospective study 3-4 side effects including asthenia and hemorrhage were reported [220]. Shao et al. used an alternative regimen of of 113 patients; prolonged 5-year OS of 86.6% was noted in maintenance group compared to control groups, 68.5% thalidomide and metronomic UFT and also got comparable [213]. In CAIRO 3 study, a phase III study was planned to results of median PFS of 0.9 months and a median OS of 4.6 months [221]. A novel use of metronomic chemotherapy ascertain the efficacy of maintenance metronomic treatment with capecitabine plus bevacizumab after an induction treat- was experimented in a Korean trial. In 30 HCC patients with ment with six 3 weekly cycles of capecitabine, oxaliplatin, portal vein thrombosis, an intrahepatic arterial metronomic and bevacizumab (CAPOX-B). 558 previously untreated infusion of epirubicin, cisplatin, and 5FU was performed. Six metastatic CRC patients were allocated into either the main- patients achieved a partial response and six other patients had stable disease. The median overall survival was 162 days [222]. tenance or the observation group on a 1:1 basis. Capecitabine 625 mg/m2 oral twice daily and bevacizumab 7.5 mg/m2 Success of metronomic capecitabine versus observation alone intravenously every 3 weeks were the maintenance treatment. was retrospectively assessed as a second-line treatment; median PFS of the prior group was 12.0 months, while the During the follow-up, progressing patients in maintenance of observation groups were given their second CAPOX-B; other groups had shorter median OS of 9.0 months; authors nonprogressing ones were followed. With a median follow- concluded a 46% reduction in death risk [223]. Another up of 48 months, PFS was signicfi antly 3.2 months longer study retrospectively analyzed the success of metronomic in maintenance group, 8.5 months versus 11.7 months. It protocol of 5-FU, cisplatin, and capecitabine via hepatic was reported that the global qualities of life are similar arterial infusion chemoport versus sorafenib treatment in between the groups [214]. A following randomized study advanced HCC patients with portal vein thrombosis. OS was questioned the efficacy of bevacizumab alone or combined 158 and 117 days, respectively, for the two groups [224]. In summary, HCC has a dismal prognosis and beyond with metronomic CPA plus capecitabine in unresectable CRC patients; the combination did not improve PFS [215]. first-line treatment has little impact on OS of these patients. In the metronomic treatment of gastrointestinal malig- In terms of metronomic treatment, beyond TKI, capecitabine might have a role in patients with higher Karnofsky perfor- nancies, especially for mCRC, the role of capecitabine with/without bevacizumab has a definitively important role mance scores. in the palliative setting and in maintenance therapy for .. Clinical Experience in Multiple Myeloma. MTD with patients who have a response on first-line treatment. autologous stem cell treatment for available patients is a cura- tive regimen for most of the middle-to-high-risk patients. .. Clinical Experience in Hepatocellular Cancer. Advanced Nevertheless, the morbidity of bone marrow transplantation hepatocellular cancer (HCC) has a dismal prognosis. In the and the toxicity profile of the commonly used drugs narrow early stages when the patients are candidates for systemic down the treatment options, especially for relapsed or refrac- treatment, options are scarce. Systemic adriamycin was the tory multiple myeloma. only chemotherapeutic agent that was accepted as standard Vasculogenesis is an important element in pathogenesis first-line treatment for patients who are not eligible for of multiple myeloma; thus employment of antiangiogenic transplant or local ablative therapies. More recently, sorafenib drugs with metronomic schedules can be rational [225]. was recognized as a standard treatment. As HCC is usually The subject has also a historical value: a still used drug, concomitant with cirrhosis, a tolerable combination and/or thalidomide, was discovered to be antiangiogenic and it maintenance treatment with less adverse events is required was rs fi t experimented in multiple myeloma [226, 227]. to improve the survival benefit of sorafenib (Table 4). Cyclophosphamide and thalidomide derivatives are widely Brandi et al. tested metronomic capecitabine in a 69- used drugs with a metronomic regimen. year-old patient with advanced HCC with therapeutic suc- For relapsed or refractory multiple myeloma (RRMM), cess [216]. Following this study, same team experimented Suvannasankha et al. combined oral cyclophosphamide metronomic capecitabine in 90 patients, in whom 59 were (50 mg two per day for 21 days), thalidomide (200 mg daily chemotherapy-naive and 31 were resistant or intolerant to day), and prednisone with 28-day cycles. In 35 patients, CB sorafenib. Median PFS of rfi st cohort was 6.03 months and was 85.8%, with 20% complete response, 5.7% near complete OS was 14.47 months. Second cohort achieved a median response, 13% partial response, and 22.9% stable disease. PFS of 3.27 months and a median OS of 9.77 months [217]. Grade 3 and grade 4 toxicities were reported; hemato- Granito et al. also retrospectively evaluated the ecffi acy and logical ones were most common [228]. Further studies safety of metronomic capecitabine in 26 patients pretreated evaluated thalidomide combined with CP and prednisone. with sorafenib. Median treatment duration was 3.2 months, Reece et al. combined lenalidomide 25 mg on days 1 and median TTP was 4 months, and OS was 8 months [218]. Another trial combined sorafenib with metronomic UFT as 21, cyclophosphamide on 300 mg/m on days 1, 8, and 15, a rfi st-line therapy; median PFS and OS were 3.7 months and and prednisone 100 mg every other day in a cycle of 28 7.4 months, respectively. Hand foot skin reaction occurred days. With a median follow-up of 28 months, ORR was in grade 3 in 9% of patients and was reported to be the 94% and median PFS was 161 months [229]. Zhuo et al. major adverse event resulting in dose reduction [219]. A evaluated metronomic CP with corticosteroids as salvage different study evaluated the efficacy of bevacizumab with therapy in comorbid and heavily pretreated patients, ORR Journal of Oncology 19 Th Table 4: Table showing the studies using metronomic regimens in hepatocellular cancer. UFT, Tegafur-5 FU. Author Treatment N Patient type SD PR CR ORR TTP PFS OS Sorafenib 400 mg bid Untreated, 26 4 Hsu, 2010 53 3.7 m 7.4 m UFT 125mg/m2 Child-Pugh class A (49%) (8%) Bevacizumab 5 mg/kg or 10 6 Boige, 2012 43 Advanced N/A N/A 14.0% mg/kg q14d (14.0%) alidomide 100 mg bid Shao, 2012 43 Untreated, 9% 1.9 m UFT 125mg/m2 (Into the hepatic artery) Epirubicin 30 mg/m2 q28d Portal vein 6 Woo, 2012 30 63 d 63 d Cisplatin 15mg/m2 q21d thrombosis (20.0%) 5-FU 50 mg/m2 q21d 59 Untreated 30 1 2 6.03 m 14.47 m Brandi, 2013 Capecitabine 500 mg bid Sorafenib 31 10 N/A N/A 3.27 m 9.77 m refractory Sorafenib Granito, 2015 Capecitabine 500 mg bid 26 4m 8 m refractory 20 Journal of Oncology Th ff Table 5: Table showing the studies using metronomic regimens in glioblastoma multiforme (GBM). CP, Cyclophosphamide; TMZ, Temozolomide. Author Treatment N Patient type SD PR ORR TTP PFS 6 OS TMZ 75 mg/ m days Chemonaive, refractory to RT Brandes, 2006 33 -- 9% - 30.3% - 1-21 q28d and/or surgery Etoposide 35 mg/ m 11 w 41.5 w days 1-21 GBM and (GBM) (GBM) Kesari, 2007 CP 2 mg/kg days 22-42, 48 59% 11% - - AG 14 w 42 w alidomide (AG) (AG) Celecoxib TMZ 200 mg/ m GBM, 4.2 m 8.8 m Balmaceda, 2008 120 anaplastic astrocytoma, --- - 5.8 m 14.6 m followed by 90 mg/m2 q12h 9 times anaplastic oligodendroglioma 7.7 m 18 m 1:GBM-refractory to 1:21 1:17% conventional TMZ, 2:GBM-refractory to Perry, 2008 TMZ 50 mg/ m qd 2:14 conventional and adjuvant --- - 2:57% - TMZ 3:AG-refractory to 3:14 3:42% conventional TMZ, Pretreated with standard TMZ Clarke, 2009 TMZ 50 mg/ m qd 43 --- - - 15.1m +RT Bevacizumab 10 mg/kg 40.6% 63.1 w two times a week 59 GBM and grade 3 glioma Reardon, 2009 --- - Etoposide 50 mg/ m qd 44.4% 44.4 w days 1-21 q30d 2 2 TMZ 40 mg/ m m qd 56.0% Kong, 2010 38 Pretreated GBM - - - - 32.5% or 50 mg/ m qd (6 m) TMZ 10 mg/ m bid Stockhammer, 2010 28 Pretreated GBM - - - 4.2 m 43 % - Celecoxib 200 mg Bevacizumab 10 mg/kg Verhoe, 2010 q21d 23 High grade glioma - - 20% - 17.4 % 17.1 w TMZ 50 mg/ m qd Bevacizumab 10 mg/kg q14d With Etoposide 50 mg/ Bevacizumab pretreated Reardon, 2011 m days 1-21 q 30d 23 52% - - - 4.4% - GBM, or With TMZ 50 mg/ m m qd Pretreated grade 3 malignant Omuro, 2013 TMZ 50 mg/ m qd 47 --- - 19% 7m glioma and GBM TMZ 40 mg/ m qd Zustovich, 2013 43 Pretreated GBM - - - - 26% 7.5 m Sorafenib 400 mq qd Journal of Oncology 21 was 66.7%, and PFS of respondent patients was not reached As far as melanoma treatment and recent advances are at the study [230]. Same author questioned the use of concerned, still, main part of successful therapy lies on immunotherapeutic approaches and dual targeted therapies metronomic regimens in patients with heart failure who are in driver mutation carrier patients. Besides, during the not eligible for standard treatment protocols. In 54 relapsed treatment process, temozolomide will definitely have a role. or refractory MM patients who also had a severe heart failure (NYHA III/IV), continuous low dose CP and dexamethasone .. Clinical Experience in Head and Neck Cancers. Ad- were administered, 63% clinical benefit was achieved, and vanced head and neck cancers are another group of cancer PFS was reported to be 6 months [231]. Papanikolau et with limited surgical options and inadequate efficacy of al. retrospectively evaluated 186 multiple myeloma patients cytotoxic chemotherapy. who were administered a novel metronomic regimen of Metronomic methotrexate and celecoxib were evalu- bortezomib, thalidomide, dexamethasone, doxorubicin, and ated in platinum-resistant oral cancer without achieving an cisplatin with or without rapamycin. For 186 patients, median acceptable efficacy [241]. In another study in India, oral age was 61, with median 14 pretreatments. Patients have cancer evaluated the success of a metronomic regimen of had median 1 cycle of therapy; median OS was 11.2 months. oral methotrexate and celecoxib starting preoperatively and Median PFS was 3.6 months for an overall response rate continuing as a maintenance after the standard treatment of 63% (117 of 186 patients). Toxicities related to therapy protocol. The disease-free survival rates were 86,5% in metro- were reported to be not trustworthy as some of the patients nomic group versus 71.6% in control group, showing a statis- have had a hematologic condition prior to treatment [232]. tical significance [242]. A similar study from India enrolling Regarding RRMM patients, a prospective phase 1/2 study was operable oral cavity cancer with maintenance metronomic conducted for the effectiveness of metronomic combination therapy showed a median DFS of 13 months [243]. For of lenalidomide, CPA, and dexamethasone. Reported median head and neck cancer, another study evaluated metronomic values of PFS and OS were 12,1 and 29.0 months, respectively oral regimen of methotrexate, erlotinib, and celecoxib in [233]. A dieff rent phase 2 study evaluated low dose daily palliative treatment of patients with head and neck cancers administration of pomalidomide and CPA in lenalidomide and ineligible for MTD. Reported median PFS was 148 days pretreated RRMM patients yielding an ORR of 67% and PFS [244]. Same authors retrospectively evaluated the adequacy of 14 months [234]. of oral low dose chemotherapy for palliative treatment in For patients who are not eligible for stem cell trans- a heterogenous group of head and neck cancer patients, plantation, adequacy of low dose thalidomide maintenance revealing median OS of 155 days with oral cancers having a was assessed after standard induction chemotherapy. With tendency for a shorter OS [245]. 24 months of thalidomide maintenance, median PFS and OS In the light of results of metronomic studies, it can be were 27 and 39 months, respectively [235]. concluded that metronomic MTX (iv, weekly) may have a role In summary, thalidomide and lenalidomide have proven in patients who are heavily treated and are still in need for efficacy with less pronounced toxicity in myeloma patients, chemotherapy for symptom control. which lead to their use widely, especially for maintenance in posttransplantation treatment. .. Clinical Experience in Miscellaneous Cancers. Metro- nomic chemotherapy was also experimented with other .. Clinical Experience in Melanoma. Treatment of melano- cancers. ma has shown a great advancement in the past decade with Berruti et al. used long acting octreotide, metronomic targeted therapies, immunotherapy, and combinations [236]. capecitabine, and bevacizumab in metastatic well-moderately As angiogenesis plays a role in pathogenesis of melanoma and differentiated neuroendocrine tumors. The median PFS was is known to be a prognostic factor, metronomic chemother- 14.9 months. Biochemical response was seen in 52.9% and apy is a particularly appealing strategy [237]. Bhatt et al. symptomatic response was seen in 82.3% of cases [246]. used continuous infusion and paclitaxel 10 mg/m2 and oral Metronomic chemotherapy is also a feasible instrument celecoxib 400 mg twice daily in twenty patients. Median TTP for treating sarcomas, as angiogenesis is a rational target to was 57 days and OS was 212 days. Grade 3-4 toxicities were control the diseaseand thetypical population bearing the catheter-related only [238]. Another study used metronomic cancer can possibly be debilitated for standard doxorubicin or CPA for 3 weeks on 1 week off protocol for 13 untfi elderly ifosfamide based treatment, so administrating a more pallia- people. Median OS was 8 months, ranging from 4 to 37 tive and tolerable regimen is needed [247, 248]. Metronomic [239]. Ellebaek et al. combined CPA and COX inhibitor based cyclophosphamide with daily prednisolone was administered metronomic therapy with immune modulatory autologous to 26 elderly sarcoma patients with one-week cycle. It was augmented dendritic cell (DC) vaccine. Metronomic CPA reported that grade 3-4 lymphopenia was seen in 81% of anda COX-2 inhibitor have been addedto a DC vaccine patients. Total response rate was 26.9% [249]. with the intention to dampen. 8 patients had prolonged SD of 7-13 months [34]. TMZ was also retrospectively evaluated 4. Discussion in a single-center experience; 33 patients were treated with 2 2 cisplatin 75 mg/m every 28 days and TMSZ 75 mg/m for There is no doubt that metronomic chemotherapy has been days 2-21 in patients with younger age and good performance; a great enthusiasm. Medical society needs an innovative median PFS was 24 weeks and OS was 50 weeks [240]. consensual intellect to seize the expanding knowledge about 22 Journal of Oncology biology of cancer and deploy this knowledge to develop References strategies to manage and treat cancer. Metronomic chem- [1] T. Browder,C. E.Butterfield, B. M. Kr¨aling et al., “Antiangio- otherapy is a seminal model for this intellect, integrating genic scheduling of chemotherapy improves efficacy against the concepts of angiogenesis and angiogenetic machinery, experimental drug-resistant cancer,” Cancer Research,vol. 60, tumoral microenvironment, cancer stem cells, and tumoral no. 7, pp. 1878–1886, 2000. immunology. 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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2019 Cem Simsek et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2019/5483791
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Abstract

Hindawi Journal of Oncology Volume 2019, Article ID 5483791, 31 pages https://doi.org/10.1155/2019/5483791 Review Article Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience 1 2 3 Cem Simsek , Ece Esin , and Suayib Yalcin Department of Internal Medicine, Hacettepe University, Ankara, Turkey Department of Medical Oncology, A.Y. Ankara Training Hospital, Ankara, Turkey Department of Medical Oncology, Hacettepe University, Ankara, Turkey Correspondence should be addressed to Cem Simsek; cemsimsek111@gmail.com Received 27 April 2018; Revised 24 December 2018; Accepted 5 February 2019; Published 20 March 2019 Academic Editor: Akira Iyoda Copyright © 2019 Cem Simsek et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. eTh literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management. 1. Introduction (ASCO) Annual Meetings (2005 to 2017), and European Society for Medical Oncology (ESMO) Congresses (2005 to While our understanding about the biology of cancer and the 2017) were performed. The reviewing process was done in interaction of malignant cell with their microenvironment compliance with the Preferred Reporting Items for Systematic has improved, the research revealed that, apart from the Reviews and Meta-Analyses statement (PRISMA) [4]. Arti- molecule administered per se´, thedoseand schemeof admin- cles were also screened manually and related citations were istration are important for therapeutic efficacy [1]. The idea of included into the systematic review to increase the sensitivity. metronomic chemotherapy, the term rfi st used by Hanahan, Studies conducted in adult patients in English language, was rfi st revealed with this standpoint [2]. Preclinical and published in peer-reviewed journals as phase II or III clinical studies have been investigating the use of metronomic randomized controlled trials (RCTs) comparing continuous therapy as an augmentation or as a substitute for conventional chemotherapy to an intermittent strategy of chemotherapy, regimens [3]. However, there is still ongoing debate about with or without maintenance therapy including at least one the current role of metronomic regimens in the treatment of of the outcomes of interest, were included. The ASCO and cancer. The purpose of this systematic review is to reevaluate ESMO meeting abstracts as well as systematic reviews and the position of metronomic chemotherapy in modern cancer meta-analyses were also accepted for inclusion. management and make a projection about the future role in the treatment of malignancies. 3. Results 2. Materials and Methods .. Literature Search Results. Entire literature search re- Literature searches of PubMed (2005 to November 2017), trieved 5285 results. 1263 were regarded as potentially rele- ISIS (2005 to 2017), American Society of Clinical Oncology vant and fully reviewed. 266 of them were retained in the 2 Journal of Oncology NK Ｌ？Ａ Interactions Increased Decreased cytotoxic response immune tolerance MDSC ４ Decreased cancer stem cells CSC Decreased Increased Tumor endothelial progenitors endothelial toxicity microenvironment Endothelium Endothelial progenitor cells Decreased Increased anti-angiogenic cytokines angiogenic cytokines TSP-1 Figure 1: Proposed mechanisms for actions of metronomic chemotherapy regimens. study. Twelve abstracts from ASCO meeting abstracts were which is selectively sensitive to metronomic administration of certain types of drugs [7–12]. The endothelial progenitor retrieved and 4 of them were retained. Two ESMO meeting abstracts were also included. cell (EPC) is another major player in tumor vasculogenesis, which is another target of MTC [13, 14]. Apart from toxi- .. e Deﬁnition of Metronomic erapy. The term “metro- city to endothelial cells, MTC also induces antiangiogenic nomic chemotherapy” (MTC) is currently used for frequent protein Thrombospondin-1, inhibits angiogenic HIF-1 𝛼 ,and and regular administration of lower doses of chemotherapeu- decreases circulating VEGF levels [15–18]. tic drugs with minimal drug free time intervals, or simply Secondly, as the tumor transforms its surroundings to cre- “lower doses, longer times”, in order to establish a prolonged ate a viable microenvironment, it modifies the hosts’ immune and lower albeit an active range of plasma concentration system and establishes a conciliatory climate. Restoring and enabling a favorable side-eeff ct profile [5]. In the opposite enhancing the antitumor immune response is another aspect way, conventional regimens are used as maximum tolerated of metronomic regimens (Figure 1) [19]. Regulatory T cell (Treg) as one of the key players “locks down” cytotoxic dose (MTD), in which relatively high doses are given with 2- 3-week intervals [6]. response and thus maintains the tumor immune-tolerance [20]. MTC selectively depletes Treg and thus restores the .. e Mechanisms of Metronomic Action. The preliminary natural killer (NK) and T cell functions [21, 22]. Repression role of MTC is derived from its antiangiogenic mode of of the myeloid derived stem cell, another immune suppressor, was also demonstrated in clinical trials [23, 24]. Besides, MTC action (Figure 1). Thismodeofaction isshared bytwo classes of therapies, metronomic chemotherapy and anti- enhances the cytotoxic response by inducing the antigen VEGF monoclonal antibodies. However, they have several presenting dendritic cell maturation, augmenting its function and increasing tumorigenic antigen presentation that assem- dieff rent aspects. The antiangiogenic drugs directly impair the action of vascular endothelial growth factor (VEGF) and bles the immunogenic cancer death. Immunogenic cancer the metronomic chemotherapy disables the cells enrolled death is the process in which the dendritic cell recognizes the immune-adjuvant damage associated molecular patterns in the angiogenic mechanisms, suggesting that the tumoral endothelial cells could be a better target to overcome the (DAMPs) like HGMB-1, calreticulin, and ATP and comple- drug resistance (Tan et al.). Tumor endothelial cells (TEC) ments the cytotoxic cell death [25–33]. With its immune are distinguishable from typical endothelial cells as they have modulatory aspects, MTC was shown to increase potency of dieff rent characteristics of proliferation, migration, genetic other immune stimulatory modalities like vaccines [33, 34]. Another resident in the cancer microenvironment are outline, and discrete reactions to growth factors. TEC is a major target for the antiangiogenetic action of MTC, cancer stem cells, which were discovered to take part in Journal of Oncology 3 cellular dedieff rentiation, tumoral heterogeneity, invasion, In another study with metastatic hormone receptor positive metastasis, and drug resistance [35, 36]. MTC was shown patients, metronomic combination of CP with vinorelbine to decrease the number of triple positive CD133+/CD44+/ and capecitabine was evaluated for both na¨ıve and pretreated patients. Na¨ıve patients had a TTP of 25.1 months, while pre- CD24+ and CD44+ stem cells; however, its therapeutic impli- cation has not been well defined yet [37, 38]. Heterogeneity of treated patients’ median TTP was 11.2 months [57]. Zhang et cancer cells can stem from the positive selection of resistant al. evaluated addition of metronomic CP to docetaxel in non- triple-negative patients as a rfi st-line treatment compared to cancer clones aer ft chemotherapy. With this perspective, the “chemo-switch” protocol, studied by Pietars et al, to control docetaxel alone. There were no differences between groups the tumoral stromal cells was also suggested to surpass this with respect to the ORR, PFS, and OS; the authors concluded evolutionary process [39, 40]. that the combination was not effective in this setting [58]. Tumoral dormancy arises when proliferation of cancer CP and MTX have a diverse combination schedules with cells is countervailed by their apoptosis [41]. The major targeted agents. Bevacizumab and trastuzumab (in HER- factors hypothesized to maintain this balance are inu fl ence of 2 positive patients) with CM combination were tested by microenvironment, impediment vascularization (angiogenic Garcai-Sanex et al. in a population of taxane and anthra- dormancy), and immune surveillance [42]. There are plen- cycline refractory patients. An overall survival (OS) of tiful data that demonstrate that MTC particularly induces 13,6 months was achieved [59]. The highest clinical benefit angiogenic dormancy by upregulating and downregulating rate (68%) was reported with the combination of CP with antiangiogenic factors such as TSP-1 and proangiogenic bevacizumab and capecitabine in pretreated breast cancer factors such as VEGF, respectively [43]. patients. Vandetanib was also integrated with CM based Another demonstrated mechanism of action is selective metronomic therapy in a phase I dose escalation study. modulation of certain gene and protein functions in tumor Adverse events resulted in loss of chemotherapy adherence in cells, which can be used as a means of an antiproliferative 1/3 of patients yielding a 10% partial response of the remain- effect on tumor cells or to sensitize the tumor to certain ing 20 patients [60]. Perraud et al. experimented CM plus a chemotherapy actions [44]. selective cyclooxygenase-2 inhibitor celecoxib in 15 patients; With its aforementioned interaction of these factors, clinical benefit (CB) rate was 46.7% with no serious toxicities MTC has been deduced to have a role in induction of tumor [61]. Aurilio et al. used CM with fulvestrant, which resulted dormancy (Figure 1) [45]. Additionally, MTC has been shown with prolonged CB [62]. to decrease metastasis; however, the mechanism of this effect The aim of metronomic treatment is not solely palliative has not been established [46, 47]. treatment; neoadjuvant setting is an active area of investi- gation. Dellapasqua et al. reported the results of CP plus .. Clinical Experience in Breast Cancer. Breast cancer is one liposomal doxorubicin (PLD) as an initial therapy in locally of the broadest tracks for the “metronomic march.” The grow- advanced breast cancer patients; the rate of breast conserving ing number of patients with incurable metastatic disease who surgery was found to be 44.8%. Additionally, 62.1% of patients need palliative treatment, the cumulative toxicity of cytotoxic were reported to have a PR, importantly without grade 4 therapy, and lastly the economic burden led a concerted effort toxicity [63]. An immunogenic mechanism was also explored to find alternatives for conventional regimens including tax- with CM and an immunogenic vaccine; ORR was 23.8% [64]. anes, anthracyclines, pyrimidine antimetabolites, and tubulin A metronomic based chemohormonal scheme, CP plus inhibitors [48]. megestrol acetate was used in 29 patients, ORR was 31.0%, Cyclophosphamide (CP) and methotrexate (MTX) were and CBR was not reported [65]. An all oral scheme of CP on the top of the list to be tested in metronomic scheme in 2 2 (65 mg/m daily on days 1-14) plus capecitabine (1,000 mg/m breast cancer [49–51]. The earlier studies investigated the oral twice daily on days 1-14 repeating every 28 days) treatment metronomic use of CP and MTX together (CM) in pretreated was evaluated in 68 pretreated patients. After median follow- metastatic breast cancer patients (Table 1). Colleoni tested up of 26 months, a CB was 53%; grade 4 toxicity occurred the combination of CP 50 mg daily with MTX 2.5 mg twice in 5% of patients [66]. Another CP (33 mg/m twice daily, daily 2 days per week, obtaining objective response rate days 1-14) and capecitabine (capecitabine 828 mg/m twice (ORR) of 20.9% and a clinical benefit [18] (at least 24 weeks daily) treatment repeating every three weeks by Yoshimoto of objective response and stable disease) of 31.7% [49]. In et al. resulted in a clinical benefit of 57.8% without any grade the long-term follow-up, those patients yielded a 15.7% pro- 4toxicity [67]. longed clinical benefit (longer than 12 months) [52]. Miscoria As an extensively experienced drug for about 5 decades, 5- et al. and Gebbia et al. showed similar disease control and FU is still being used for breast cancer. With the discovery of tolerable toxicity profiles in trials tested for CP alone or capecitabine, an oral prodrug of 5-FU, thymidylate synthase in combination with MTX [53, 54]. Metronomic CP and inhibitors have been extensively researched for metronomic MTD liposomal doxorubicin combination were evaluated in metastatic patients; CB was 75% with a median OS of 6.4 use [68]. Oral capecitabine (828 mg/m twice daily) with months [55]. weekly paclitaxel was evaluated by Taguchi et al. PFS and OS A more recent study in pretreated metastatic breast were reported to be 8.3 months and 22.9 months, respectively cancer combination of metronomic CP with MTX was tested; [69]. First phase III study was published by Watanabe et medians of PFS and OS were 5 and 7 months, respectively. al. comparing the adjuvant activity of oral uracil-tegafur Out of 48 patients, 1 patient had complete response [56]. with conventional CMF (cyclophosphamide, methotrexate, 4 Journal of Oncology Th Table 1: Table showing the studies using metronomic regimens in breast cancer. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS CP 50 mg qd po Metastatic Colleoni, 2002 MTX 2.5 mg bd 2 days of 1 63 - 16% 3% 19.0% - 31.7% - - pretreated week po CP 50 mg qd po Metastatic, Colleoni, 2006 MTX 2.5 mg bd on 1st and 86 pretreated and -17% 3 20.9% - 41.5% - - 4th days po untreated CP 50 mg qd po Metastatic, MTX 2.5 mg bd on 1st and Colleoni, 2006 85 - 8% 3 11.8% - 41.5% - - pretreated or 4th days po untreated alidomide 200 mg qd po MTX 2.5 mg bid on 1st and Metastatic, 15.7% (12 Orlando, 2006 2nd or 4th days po 153 pretreated or -16% 5 - - -- months ) CP 50 mg qd po untreated CP 50 mg qd po MTX 2.5 mg bid days 1, 4 Metastatic, Orlando, 2006 22 46% 18% --- 6m q1w pretreated, HER2 + Trastuzumab 6 mg/kg q3w CP 50 mg qd po Metastatic Miscoria, 2012 MTX 2.5 mg bid days 1, 4 62 -- - - 2.6m 7.1m pretreated q1w CP 50 mg qd po 22 9% 3% 0% - 3.8 m ? - 12.8 m Metastatic vs. Vs. Vs. Vs. Vs. Vs. Vs. pretreated Gebbia, 2012 CP 50 mg qd po with MTX 39 12% 8% 0% 4.2 m 14 m hormone resistant 2.5 mg bid 2 days per week CP 50 mg qd po Metastatic, MTX 2.5 mg bid po two Wong, 2010 41 pretreated or 7% 2% 15% 24% 10 w 24% 48 w days q1w Prednisone 5 mg untreated qd CP 50 mg qd MTX 1 mg/kg iv q14d Metastatic, Garcia-Saenz, 32% Bevacizumab 10 mg/kg iv 22 pretreated, HER2 32% - - - 63.6% 7.5 m 13.6 m 2008 (24 w) q14d +/- Trastuzumab (in HER2 +) CP 50 mg qd MTX 2.5 mg qd 2 days per Metastatic, 15% Mayer, 2012 week 20 pretreated or 10% - ---- - (24 w) Vandetanib 100 mg / 200 untreated mg / 300 mg qd CP 50 mg qd po 3% 24 w 12 m Perroud, 2013 155 !! 1patient - - 14 w 46.7% Celecoxib 200 mg bid po (24 w) (40%) (46.7%) CP 50 mg qd po MTX 2.5 mg bd on 1st and Metastatic, Aurilio, 2012 32 !! !! !! !! !! 56% - - 4th days per week po pretreated, HR + Fulvestrant 250 mg im q28d Journal of Oncology 5 Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS CP 50 mg qd po Non-metastatic, 42 w Crivellari, 2013 MTX 2.5 mg bd on 1st and 36 >65 y, untreatable, - Closedearly - --- - (81%) 4th days per week po HR- CP 50 mg qd po Non-metastatic, Dellapasque, Liposomal Doxorubicin 29 untreatable, 34.5% 62.1% - ---- - 20mg/m2 preoperatively CP 50 mg qd po Soriano, 2011 MTX 2.5 mg bid 21 Metastatic, 4% - - - 9.8 m - - 12.9 m 1E10-Alum CP 50 mg qd po Dellapasque, Capecitabine 500 mg tid po 46 Metastatic 17% 46% 2% 42 w 68% - - Bevacizumab 10 mg/kg q2w CP 50 mg day 1-21 q28d po Metastatic, Licchetta, 2010 Megestrol acetate 80 mg bid 29 pretreated, 31% 7.4 m 13.4 m po HR +/-, HER2 +/- CP 65 mg /m2 iv days 1-14 q3w Metastatic, Wang, 2012 68 - - - 30.3% 5.2 m 53.0% - 16.9 m Capecitabine 1000 mg/m2 pretreated bid days 1-14 q3w CP 33 mg/m2 bid days 1-14 q3w Metastatic, HER2- 1y (86%) Yoshimoto, 2012 51 13% - - 44.4% - - 10.7/13.2 Capecitabine 828 mg/m2 ER-/ER+ 2y (71%) bid days 1-14 q3w 5-FU 1 mg/m2 days 1-28 q35d po 24% Smith, 2000 29 Metastatic 55% Eniluracil 10 mg/m2 days (3 m) 1-28 q35d po Capecitabine 825 mg/m2 Metastatic, 24% Taguchi, 2010 33 -- 18% - - 6.9m 24.8m bid days 1-21 q 28d untreated recurrent (> 6m) 2 7 Metastatic, (pretreated with (pretreated Fedele, 2012 Capecitabine 1500 mg qd 58 7m 62% 17m pretreated Standard with Standard Capecitabine) Capecitabine) T0, high risk, (RFS) 5 y Watanabe, 2009 UFT 300 mg tid --- - - - 5y(96.2 %) adjuvant (87.8 %) 6 Journal of Oncology Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Capecitabine 500 mg tid Metastatic, Cazzaniga, 2014 Vinorelbine 20-30-40 31 --- - - 58.1% - - pretreated, mg/tot Capecitabine 1250 mg/m2 qd Metastatic, 8% Young, 2012 38 34% - - 3.6 m 42% - - Docetaxel 15mg/m2 pretreated (6 m) Celecoxib 200 mg bid Capecitabine 1500/2000 mg daily in divided doses Schwartzberg, Metastatic, HR+, Fulvestrant 500 mg day 1, 41 - - - - 26.94 m - 14.98 m 28.65 m 2014 HER2- 250 mg day 1, 15, 28 followed by 250 mg q28d Irinotecan 60 mg/m2 days 1, 8, 15 q4w Metastatic, Otsuka, 2015 34 3% 44% - - - TS-1 80 mg/m2 days 3-7, recurrent 10-14, 17-21 q4w Operated, neoadjuvant -DFS- 44.34 m Alagizy, 2015 Capecitabine 500 mg bid po 41 FEC100+, +/- --- - - - 42.4 m (estimated) Postoperative RT, HR-, HER2- Temozolomide with radiotherapy and following 4w Temozolomide 75 mg/m2 Untreated brain Addeo, 2012 36 44% 8% 52% - - 8 m 11 m days 1-21 q4w metastasis, Vinorelbine 70 mg/m2 1,3,5 weekly for 3 w q4w, max 12 cycles Vinorelbine 70 mg/m2 1,3,5 Addeo, 2013 weekly for 3 w q4w, max 12 34 Metastatic - 32% 6% --- 7.7m 15.9m cycles Vinorelbine 50 mg 3 times per week Metastatic, Saloustros, 2011 13 46% 8% Closedearly ---- - Bevacizumab 10 mg/kg 2 pretreated times per week q28d De Iuliis, 2015 Vinorelbine 30 mg q2d 32 Metastatic - - - - 50% - - Journal of Oncology 7 Table 1: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Letrozole 2.5 mg qd 57 71.9% Letrozole 2.5 mg qd and CP Bottini, 2006 HR+, - - - 57 87.7% 50 mg qd 6 months NP-Liposomal Doxorubicin 30 mg iv 5-FU 500 mg iv Metastatic, Manso, 2013 38 27% - - 281 d 8.4 m 21 m Vincristine 0.25 mg iv pretreated CP 50 mg qd po Prednisone 20 mg Paclitaxel 80 mg/m2 days 1. 8. 15, 4 cycles Cyclophosphamide 50 mg qd po 4 cycles Capecitabine 1200 mg/m2 qd 4 cycles HR-, ER-, 31 Masuda, 2014 33 -54.5% - - - -- 5-FU 500 mg/m2 q3w, 4 preoperative (93.9%) cycles Epirubicin 100 mg/m2 q3w, 4cycles CP 500 mg/m2 q3w, 4 cycles Capecitabine 500 mg tid Metastatic, CP 50 mg qd 21% Montagna, 2012 24 untreated, HR -, 58% 4% - - 75% 43 w - Bevacizumab 15mg/kg q3w (9 w) HER2- Erlotinib 100 mg qd Metastatic, Munzone, 2010 P Liposomal-Doxorubicin 45 untreated, 39% 18% -- - 45% -- pretreated CP 50 mg qd po Metastatic, Mutlu, 2015 Etoposide 50 mg bid 2 days - - - - 7.03 m 32.5 m pretreated per week Capecitabine 828 mg/m2 bid po days 1-21 q28d Metastatic, Taguchi, 2013 43 46.5% 8.3 m 22.9 m Paclitaxel 80 mg/m2 days 1, pretreated 8, 15 q28d Capecitabine 1000 m2 bid Metastatic, Ambros, 2014 po days 1-14 q21d 86 24.3% 7 m 55.8% 24.0 m pretreated, HER2- Metastatic, Etoposide 50 mg/m2 po Neskovic, 1996 18 untreated, 28% 6% days 1-14 q 28d pretreated Etoposide 60 mg/m2 po Metastatic, Yuan, 2015 75 39% 9% 4.5 m days 1-10 q 21d pretreated 8 Journal of Oncology and uo fl rouracil) in node negative high-risk breast cancer Antiangiogenic action of microtubule inhibitors is impor- patients. With 733 patients and 6.2 years of median follow- tant as a means to metronomic therapy. Oral form of vinorel- up, relapse free survival and overall survival rates of two com- bine has been experimented in 34 elderly metastatic breast cancer patients; an OR of 38% was reported [84]. The same binations were similar, and uracil-tegafur group expressed a better quality of life [70]. Capecitabine was also combined author used temozolomide during whole-brain radiotherapy with an oral tubulin inhibitor, vinorelbine. Cazzaniga et and metronomic vinorelbine aer ft wards in 36 patients with cerebral metastasis; OR was 52%. [85]. Vinorelbine was added al. used the metronomic combination of vinorelbine with capecitabine with CB of 58% in 34 patients [71–73]. Same to bevacizumab in a trial by Saloustras et al. but study was team conducted another study using the same combina- closed prematurely due to lack of efficacy (OR was 7.7%) [86]. tion; CB was 45.7% and 51.1% in rfi st-line and second-line Another study with an alternative on and off metronomic therapies, respectively. [74] Young et al. investigated the regimen of vinorelbine was dosed every other day for 4 years with a cumulative dose of 30 mgs; a 50% CB was reported, capecitabine with weekly docetaxel to low dose of taxane therapy to induce thymidine phosphorylase expression with without grade 3 or 4 toxicity [87]. addition of daily celecoxib; a 42% of CB was observed with Oral etoposide is a well-tolerated and effective drug for metastatic breast cancer. Two decades ago, Calvert et al. used median time of disease progression (TTP) of 3.6 months [75]. In hormone receptor positive tumors, conventional scheme oral etoposide of 50 mg/m2 for rfi st 14 days of 28-day cycles of fulvestrant was added to capecitabine in 41 patients; CB in 38 pretreated metastatic breast cancer patients. Eight of the patients had a partial response with median TTP of 16 weeks of 58.1% was obtained with 14.9 months’ median PFS [76]. A newer study by Otsuka et al. demonstrated an OR rate of [88]. Bontenbal also used etoposide with 50 mg/m2 orally 47% with metronomic tegafur-gimeracil-oteracil and MTD for rfi st 21 days of 28 days in 27 pretreated metastatic breast irinotecan [77]. cancer patients, achieving a CBR of 43% [89]. Another two- Triple negative breast cancer (TNBC) is another area phase II trial used the same scheme in 43 and 18 pretreated metastatic breast cancer patients; ORR of 35% and PR of 21% where we have a significant shortage of viable treatment strategies; metronomic chemotherapy can be employed in were reported, respectively [90, 91]. The same regimen was multiple settings. An elegant preclinical study demonstrated used as a rst- fi line drug in metastatic patients; one CR and vfi e PR were obtained [92]. In a recent multicenter phase II trial, the action of metronomic chemotherapy in TNBC. In this study, metronomic topotecan was combined with pazopanib oral etoposide of 60 mg/m2 in rfi st 10 days of 21-day cycles was in an orthotopic metastatic breast cancer model to eval- used in 75 patients. A CB of 21.3% was achieved with median uate its potential mechanism of actions and the thera- PFS of 4.5 months [93]. peutic efficacy. The combination was shown to modulate Metastatic breast cancer is a diverse and heterogenous angiogenesis, drug resistance, apoptosis, and proliferation disease with specific targets in which stepwise and sequen- and subsequently prolonged the survival [78]. For neoadju- tial treatment can add survival benefit at the end. Hence, vant regimens, metronomic CP was recruited with weekly metronomic treatments are well known and extensively studied for these types of tumors. In metastatic setting, for paclitaxel aer ft epidoxorubicin-cisplatin-uo fl rouracil (ECF). Pathological response rates were evaluated; posttreatment hormone-receptor expressing tumor types, weekly paclitaxel, Ki-67 was found to be decreased by 41% and 91% of the oral vinorelbine, capecitabine, and ixabepilone have proven efficacy with different side effect profiles. In triple negative patients had complete pathological response [79]. Metro- nomic chemotherapy has also been evaluated for first-line tumor type, capecitabine is now a standard approach aer ft therapy in metastatic TNBC; a multicenter phase III study neoadjuvant setting for patients with residual disease. In compared the toxicity and efficacy of bevacizumab combined heavily pretreated patients, for palliative purpose, oral CYP with metronomic CP versus bevacizumab with paclitaxel; and etoposide were used either as single agents or alterna- there were no differences in ORR or PFS. A novel poly-ADP- tively. ribose-polymerase inhibitor drug veliparib was evaluated in BRCA associated metastatic pretreated TNBC; objective .. Clinical Experience in Castration-Resistant Prostate Can- response occurred in 43% of BRCA associated patients and cer. Castration-resistant prostate cancer (CRPC) is an area 11% of BRCA negative/unknown patients [80]. Metronomic in which there are significant gaps in therapy with cur- chemotherapy was also evaluated as maintenance therapy in rent strategies; for now progressive disease is inescapable TNBC patients. In a prospective controlled study with 158 eventually. But frailty of patients makes the management of stage II-III TNBC patients, group treated with additional this disease more difficult. There has been a comprehensive maintenance metronomic after adjuvant FEC-100 and doc- research for treatment CRPC. Hence, the research continues etaxel was compared to control group without maintenance for possible treatment options for docetaxel-resistant tumors therapy; metronomic group’s DFS and OS were 28 and 37 (i.e., androgen synthesis inhibitors, specific or nonspecific months, respectively, compared to control groups’ DFS of 24 immunotherapy, mitoxantrone, and targeted therapy), and months and OS of 29 months [81]. For advanced pretreated when the frailty of the patients is taken into consideration, TNBC, Viale et al. tested the combination of metronomic CP metronomic therapies were repeatedly tested (Table 2) [94]. with cisplatin yielding a 23.3% clinical benefit at 6 months For CRPC, metronomic CP was an early drug to be after treatment [82]. A different paper evaluated postadjuvant tested and, combined or alone, is still a favored choice. A (FEC100 + radiotherapy) metronomic capecitabine of 6 study investigating CP in CRPC was by Raghavan in 1993; months; mean disease free survival was 42.4 months [83]. of 30 HRPC patients, 18 had a CB and improvement of Journal of Oncology 9 Table 2: Table showing the studies using metronomic regimens in prostate cancer. Duration of Author Treatment N Patient type PSA PR TTP PFS OS Response CP 2 mg/kg qd days 1-14 q28 d Hormone Bracarda, 2000 32 43.7% - - - - - Estramustine 10 mg/kg/day refractory days 1-14 q28d Etoposide 50mg/m2 qd days 1-21 q28d Hormone Pienta, 2001 55 22% Estramustine 15 mg/kg qd refractory days 1-21 q28d CP 100 mg qd Hormone Nishimura, 2001 UFT 400 mg qd 21 57% 7 m - - - - refractory Estramustine 560 mg qd Vinorelbine 25 mg/m2 iv Hormone Robles, 2003 q7d 12 weeks than q14d 14 refractory, 36% Prednisone 10 mg qd po metastatic CP 50 mg qd Hormone Glode, 2003 34 58% 8 m - - - - Dexamethasone 1m g qd refractory CP 100 mg days 1-20 q30d Hellerstedt, Hormone Prednisone 10 mg qd 36 42% 4.5 m - - - 16.4 m 2003 refractory DES 1 mg qd Hormone Lord, 2007 CP 50 mg qd 58 34.5% 7.5 m - - - - refractory Venkirataman, Dexamethasone 0.5 mg qd 102 Castration resistant 49% CP 500 mg/ m bolus than 50 mg qd po Hormone Fontana, 2009 Celecoxib 200 mg bid 28 32% - - - 3 m 21 m refractory Dexamethasone 1 mg/day po CP 50 mg qd Hormone Ladoire, 2010 23 26% - - - 6 m 11 m Prednisolone 10 mg qd refractory CP 50 mg qd Hormone Nelius, 2010 Dexamethasone 1 mg/day 17 23.5% - - - - 24 m refractory po CP 50 mg qd MTX 2.4 mg po two times a Castration Gebbia, 2011 58 25% 24% 28% - - - week resistant, LHRH analogue CP 100 mg qd Hormone Hatano, 2011 UFT 400 mg qd 57 63% - - 13.3 m - - refractory Dexamethasone 10 mg/day 10 Journal of Oncology Th Table 2: Continued. Duration of Author Treatment N Patient type PSA PR TTP PFS OS Response CP 50 mg bid weeks 1,3,5 Ketoconazole 200 mg tid weeks 1,3,5 Castration Jellvert, 2011 Etoposide 50 mg bid weeks 17 59% - - - - - resistant, 2,4,6 Estramustine 140 mg bid weeks 2,4,6 CP 50 mg qd MTX 2.5 mg bid two times Hormone Khan, 2011 69 N/A 57 days a week refractory Celecoxib 400 mg bid CP 50 mg qd Meng, 2012 Capecitabine 1000 mg bid Castration 28 35.7% - - - 4.7 m 19.5 m alidomide 100 mg qd resistant, Prednisone 5 mg bid CP 50 mg qd 634CC 2.2 m Castration Orlandi, 2013 Cetuximab 200 mg bid po 43 32% - - - 634CG/GG - resistant, Dexamethasone 1 mg qd po 6.25 m CP 50 mg qd po Docetaxel 06 mg/ m in q21d Castration Derosa, 2014 41 82% - - - - - Prednisone 10 mg qd from resistant, untreated day 2 Celecoxib 400 mg qd Castration CP 50 mg qd po Yashi, 2014 24 33.3% - - - 5.0 m 19.0 m resistant, Dexamethasone 1 mg qd po metastatic Etoposide 25mg/m2 bid days 1-21, q28d Castration 39 41% 5.9 m Zhu, 2014 Prednisone 5 mg bid days resistant, 1-21, q28d Castration Barroso-Sousa, CP 50 mg qd or CP 150 mg resistant, 2015 days 1-14, q21d 40 20% - - - - - pretreated, Prednisone 10 mg po metastatic CP 50 mg qd po Castration Wang, 2015 Lenalidomide 25 mg qd 6 resistant, 31.7% - - - - - days 1-21 q28d metastatic Abiraterone 25 mg qd po Petrioli, 2015 26 Castration resistant 69.2% 6.4 m 14.3 m Prednisone 5 mg qd po Journal of Oncology 11 the symptoms [95]. After a decade, Nicolini et al. used CP the progression rate was 65.7% and there were no objective in eight metastatic HRPC patients; a CB of 62.5% and a responses [113]. In a phase I trial, adding thalidomide to CP, greater than 50% PSA response in 2 patients were reported 10 out of 13 patients (76.9%) had a progression of PSA> 25%, [96]. Of 80 other patients in whom CP was tested, rate of with 2 (15%) having a>50 reduction [114]. CP, corticosteroid, response was 34.5% including both objective and prostate capecitabine, and thalidomide were evaluated in 8 patients for specific antigen response [97]. Glode et al. tested CP with a median time of 6 months; overall survival was 19.5 months corticosteroids, as both drugs have been used for CRPC and [115]. Another study by Bracarda et al. used estramustine and both were shown to have antiangiogenic properties. Of 34 CP in docetaxel naive patients; the 50% reduction was seen patients, 26% experienced disease progression and 6% were in 14 (43.7%) of 32 patients [116]. Nishimura et al. added found to have a <50% decrease in PSA; 29% of patients tegafur to the estramustine and CP combination; 12 (57.1%) were found to have a greater than or equal to 80% and of 21 patients showed a PSA decline of 50% or greater [117]. 39% were found to have a 50-79% reduction in PSA [98]. Hatano et al. retrospectively evaluated oral UFT and CP Another study with 18 patients and a shorter follow-up of with dexamethasone in 57 patients. 63% of PSA response 12 weeks reported a decrease in PSA of greater than 50% in was achieved; in the PSA responder group, median time to 23.5% and stable disease corresponding to a PSA response progression was 13.3 months [118]. Derosa et al. combined of less than 50% was seen in 29% of the patients [99]. In a first- and second-line drugs in metastatic chemotherapy- retrospective analysis of 40 patients, PSA response rate was naive CRPC patients and used CP and prednisone together achieved in 20.0% of patients [100]. A retrospective analysis with docetaxel; of 41 patients, 87% were free of progression of CP plus prednisolone regimen reported a more than 50% at 6 months, and a decrease in PSA 50% was observed PSA decrease in 26%of patients [101]. Additionally, in a study in 82%. No grade 4 toxicities were reported, with grade 3 of 24 patients, the median PSA progression-free survival was toxicities being neutropenia (5%), thrombocytopenia, diar- 5.0 months and a PSA decrease of 50% was observed in 8 rhea, and stomatitis (2.5%) [119]. Another modiefi d scheme patients (33.3%) [102]. In a multicenter retrospective study consisting of ketoconazole in combination with estramustine, with 48 patients pretreated with docetaxel and another drug, cyclophosphamide, or etoposide administered on alternate ecffi acy of metronomic CPA was retrospectively evaluated. weeks, suggested by Jellvert et al, achieved a 59% decrease 14% of patients had a biochemical response (PSA decrease in PSA>50% [120]. In another multicenter trial with oral greater than 50%); median PFS and OS were reported as etoposide and estramustine 15 mg/kg daily in 55 patients, 22% 3,5 and 6,9 months, respectively [103]. Another study eval- of PSA response was reported [121]. Oral dexamethasone uating biochemical response for 18 patients with median 2 0.5 mg daily alone was evaluated in 102 castration-resistant months of metronomic CPA exposure reported a biochemical patients with 49% achieving a PSA response [122]. Daily oral response of 44% [104]. Fea et al. evaluated the efficacy of CP 100mg with 50mg etoposide (14/21 days) was evaluated in metronomic CPA with ongoing LHRH agonist therapy until 20 hormone refractory patients; an OR of 35% was reported disease progression or toxicity in pretreated patients; PSA [123]. In a retrospective evaluation of oral dexamethasone response rate was 16% without any grade 3 or 4 toxicities regimen in 99 patients, 40.4% of PSA response was found [105]. [124]. Intravenous vinorelbine 25 mg/m weekly for first 12 Thereareother possibleeeff ctive combinations of weeks and biweekly aer ft wards was used with low dose oral cyclophosphamide in pretreated CRPC. In a phase II trial prednisone in 14 patients, with a PSA response in 29% [125]. combining DES with CP and corticosteroids, with reference Oral metronomic vinorelbine was also evaluated with serum to prior shown success of DES in hormone refractory disease, markers of tumor response and activity. PSA response was 15 (42%) of 36 patients had a>50% PSA response and the 61%, and a decrease in VEGF and TSP-1 was observed in overall median survival was 16.4 months [106]. Celecoxib was responders [126]. Vinorelbine alone was compared to weekly also used with CP as it has been shown to have antiangiogenic docetaxel in frail CRPC patients for efficacy, tolerability, action [107]. In consecutive elderly 29 patients, 13 (45%) had toxicity, and compliance. Efficacy and tolerability of the a confirmed PSA decrease of 50% or greater [108]. Another two regimens were found to be similar in elderly unfit study combining celecoxib with CP, by Orlandi et al., 14 (32%) patients [127]. In another phase I/II trial, CP 50 mg daily with showed a PSA>50% decrease; the study also investigated the lenalidomide 25 mg daily in rs fi t 21 days repeating every four pharmacogenetics of VEGF-A and showed that a genotype of weeks was tried in 6 patients with PSA reduction in 31.7%, VEGF-A has impacts on FPS. In 28 advanced CRPC patients, with improved markers of neovascularization [128]. Oral Fontana et al. studied CP 50 mg daily with Celecoxib 200 mg etoposide 25 mg twice daily with oral prednisone twice daily twice daily and dexamethasone 1 mg daily. 32% of the patients was administered for 21 of 28-day cycles; 41% of biochemical had a PSA response. Median OS and PFS were 3 months response was achieved with a PFS of 5.9 months[129]. and 21 months, respectively [109]. In another phase II trial, CP 50 mg daily was combined with MTX 2.4 mg twice a Onestudy hasevaluated themetronomictherapy in week. PSA response was observed in 25% of the patients nonmetastatic prostate cancer. In this prospective single- [110, 111]. Dexamethasone combination with celecoxib and arm study, metronomic CPA was administered for 6 months metronomic CPA was tested by another group for pretreated to patients with only biochemical recurrence after curative CRPC; reported PSA response was 39% with a median OS local therapy before androgen deprivation. 38 patients were of 13,3 months for 22 patients [112]. CP and MTX joined enrolled; 37% of patients had a PSA stabilization, and 58% with celecoxib were evaluated in another phase II trial, but had PSA progression [130]. 12 Journal of Oncology In castration-resistant prostate cancer, with the invention having a partial response of 11 months [136]. In another of new class antitestosterone drugs (enzalutamide and abi- multicenter retrospective study using the same dose of raterone), the role for CYP, etoposide, estramustine, and keto- oral etoposide for 14 days of 21-day cycles regimen in 51 conazole diminished. On the other hand, in a limited number platinum-resistant patients, PFS of 3.9 months and OS of of patients who were progressed on standard approaches and 16.4 months were achieved [137]. As cyclophosphamide is still in need for treatment, oral etoposide and ketoconazole a part of conventional treatment of ovarian cancer and it may have a role. Of note, dexamethasone may have both is favorable for metronomic regimen, Samaritani et al. tried tumor-static effects and antiangiogenic effect in addition to metronomic cyclophosphamide in a 17-year-old female with blocking androgen synthesis for CRPC patients. advanced ovarian cancer with PFS of 65 months. [138] Another study experiencing oral CP alone as salvage ther- . . Clinical Experience in Ovarian Cancer. High recurrence apy in platinum-sensitive heterogeneous patients reported rates even after achievement of complete response to standard median PFS for 4 months and median OS of 13 months [139]. surgical debulking and platinum-based combination therapy Metronomic doses of CPA plus temozolomide were studied make ovarian cancer a challenging entity for clinicians; thus in 55 platinum-refractory patients; an ORR of 44.4% was newer therapeutic approaches have been under investigation. achieved with a median PFS of 5.9 months and a median OS As angiogenesis plays a prominent role in pathogenesis of 10.1 months [140]. Again in platinum-refractory patients, of ovarian cancer, metronomic chemotherapy with other CPA was combined with antiangiogenic pazopanib with antiangiogenetic agents has been a distinguished area for metronomic dosing scheme with median PFS and OS being research [131] for both first-line, maintenance and salvage 8,3 and 24.9 months, respectively [141]. CP and bevacizumab were also tested for pretreated therapy (Table 3). Bevacizumab as an antiangiogenic molecule and its platinum-resistant ovarian cancer. Two studies by Sanches synergism with metronomic chemotherapy were tested for et al. and Garcia et al. combined CP 50 mg/day with beva- ovarian cancer [132]. Bevacizumab was incorporated into cizumab 10 mg/kg intravenously every 2 weeks; the PFS was standard first-line therapy in a phase III study by Burger et al. 4.5 months and 7 months and OS was 7 and 17 months, fortifying the position of bevacizumab, comparing patients respectively [142, 143]. Barber et al. also reported an OS of having carboplatin paclitaxel in three groups. The First one 20 months in 66 patients [144]. Jurado et al. retrospectively was without bevacizumab and the second and third groups evaluated CP and bevacizumab; median progression time was 5.5 months [145]. In another study using the same combi- were with initial and throughout bevacizumab, respectively. It was reported that bevacizumab prolonged the median PFS nation with identical dosage in heavily pretreated patients by about 4 months with a median time of 14.1 months versus with a median previous chemotherapy number of 8, a total response of 53.3% was reported [146]. Bevacizumab was also control groups’ 10.3 months [133]. Two studies evaluated metronomic regimens for mainte- integrated with other conventional regimens. Topotecan in nance therapy. In a nonrandomized study enrolling ECOG cycles of 1, 8, and 15 days of 28-day administrations with 0-1 patients with complete response to standard rfi st-line biweekly bevacizumab resulted in PFS of 7.8 months and OS therapy, metronomic regimen of CPA and MTX was com- of 16.6 months [147]. Pujade-Lauraine et al. experimented pared to observation alone. Maintenance arm had a longer bevacizumab with three different combinations: pegylated PFS of 18 months versus 15 months of observation arm liposomal doxorubicin, weekly paclitaxel, and topotecan; the without any grade 3 or 4 toxicity. Another retrospective median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab [148]. Weekly administered study evaluated a group of patients who were administered a metronomic regimen for neoadjuvant therapy and also ixabepilone was retrospectively evaluated with or without 6 months as a maintenance after adjuvant standard ther- bevacizumab for 24 uterine and 36 ovarian, primary peri- toneal and fallopian tube cancers. For uterine cancers, addi- apy. Metronomic neoadjuvant plus metronomic maintenance group was reported to have a prolonged DFS of 3 months tion of bevacizumab significantly increased both PFS (3.0 without increased toxicity prole fi [134]. months versus 6.5 months) and OS (4.2 months versus 9.6 Neoadjuvant chemotherapy is standard before maxi- months); it was reported that similar results were estimated mal debulking surgery; nevertheless there is an important for ovarian cancer [149]. A meta-analysis evaluating the fraction of patient who are not suitable for eeff ctive but role of bevacizumab concluded that there is an advantage highly toxic platinum-based regimens. Dessai et al. used of PFS and OS when chemotherapy was combined with paclitaxel and carboplatin with an alternative weekly metro- bevacizumab and increased risk of non-CNS bleeding, hyper- tension, gastrointestinal perforation, thromboembolism, and nomic scheme (80 mg/m2 / AUC-2) in patients regarded as unsuitable for standard 3-week regimen. The response proteinuria [150]. The tyrosine kinase inhibitor sorafenib was to the neoadjuvant chemotherapy was 100%; two grade 3-4 also investigated for metronomic efficacy with topotecan; grade 3-4 toxicities of leukopenia/neutropenia (23%), throm- toxicities were reported [135]. Although response rates of ovarian cancer to plat- bocytopenia (17%), and anemia (10%) had occurred. Of 16 inum regimens are considerably high, platinum resistance patients, PR was reported in 5 (16.7%) and SD was reported is inevitable; thus developing treatment strategies in case in 14 (46.7%) [151]. Celecoxib was joined with carboplatin by of platinum-refractoriness is an essential area for research. Legge et al. Median PFS and OS were 5 and 13 months, respec- Oral etoposide of 50 mg/m tively [152]. A cohort comparing metronomic thalidomide for twenty days repeated every 28 days was used in 18 pretreated patients with 1 patient versus tamoxifen in only biochemically recurrent ovarian Journal of Oncology 13 ft Th Th Th Table 3: Table showing the studies using metronomic regimens in ovarian cancer. Bev, Bevacizumab; CP, Cyclophosphamide. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Bev 10 mg/kg q14d Pretreated, 3 6 2 Chura, 2007 15 53% - - - - CP 50 mg qd po recurrent (20%) (40%) (13.3%) Standard regimens 18 60% 6.7% 3.7 m Pretreated, ovarian or Gordinier, 2007 alidomide 200 mg qd 18 53.8% 5% - --- 3.8 m - primary peritoneal None 4 ? ? ? Topotecan 1.25 mg/ m days 30 - 17% 30% 47% - - - 19 m 1-5, q21d alidomide 200 mg qd Recurrent, epithelial, increasing to maximum Downs, 2008 Vs. Vs. Vs. Vs. Vs. platinum refractory tolerated Vs. Topotecan 1.25 mg/ m 39 - 3% 18% 21% - - - 15 m days 1-5, q21d Bev 10 mg/kg q14d Recurrent, 17 6m Garcia, 2008 17 - -- 7.2m - 16.9 m CP 50 mg qd po platinum refractory (24%) (56%) Bev 10 mg/kg q14d Recurrent, platinum 2 2 2 4 6m Jurado, 2008 9 5.5 m - - CP 50 mg qd po refractory (22%) (22%) (22%) (44%) (33%) alidomide 200 mg qd increasing to maximum tolerated or 400 mg Stage III/IV, disease Hurteau, 2010 138 Closed early, interim analysis showed thalidomide was inferior to tamoxifen vs free aer 1st line, Tamoxifen 20 mg qd po for 1year 14 Journal of Oncology Table 3: Continued. Author Treatment N Patient type SD PR CR ORR TTP CB PFS OS Sanchez-Munoz, Bev 10 mg/kg q14d 12 3 38 Pretreated, recurrent (8.1%) --- 4.5m 10.7m 2010 CP 50 mg qd po (32.4%) (8.1%) (6 w) Carboplatin AUC5, q28d Legge, 2011 45 Pretreated, recurrent 10 3 29% - - 5 m 13 m Celecoxib 400 mg qd Bev 10 mg/kg days 1, 13 Platinum resistant, q28d 14 10 McGonigle, 2011 40 ovarian / peritoneal / - --- 7.8m 16.6m Topotecan 4 mg/ m days 1, (35%) (25%) fallopian 8, 15 q28d Sorafenib 400 mg qd Ramasubbaiah, Platinum 14 5 Topotecan 3.5 mg/ m days 14 - --- - - 2011 resistant, (46.7%) (16.7%) 1, 8, 15 q28d Etoposide 50 mg qd po Kucukoner, 2012 51 Platinum resistant, 25.5% 17.6% 3.9 m 16.4 m days 1-14 q28d Bev 10 mg/kg q14d 15 21 7 5m 20 m Barber, 2013 66 Pretreated, recurrent 42.4% CP 50 mg qd po (22.7%) (31.8%) (10.6%) responders) responders) Platinum 11 Ferrandina, 2014 CP 50 mg qd po 54 - -20.4% 4m 13m resistant/sensitive (20.4%) CP 50 mg qd po Bhattacharyya, TMZ 20 mg bid days 1-14, 55 Platinum resistant, 24 N/A 44% 5.9 m 10.1 m q21d Ixabepilone 16-20 mg/ m 8/3 - - - 41.7% - - 3.0 m/- - days 1, 8, 15, q28d Roque, 2015 Uterine/Ovarian- Vs 9.6 m fallopian-peritoneal Ixabepilone 16-20 mg/ m days 1, 8, 15, q28d 16/33 --- --- 6.5m/- - Bev 10 mg/kg q14d Journal of Oncology 15 cancer wasclosed asinterim analysis and itwas shownthat compared metronomic and standard TMZ regimens; thalidomide was not more effective in reducing the recur- although 6-month OS did not have a significant difference, rence rate relative to tamoxifen and higher toxicity rate [153]. PFS was detected to be significantly higher in metronomic Another study evaluating metronomic thalidomide versus schedules[164]. TMZ wasalsocombined withother single-agent chemotherapy in recurrent ovarian cancer and antiangiogenic agents like COX-2 inhibitors; Tuettenberg primary peritoneal cancer showed no significant difference et al. showed that the metronomic TMZ and rofecoxib [154]. Thalidomide with standard topotecan resulted in 2 combination showed antiangiogenic action [165]. A similar months’ increase in PFS in a different phase II trial [155]. study with TMZ and celecoxib in refractory GBM patients Noronha et al. evaluated weekly paclitaxel 80 of mg/m2 in resulted in a PFS of 6 months in 43% of patients [166]. platinum refractory and platinum ineligible 37 non-small cell Another current approach for treatment of GBM with lung cancer patients; the response rate was reported as 35%, bevacizumab was also evaluated by Reardon et al. using bevacizumab with metronomic etoposide for recurrent with median PFS of 4 months [156]. Temozolomide twice daily for fourteen days repeated every three weeks was com- GBM; authors reported similar activity but increased bined with daily CP in 54 patients. There were grade 3 and toxicity [167]. Same authors also tried metronomic etoposide grade 4 toxicities which were mostly hematologic. Overall or temozolomide administered with bevacizumab for response was 44.4%; median PFS was 5.9 months [140]. bevacizumab recurrent GBM but the trial was closed at In conclusion, metastatic epithelial ovarian cancer is a thefirstinterim dueto lackof activity [168]. Twenty-three long-standing malignancy with a need for further treatment high-grade glioma patients were administered bevacizumab options. In heavily pretreated patients, oral metronomic (1 mg/kg every three weeks) and TMZ (50 mg/m2 daily) until CYP has a role. Topotecan is also an effective agent for clinical or radiological progression; 6 months of PFS were platinum-resistant patients as a single agent. Bevacizumab is reported to be lower with respect to other bevacizumab- an approved agent in both platinum-sensitive relapsed and including regimens [169]. With respect to the results with bevacizumab, Zustovich et al. tried another tyrosine kinase resistant ovarian cancer patients in induction and mainte- nance period. There is a growing interest for further studies inhibitor, sorafenib, twice daily with metronomic TMZ; in metronomic, angiogenesis-targeted treatment approaches 6-month PFS was 26%, and median OS was 7.4 months [170]. in this tumor type. In a highly aggressive and resistant tumor type, in glial tumors, well-established metronomic treatment modality includes temozolomide. The addition of bevacizumab has . Clinical Experience in Glial Cancer. GBM has long been conflicting results; however, it is accepted that targeting treated with temozolomide (TMZ) but the results are dis- angiogenesis may improve progression-free survival. satisfying. The metronomic approach to TMZ and GBM has been beheld since the inhibition of O6-methylguanin-DNA- .. Clinical Experience in Renal Cell Cancer. Targeted ther- methltransferase (MGMT) by prolonged TMZ exposition apies have become the standard of care for renal carcinoma. [157]. Targeting angiogenesis, a key metabolism in oncogenesis of A trial with metronomic therapy of alternating etoposide- these tumors has led to improving the survival rate of these cyclophosphamide with daily thalidomide and celecoxib did patients. On the other hand, agent specific toxicities (quality not increase survival rates (Table 5) [158]. Several clinical of life deterioration, anorexia, weight loss, and fatigue) are trials experimented the metronomic TMZ. Clarke et al. major concerns in terms of treatment adherence. Besides, as compared six adjuvant cycles of either MTD (150 mg/m , the progression-free survival duration prolonged, the risk of days 1 to 7 and 15 to 21) or metronomic (50 mg/m daily) TMZ treatment resistance increases. following standard radiotherapy and daily temozolomide in When resistance to targeted therapies emerged, a pos- 85 patients. For MTD and LDM regimens, the 1-year survival sibility to increase the efficacy of targeted therapies with rates were 80% and 69% and the median OS was 7.1 months metronomic scheduling with reference to preclinical knowl- and 15.1 months, respectively [159]. Another study by Kong edge raised and generated further clinical studies [39]. An et al. showed that metronomic TMZ can be effective for elegant preclinical study demonstrated the efficacy of metro- the patients refractory to standard cyclic treatment, with nomic regimens. Metronomic topotecan was combined with pazopanib and tested against human RCC cell lines. The com- 15 patients, with 50 mg/m daily TMZ; 6-month PFS was 32.5 months and 6-month OS was 56.0% [160]; this rescue bination induced and maintained dormancy in metastatic approach was also supported by another study. Metronomic foci. Pazopanib was also shown to increase intracellular TMZ was experimented in similar doses until progression in topotecan levels [171]. An early study was by Bellmunt et highly pretreated patients including ones with bevacizumab al. investigating six cycles of combination therapy MTD exposure; 6-month PFS was 19% [161]. Again, another study gemcitabine combined with metronomic capecitabine and using 8 weeks of metronomic TMZ in relapsed GBM patients sorafenib for 6 cycles and followed by metronomic sorafenib. yielded a median OS of 6 months with a 6-month PFS The median PFS for these patients was 11.1 months. Of the 44 patients, a partial response was achieved in 20 patients, and of 20%. Authors also evaluated the micro vessel density in patients who needed reoperation after maintenance therapy stable disease was reported in 17 [172]. Another study used and demonstrated a decrement [162]. etoricoxib plus pioglitazone daily, with low-dose interferon three times a week and capecitabine twice daily orally for 4 Bevacizumab refractory patients were reported to have a worse response [163]. A published meta-analysis days, every 3 weeks. Median OS and PFS for the total cohort 16 Journal of Oncology were 26.9 and 7.2 months, respectively. Grade 4 toxicity was was reported in 31 patients, with progression-free survival seen in 48.8% [173]. In a recent trial by Tupikowski et al. of 9.53 months [181]. Kontopodis et al. used metronomic metronomic CP and interferon𝛼 combination resulted in a vinorelbine in 46 pretreated patients with a response rate of CB longer than 24 weeks, which was observed in 40% in 30 10.9%; median OS was 9.4 months; 23.9% of patients showed patients; median OS was 13.2 months [174]. grade 3-4 neutropenia [182]. In RCC, sunitinib, pazopanib, and axitinib and in limited Brain metastasis is a frequent progression in NSCLC patients sorafenib have antitumoral efficacy. Beyond tyrosine progression. Low dose TMZ of 75 mg/m for 21 days every kinase inhibitors and new era drugs, for immunotherapies, four weeks concomitant with whole-brain radiotherapy was there is no proven drug which has a metronomic action. administered in patients with brain metastasis. 2 complete Sunitinib in standard doses may be less tolerated in frail and and 11 partial responses were reported in 27 patients [183]. elderly patients. In such cases, 50 mg sunitinib in 14 days on/7 TMZ was also used in a study including brain-metastatic and days off schedule may be an option. non-brain-metastatic patients, with the dose of 75 mg/m , yielding median survival of 3.3 months; grade 3 and grade . . Clinical Experience in Lung Cancer. Lung cancer is the 4 toxicities were reported [184]. Another study evaluating leading cause of cancer-related death; unfortunately it is metastatic patients treated with metronomic regimens con- mostly diagnosed at an advanced stage. According to cluded that addition of radiotherapy may have a synergistic patient and disease characteristics, palliative or curative effect on overall survival [185]. treatments may be chosen. Regarding this point, metronomic Oral vinorelbine is a studied drug for front line, regarding chemotherapy has been a consideration especially for elderly that it has already been established as a front-line MTCR. Two and debilitated patients. studies combined oral vinorelbine. The rfi st one combined For non-small cell lung cancer, metronomic regimens vinorelbine with cisplatin as first line for inoperable advanced were tested as both a rfi st line in frail patients and as a salvage NSCLC; PFS and OS were 4.2 months and 12.0 months, therapy. Oral etoposide is a widely experienced drug for respectively [186]. The second study by Tan et al. used oral salvage therapies. Pfeiffer et al. compared 100 mg twice daily vinorelbine with three different doses of 30-60-90 mg/week oral etoposide with conventional intravenous regimen for a with sorafenib; median PFS was 4.4 and median OS was palliative treatment option for small cell lung cancer (SCLC). 8.2 months; the study showed no statistically significant 1-year survival was 9.8% in etoposide group with OS of 4.8 difference among the three different doses [187]. months, which were reported to be inferior to intravenous Metronomic chemotherapy has also been used for cyclophosphamide and etoposide or cyclophosphamide dox- patients who are ineligible for standard treatment options. orubicin and vincristine regimens [175]. Sorio et al. used oral etoposide with 17 elderly patients In another trial with oral etoposide alternating doses with advanced NSCLC with 100 mg daily for first 14 days of 100 mg in non-small cell lung cancer (NSCLC) patients, of 3- or 4-week cycles; median OS was 24 weeks with one partial response and stable disease were 28% and 34%, partial response and six stable diseases [188]. Camerini et al. respectively, with median TTP of 6 months and median OS evaluated oral vinorelbine in 43 elderly chemotherapy-naive of 9 months [176]. An all oral regimen including etoposide patients, with OS of 9 months [189]. Two other studies also 50 mg/m with UFT and leucovorin was used in pretreated tested vinorelbine for frail patients. One of the studies used advanced NSCLC. Grade 3 neutropenia and thrombocytope- oral vinorelbine (30 mg, 3 per week) for 35 chemotherapy- nia were observed in 12% and 15% patients, respectively, na¨ıve patients, yielding an ORR of 26%, median PFS of 4 with rarer grade 3 nonhematologic toxicities. 14% of stable months, and a median OS of 7 months [190]. In another disease and 28% of partial response were achieved with a study applying the same regimen in a similar frail population, median TTP of 3 months [177]. Another all oral regimen median PFS and OS were 2,5 and 5,5 months, respectively with etoposide with lomustine and cyclophosphamide was [191]. Other regimens were tested for frail, advanced NSLC used in 71 pretreated SCLC patients; ORR of 38% and severe patients. A metronomic regimen of paclitaxel and gemc- but rare hematologic toxicity were reported [178]. An earlier itabine was tested with a combination of bevacizumab with trial by Correale et al. with weekly cisplatin (30 mg/m ,days additional markers of vascularization. In 39 advanced NSCLC patients, ORR was 56%, and median PFS rates at 6 and 1, 8, 14, and 28) oral etoposide (50 mg/m ,1-21 of 28 days) showed increased efficacy; overall response rate was 45.2%, 12 months were 61% and 21%, respectively, with a median grade 3 leukopenia and anemia have been seen, and 3 of OS of 25.5 months [192]. As radiotherapy is a conventional 31 patients died from pulmonary thromboembolism [179]. option in elderly patients ineligible for cytotoxic therapy, a study evaluated the addition of metronomic regimens to Goern et al. used 25 mg/m weekly docetaxel and 50 mg radiotherapy; no significant clinical efficacy was observed daily trofosfamide in 62 stage IV NSLC patients. Overall [193]. response was 19%; median OS was 9.6 months; with PFS of 2.9 months [180]. Same authors studied efficacy of cisplatin Ecffi acy of metronomic regimens as a maintenance chemotherapy was also tested. Maintenance treatment with 30 mg/m days 1-3, with bevacizumab 5 mg/kg in day 3 and oral etoposide in days 1-15 repeating every 3 weeks oral etoposide after rfi st-line docetaxel and cisplatin treat- (mPEBev regimen) in 45 stage III/IV non-small cell lung ment was evaluated in metastatic NSCLC patients, although no complete response was observed; median overall survival cancer. Patients achieving stable disease or objective response were given erlotinib until progression. A partial response was 10 months, with 1-year survival of 41% [194]. Another Journal of Oncology 17 trial evaluating oral etoposide as a maintenance treatment 28-day cycles in 28 gastric cancers; an overall response of was conducted by Li et al. in SCLC patients who responded 50% was achieved with a median TTP of 4.5 months and to etoposide cisplatin regimen. 31 of 54 etoposide cisplatin OS of 9.5 months [201]. In another phase II study by He responsive patients were evaluated; median PFS was 9 months et al. in 45 pretreated elderly patients, 1000 mg capecitabine and OS was 14 months [195]. In a recent trial, oral etoposide was administered throughout days 1–28 every 5 weeks. was combined with bevacizumab as a maintenance therapy Objective response rate was 20.9%. The median TTP was 3.6 following cisplatin, etoposide, and bevacizumab; median PFS months and median OS was 7.6 months. No grade 4 toxicity and OS were 7.8 and 13.2 months, respectively [196]. Correale was observed [202]. Weekly paclitaxel with lower doses of et al. used oral vinorelbine for>70-year-old patients. ORR 80 mg/m was retrospectively evaluated on patients with was 18.6% [197]. unresectable esophageal cancer. After a median of 11 cycles, Metronomic chemotherapy was far less studied for small 71% of 51 patients had improvement in dysphagia. Overall cell lung cancer (SCLC). One study evaluated the efficacy response was 49%, with median progression-free survival of of more ao ff rdable weekly paclitaxel over standard MTC 4.7 months [203]. A different study retrospectively evaluated topotecan for the second-line treatment. Median PFS and OS the efficacy of metronomic capecitabine in pretreated upper were reported as 145 and 168 days, respectively [198]. gastrointestinal tract cancers including patients with esopha- In the palliative setting for heavily pretreated NSCLC gogastric and pancreaticobiliary tumors with 31% of patients patients, oral etoposide is the most studied metronomic agent achieving clinical benefit [204]. which may have an efficacy. Similar approach can be accepted Metronomic regimens were also evaluated for the second- also for SCLC patients who are in need for symptom control line treatment of CRC. A phase II trial to evaluate the and treatment beyond first- and second-line approaches. In efficacy of metronomic UFT, CPA, and etoposide for rfi st-line the elderly, frail patients who are not candidates for standard therapy in metastatic or recurrent colorectal cancer patients approaches, oral metronomic etoposide and vinorelbine may reported an ORR of 70% and a median OS of 23,5 months be the options. In the first-line treatment of NSCLC, systemic [205]. In a study evaluating ecffi acy of addition of metro- bevacizumab has a role as an antiangiogenic agent in addition nomic tegafur/uracil (UFT) to 5-FU and oxaliplatin in 28 to chemotherapy. pretreated metastatic CRC patients, yielded median OS was 13.4 months [206]. Metronomic UFT was combined with . . Clinical Experience in Gastrointestinal Cancer. Antian- 2 weekly 40 mg/m irinotecan in 49 stage IIIb and stage IV giogenesis had been the area of interest in gastrointestinal patients, yielding 5-year survival of 73% and 62%, respectively malignancies for decades. Bevacizumab is the antiangio- [207]. genic agent that is approved for metastatic colorectal cancer Metronomic regimens are again an inviting option for patients. In addition to bevacizumab, pharmacokinetics of frail patients. A study by Romiti et al. retrospectively evalu- well-known chemotherapeutic agent u fl orouracil had been ated efficacy of metronomic capecitabine of 1500 mg daily in studied for better efficacy and decreased toxicity. Hence, 86 frail patients. Overall disease control rate was 26% with a lowered but prolonged doses of standard chemotherapy for 2% partial response and 23% stable disease. 19% of patients gastrointestinal malignancies have been proposed for better were progress-free for 6 months, and the median OS was 8 efficacy, decreased toxicity, and targeting angiogenesis. months. No grade 4 toxicity was observed [208]. Another Pharmacodynamic and pharmacokinetic profiles of trial also with pretreated frail elderly patients with advanced metronomic regimens in gastrointestinal cancer were colorectal cancer evaluated the efficacy and toxicity profile evaluated using a combination metronomic regimen of UFT, of a metronomic regimen of capecitabine (1000 mg twice CP, and celecoxib in pretreated cases. This study showed that 2 2 daily), oxaliplatin (65 mg/m ), and bevacizumab (7.5 mg/m ). the cases of higher 5-FU peak concentrations and area under No grade 4 toxicity was observed; progress-free survival the curves had a better treatment response, thus elegantly was 12.3 median, with 86.7% reaching six months [209]. illustrating the relation between pharmacokinetic profile Capecitabine was also used in a metronomic regimen of 1,5 g and clinical ecffi acy. Moreover, pharmacodynamic profile of daily in frail, recurrent, pretreated colorectal cancer patients. the combination was delineated by measuring the plasma Disease control rate was 26% with a median OS of 8 months levels of pro- and antiangiogenic molecules. Patients with [210]. Another study retrospectively evaluating metastatic higher proangiogenic molecules despite chemotherapy had colorectal cancer patients reported a median TTP of 6.3 more progressive diseases which proposed an antiangiogenic moths and a tolerable toxicity prole fi [211]. activity of the regimen [199]. In another study, metronomic irinotecan was tested in pretreated cases with three Metronomic maintenance strategies for RAS mutant dieff rent metronomic dosage regimens. The combination colorectal cancer were also tested. In a study, RAS mutated achieved a similar response as conventional third- or CRC was evaluated for the response to metronomic main- fourth-line chemotherapy without any significant toxicity. tenance regimens. Patients were given one of four con- Antiangiogenic molecule Thrombospondin-1 was shown to ventional regimens (capecitabine or 5-FU plus oxaliplatin decrease concomitantly with irinotecan infusion, supporting or irinotecan); then nonprogressing ones were randomized an antiangiogenic action of the regimen [200]. with their KRAS mutational status. KRAS mutant ones were An earlier study regarding metronomic chemotherapy randomized to metronomic capecitabine or bevacizumab and in gastric cancer by Colleoni et al. used oral etoposide KRAS wild types were randomized to bevacizumab alone 50 mg/m with intravenous u fl orouracil for fourteen days of or bevacizumab plus erlotinib. The addition of erlotinib 18 Journal of Oncology in KRAS wild type patients did not significantly prolong doses of 5 mg/kg or 10 mg/kg every two weeks in 43 advanced survival [212]. For stage III colorectal carcinomas, efficacy HCC patients; 16-week disease control rate was 42%. Grade of metronomic UFT was questioned in a retrospective study 3-4 side effects including asthenia and hemorrhage were reported [220]. Shao et al. used an alternative regimen of of 113 patients; prolonged 5-year OS of 86.6% was noted in maintenance group compared to control groups, 68.5% thalidomide and metronomic UFT and also got comparable [213]. In CAIRO 3 study, a phase III study was planned to results of median PFS of 0.9 months and a median OS of 4.6 months [221]. A novel use of metronomic chemotherapy ascertain the efficacy of maintenance metronomic treatment with capecitabine plus bevacizumab after an induction treat- was experimented in a Korean trial. In 30 HCC patients with ment with six 3 weekly cycles of capecitabine, oxaliplatin, portal vein thrombosis, an intrahepatic arterial metronomic and bevacizumab (CAPOX-B). 558 previously untreated infusion of epirubicin, cisplatin, and 5FU was performed. Six metastatic CRC patients were allocated into either the main- patients achieved a partial response and six other patients had stable disease. The median overall survival was 162 days [222]. tenance or the observation group on a 1:1 basis. Capecitabine 625 mg/m2 oral twice daily and bevacizumab 7.5 mg/m2 Success of metronomic capecitabine versus observation alone intravenously every 3 weeks were the maintenance treatment. was retrospectively assessed as a second-line treatment; median PFS of the prior group was 12.0 months, while the During the follow-up, progressing patients in maintenance of observation groups were given their second CAPOX-B; other groups had shorter median OS of 9.0 months; authors nonprogressing ones were followed. With a median follow- concluded a 46% reduction in death risk [223]. Another up of 48 months, PFS was signicfi antly 3.2 months longer study retrospectively analyzed the success of metronomic in maintenance group, 8.5 months versus 11.7 months. It protocol of 5-FU, cisplatin, and capecitabine via hepatic was reported that the global qualities of life are similar arterial infusion chemoport versus sorafenib treatment in between the groups [214]. A following randomized study advanced HCC patients with portal vein thrombosis. OS was questioned the efficacy of bevacizumab alone or combined 158 and 117 days, respectively, for the two groups [224]. In summary, HCC has a dismal prognosis and beyond with metronomic CPA plus capecitabine in unresectable CRC patients; the combination did not improve PFS [215]. first-line treatment has little impact on OS of these patients. In the metronomic treatment of gastrointestinal malig- In terms of metronomic treatment, beyond TKI, capecitabine might have a role in patients with higher Karnofsky perfor- nancies, especially for mCRC, the role of capecitabine with/without bevacizumab has a definitively important role mance scores. in the palliative setting and in maintenance therapy for .. Clinical Experience in Multiple Myeloma. MTD with patients who have a response on first-line treatment. autologous stem cell treatment for available patients is a cura- tive regimen for most of the middle-to-high-risk patients. .. Clinical Experience in Hepatocellular Cancer. Advanced Nevertheless, the morbidity of bone marrow transplantation hepatocellular cancer (HCC) has a dismal prognosis. In the and the toxicity profile of the commonly used drugs narrow early stages when the patients are candidates for systemic down the treatment options, especially for relapsed or refrac- treatment, options are scarce. Systemic adriamycin was the tory multiple myeloma. only chemotherapeutic agent that was accepted as standard Vasculogenesis is an important element in pathogenesis first-line treatment for patients who are not eligible for of multiple myeloma; thus employment of antiangiogenic transplant or local ablative therapies. More recently, sorafenib drugs with metronomic schedules can be rational [225]. was recognized as a standard treatment. As HCC is usually The subject has also a historical value: a still used drug, concomitant with cirrhosis, a tolerable combination and/or thalidomide, was discovered to be antiangiogenic and it maintenance treatment with less adverse events is required was rs fi t experimented in multiple myeloma [226, 227]. to improve the survival benefit of sorafenib (Table 4). Cyclophosphamide and thalidomide derivatives are widely Brandi et al. tested metronomic capecitabine in a 69- used drugs with a metronomic regimen. year-old patient with advanced HCC with therapeutic suc- For relapsed or refractory multiple myeloma (RRMM), cess [216]. Following this study, same team experimented Suvannasankha et al. combined oral cyclophosphamide metronomic capecitabine in 90 patients, in whom 59 were (50 mg two per day for 21 days), thalidomide (200 mg daily chemotherapy-naive and 31 were resistant or intolerant to day), and prednisone with 28-day cycles. In 35 patients, CB sorafenib. Median PFS of rfi st cohort was 6.03 months and was 85.8%, with 20% complete response, 5.7% near complete OS was 14.47 months. Second cohort achieved a median response, 13% partial response, and 22.9% stable disease. PFS of 3.27 months and a median OS of 9.77 months [217]. Grade 3 and grade 4 toxicities were reported; hemato- Granito et al. also retrospectively evaluated the ecffi acy and logical ones were most common [228]. Further studies safety of metronomic capecitabine in 26 patients pretreated evaluated thalidomide combined with CP and prednisone. with sorafenib. Median treatment duration was 3.2 months, Reece et al. combined lenalidomide 25 mg on days 1 and median TTP was 4 months, and OS was 8 months [218]. Another trial combined sorafenib with metronomic UFT as 21, cyclophosphamide on 300 mg/m on days 1, 8, and 15, a rfi st-line therapy; median PFS and OS were 3.7 months and and prednisone 100 mg every other day in a cycle of 28 7.4 months, respectively. Hand foot skin reaction occurred days. With a median follow-up of 28 months, ORR was in grade 3 in 9% of patients and was reported to be the 94% and median PFS was 161 months [229]. Zhuo et al. major adverse event resulting in dose reduction [219]. A evaluated metronomic CP with corticosteroids as salvage different study evaluated the efficacy of bevacizumab with therapy in comorbid and heavily pretreated patients, ORR Journal of Oncology 19 Th Table 4: Table showing the studies using metronomic regimens in hepatocellular cancer. UFT, Tegafur-5 FU. Author Treatment N Patient type SD PR CR ORR TTP PFS OS Sorafenib 400 mg bid Untreated, 26 4 Hsu, 2010 53 3.7 m 7.4 m UFT 125mg/m2 Child-Pugh class A (49%) (8%) Bevacizumab 5 mg/kg or 10 6 Boige, 2012 43 Advanced N/A N/A 14.0% mg/kg q14d (14.0%) alidomide 100 mg bid Shao, 2012 43 Untreated, 9% 1.9 m UFT 125mg/m2 (Into the hepatic artery) Epirubicin 30 mg/m2 q28d Portal vein 6 Woo, 2012 30 63 d 63 d Cisplatin 15mg/m2 q21d thrombosis (20.0%) 5-FU 50 mg/m2 q21d 59 Untreated 30 1 2 6.03 m 14.47 m Brandi, 2013 Capecitabine 500 mg bid Sorafenib 31 10 N/A N/A 3.27 m 9.77 m refractory Sorafenib Granito, 2015 Capecitabine 500 mg bid 26 4m 8 m refractory 20 Journal of Oncology Th ff Table 5: Table showing the studies using metronomic regimens in glioblastoma multiforme (GBM). CP, Cyclophosphamide; TMZ, Temozolomide. Author Treatment N Patient type SD PR ORR TTP PFS 6 OS TMZ 75 mg/ m days Chemonaive, refractory to RT Brandes, 2006 33 -- 9% - 30.3% - 1-21 q28d and/or surgery Etoposide 35 mg/ m 11 w 41.5 w days 1-21 GBM and (GBM) (GBM) Kesari, 2007 CP 2 mg/kg days 22-42, 48 59% 11% - - AG 14 w 42 w alidomide (AG) (AG) Celecoxib TMZ 200 mg/ m GBM, 4.2 m 8.8 m Balmaceda, 2008 120 anaplastic astrocytoma, --- - 5.8 m 14.6 m followed by 90 mg/m2 q12h 9 times anaplastic oligodendroglioma 7.7 m 18 m 1:GBM-refractory to 1:21 1:17% conventional TMZ, 2:GBM-refractory to Perry, 2008 TMZ 50 mg/ m qd 2:14 conventional and adjuvant --- - 2:57% - TMZ 3:AG-refractory to 3:14 3:42% conventional TMZ, Pretreated with standard TMZ Clarke, 2009 TMZ 50 mg/ m qd 43 --- - - 15.1m +RT Bevacizumab 10 mg/kg 40.6% 63.1 w two times a week 59 GBM and grade 3 glioma Reardon, 2009 --- - Etoposide 50 mg/ m qd 44.4% 44.4 w days 1-21 q30d 2 2 TMZ 40 mg/ m m qd 56.0% Kong, 2010 38 Pretreated GBM - - - - 32.5% or 50 mg/ m qd (6 m) TMZ 10 mg/ m bid Stockhammer, 2010 28 Pretreated GBM - - - 4.2 m 43 % - Celecoxib 200 mg Bevacizumab 10 mg/kg Verhoe, 2010 q21d 23 High grade glioma - - 20% - 17.4 % 17.1 w TMZ 50 mg/ m qd Bevacizumab 10 mg/kg q14d With Etoposide 50 mg/ Bevacizumab pretreated Reardon, 2011 m days 1-21 q 30d 23 52% - - - 4.4% - GBM, or With TMZ 50 mg/ m m qd Pretreated grade 3 malignant Omuro, 2013 TMZ 50 mg/ m qd 47 --- - 19% 7m glioma and GBM TMZ 40 mg/ m qd Zustovich, 2013 43 Pretreated GBM - - - - 26% 7.5 m Sorafenib 400 mq qd Journal of Oncology 21 was 66.7%, and PFS of respondent patients was not reached As far as melanoma treatment and recent advances are at the study [230]. Same author questioned the use of concerned, still, main part of successful therapy lies on immunotherapeutic approaches and dual targeted therapies metronomic regimens in patients with heart failure who are in driver mutation carrier patients. Besides, during the not eligible for standard treatment protocols. In 54 relapsed treatment process, temozolomide will definitely have a role. or refractory MM patients who also had a severe heart failure (NYHA III/IV), continuous low dose CP and dexamethasone .. Clinical Experience in Head and Neck Cancers. Ad- were administered, 63% clinical benefit was achieved, and vanced head and neck cancers are another group of cancer PFS was reported to be 6 months [231]. Papanikolau et with limited surgical options and inadequate efficacy of al. retrospectively evaluated 186 multiple myeloma patients cytotoxic chemotherapy. who were administered a novel metronomic regimen of Metronomic methotrexate and celecoxib were evalu- bortezomib, thalidomide, dexamethasone, doxorubicin, and ated in platinum-resistant oral cancer without achieving an cisplatin with or without rapamycin. For 186 patients, median acceptable efficacy [241]. In another study in India, oral age was 61, with median 14 pretreatments. Patients have cancer evaluated the success of a metronomic regimen of had median 1 cycle of therapy; median OS was 11.2 months. oral methotrexate and celecoxib starting preoperatively and Median PFS was 3.6 months for an overall response rate continuing as a maintenance after the standard treatment of 63% (117 of 186 patients). Toxicities related to therapy protocol. The disease-free survival rates were 86,5% in metro- were reported to be not trustworthy as some of the patients nomic group versus 71.6% in control group, showing a statis- have had a hematologic condition prior to treatment [232]. tical significance [242]. A similar study from India enrolling Regarding RRMM patients, a prospective phase 1/2 study was operable oral cavity cancer with maintenance metronomic conducted for the effectiveness of metronomic combination therapy showed a median DFS of 13 months [243]. For of lenalidomide, CPA, and dexamethasone. Reported median head and neck cancer, another study evaluated metronomic values of PFS and OS were 12,1 and 29.0 months, respectively oral regimen of methotrexate, erlotinib, and celecoxib in [233]. A dieff rent phase 2 study evaluated low dose daily palliative treatment of patients with head and neck cancers administration of pomalidomide and CPA in lenalidomide and ineligible for MTD. Reported median PFS was 148 days pretreated RRMM patients yielding an ORR of 67% and PFS [244]. Same authors retrospectively evaluated the adequacy of 14 months [234]. of oral low dose chemotherapy for palliative treatment in For patients who are not eligible for stem cell trans- a heterogenous group of head and neck cancer patients, plantation, adequacy of low dose thalidomide maintenance revealing median OS of 155 days with oral cancers having a was assessed after standard induction chemotherapy. With tendency for a shorter OS [245]. 24 months of thalidomide maintenance, median PFS and OS In the light of results of metronomic studies, it can be were 27 and 39 months, respectively [235]. concluded that metronomic MTX (iv, weekly) may have a role In summary, thalidomide and lenalidomide have proven in patients who are heavily treated and are still in need for efficacy with less pronounced toxicity in myeloma patients, chemotherapy for symptom control. which lead to their use widely, especially for maintenance in posttransplantation treatment. .. Clinical Experience in Miscellaneous Cancers. Metro- nomic chemotherapy was also experimented with other .. Clinical Experience in Melanoma. Treatment of melano- cancers. ma has shown a great advancement in the past decade with Berruti et al. used long acting octreotide, metronomic targeted therapies, immunotherapy, and combinations [236]. capecitabine, and bevacizumab in metastatic well-moderately As angiogenesis plays a role in pathogenesis of melanoma and differentiated neuroendocrine tumors. The median PFS was is known to be a prognostic factor, metronomic chemother- 14.9 months. Biochemical response was seen in 52.9% and apy is a particularly appealing strategy [237]. Bhatt et al. symptomatic response was seen in 82.3% of cases [246]. used continuous infusion and paclitaxel 10 mg/m2 and oral Metronomic chemotherapy is also a feasible instrument celecoxib 400 mg twice daily in twenty patients. Median TTP for treating sarcomas, as angiogenesis is a rational target to was 57 days and OS was 212 days. Grade 3-4 toxicities were control the diseaseand thetypical population bearing the catheter-related only [238]. Another study used metronomic cancer can possibly be debilitated for standard doxorubicin or CPA for 3 weeks on 1 week off protocol for 13 untfi elderly ifosfamide based treatment, so administrating a more pallia- people. Median OS was 8 months, ranging from 4 to 37 tive and tolerable regimen is needed [247, 248]. Metronomic [239]. Ellebaek et al. combined CPA and COX inhibitor based cyclophosphamide with daily prednisolone was administered metronomic therapy with immune modulatory autologous to 26 elderly sarcoma patients with one-week cycle. It was augmented dendritic cell (DC) vaccine. Metronomic CPA reported that grade 3-4 lymphopenia was seen in 81% of anda COX-2 inhibitor have been addedto a DC vaccine patients. Total response rate was 26.9% [249]. with the intention to dampen. 8 patients had prolonged SD of 7-13 months [34]. TMZ was also retrospectively evaluated 4. Discussion in a single-center experience; 33 patients were treated with 2 2 cisplatin 75 mg/m every 28 days and TMSZ 75 mg/m for There is no doubt that metronomic chemotherapy has been days 2-21 in patients with younger age and good performance; a great enthusiasm. Medical society needs an innovative median PFS was 24 weeks and OS was 50 weeks [240]. consensual intellect to seize the expanding knowledge about 22 Journal of Oncology biology of cancer and deploy this knowledge to develop References strategies to manage and treat cancer. Metronomic chem- [1] T. Browder,C. E.Butterfield, B. M. Kr¨aling et al., “Antiangio- otherapy is a seminal model for this intellect, integrating genic scheduling of chemotherapy improves efficacy against the concepts of angiogenesis and angiogenetic machinery, experimental drug-resistant cancer,” Cancer Research,vol. 60, tumoral microenvironment, cancer stem cells, and tumoral no. 7, pp. 1878–1886, 2000. immunology. 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Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

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Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

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