Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan

Gauthier Bouche1, Nicolas André2, Shripad Banavali3, Frank Berthold4, Alfredo Berruti5, Guido Bocci6, Giovanni Brandi7, Ugo Cavallaro8, Saviero Cinieri9, Marco Colleoni10, Giuseppe Curigliano11, Teresa Di Desidero6, Alexandru Eniu12, Nicola Fazio13, Robert Kerbel14, Lisa Hutchinson15, Urszula Ledzewicz16, Elisabetta Munzone17, Eddy Pasquier18, O Graciela Scharovsky19, Yuval Shaked20, Jaroslav Štěrba21, Martin Villalba22 and Francesco Bertolini23

1Anticancer Fund, Strombeek-Bever B1853, Belgium 2Metronomics Global Health Initiative; Aix Marseille Université, Inserm, CRO2 UMR_S 911; & Paediatric Haematology and Oncology Department, Children’s Hospital of La Timone, Marseille 13005, France 3Tata Memorial Centre, Mumbai 400012, India 4Department of Paediatric Oncology, University of Cologne D50924, Germany 5Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Azienda Ospedaliera Spedali Civili, Brescia 25123, Italy 6Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, via Roma 55, Pisa 56126, Italy 7Department of Experimental, Diagnostic and Specialty Medicine University Hospital S. Orsola-Malpighi Bologna, 40138, Italy 8Molecular Medicine Programme, European Institute of Oncology, Milan 20141, Italy 9Medical Oncology Department, Brindisi 72100, Italy 10Division of Medical Senology, European Institute of Oncology, European Institute of Oncology, Milan 20141, Italy 11Division of Experimental Therapeutics, European Institute of Oncology, Milan 20141, Italy 12Cancer Institute ‘I. Chiricuta’, Cluj-Napoca 400015, Romania 13Unit of Gastrointestinal Medical Oncology and Neuroendocrine Unit, European Institute of Oncology, Milan 20141, Italy 14Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto M4N 3M5, Canada 15Nature Reviews Clinical Oncology, London N1 9XW, UK 16Department of Mathematics and Statistics, Southern Illinois University, Edwardsville, IL 62026, USA Report Conference 17Division of Medical Senology, European Institute of Oncology, Milan 20141, Italy 18Tumour Biology and Targeting Programme, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Australia; Metronomics Global Health Initiative, Marseille 13005, France; & Centre for Research in Oncobiology and Oncopharmacology, INSERM UMR911, Marseille 13005, France 19Jefa Sección Oncología Experimental, Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, 2000, Argentina 20Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel 21Department of Pediatric Oncology, Masaryk University School of Medicine and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic 22INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier 34295, France & Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier 34295, France 23Laboratory of Haematology-Oncology, European Institute of Oncology, Milan 20141, Italy

Correspondence to: Francesco Bertolini; Nicolas André. Email: [email protected]; [email protected]

Published: 09/09/2014 Received: 28/07/2014 ecancer 2014, 8:463 DOI: 10.3332/ecancer.2014.463

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 administering of way this describe to ‘metronomic’ term the coined colleagues and Hanahan group, Folkman’s from study the on also and group, Kerbel’s by study the on commenting the editorial, of accompanying an In survival mice. increasing and growth tumour suppressing in chemotherapy dose tolerated maximum to superior was chemotherapy low-doseof administration regular frequent that melanoma—indicated and cancer lung including tumours, mouse primary transplanted [2] group his from one 2000, in published papers seminal two the since hisfield the in experience of overview an Toronto)gave of University Centre, Sciences Health Sunnybrook Institute, Research (Sunnybrook Kerbel Robert Session 1:Thelandscapeofthefield cost. Reimbursingthesedrugswouldonlyincreasethe1.8billiondeficitaccumulateduntilnow. their of because system service health Italian the by reimbursed be cancer,not breast will in trials III phase in efficacy shown have which drugs two TDM-1, and pertuzumab that reporting by situation this illustrated He world. the in countries richest the for even unaffordable become have to known is drugs anticancer approved recently of cost safety.The and efficacy on compromising without money save to (LMICs) countries middle-income and low- as well as high-income that in Services Health National for audience opportunity major a represent the they but reminding by started and attendees all welcomed warmly metronomic chemotherapy Oncology) as well as of repurposed drugs are not Institute only promising approaches in European many different cancer the types and populations, at held was (which Prof. Francesco Bertolini (Laboratory of Haematology-Oncology, European Institute of Oncology, Milan, Italy), organiser of the conference Introduction Keywords: metronomicchemotherapy, cancer, drugrepurposing,anti-, pharmacoeconomics,adult,child cheap rescuestrategy. a as not and affordableapproaches innovative new with up come to chance a as seen be always should Metronomics issue. financial the demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing absence of commercial interest the for of companies. because part However,in practice, clinical performing in used well-designed rarely were clinical approaches trials those that of admitted was metronomic it effective, and be to repurposing shown been approaches have that more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches allow will which results encouraging very gave regimens affordable with countries middle-income and low- from experiences clinical The metformin, celecoxib, or as valproic such acid in drugs the metronomic repurposed regimen was of reported and use highlighted The the cancer.potential breast of other in candidate drugs and to cancer,be prostate repurposed. in carcinoma, hepatocellular in beta-blockers), with (together angiosarcoma in tumours], (CNS) system nervous central and neuroblastoma [especially cancers paediatric in particular in presented were chemotherapy metronomic of results clinical New micro-environment. tumour the of compartments vessel blood and From the . pre-clinical metronomic side, of new trials clinical research the findings during indicate performed additional studies possible ancillary mechanisms from of lot actions a of learn metronomic would schedule field on the the that immune and understood metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on translational true a was meeting The 2014. June 24–25 Milan in held was Meeting Therapy and Anti-angiogenic Metronomic Fourth The Abstract trials are small phase II trials, the majority of which are non-randomised, but there are also a number of randomised phase III III phase randomised of number a also are there but non-randomised, are which of majority the clinical trials. trials, This information highlighted the II fact that metronomic chemotherapy largely phase remains a niche treatment concept small in oncology, in are chemotherapy’ ‘metronomic trials of heading the under summarised is information This of variety a cancers. in chemotherapy metronomic of efficacy and safety the evaluate to designed trials clinical 90 approximately identify to able . andxenografts, (NB) neuroblastoma human primary transplanted including models, several results—in impressive the time, that At 2 [1] and the other from Dr Folkman’s groupFolkman’s Dr from other the and www.clinicaltrials.gov [3] . As of June 2014 Kerbel was was Kerbel 2014 June of As . ecancer www.ecancer.org Ms o these of Most . 2014,8:463

Conference Report to need the as well as readership, journal’s the among popular was thus and article cited highly a was this that was article 2010 first in the published of update an commissioning for motivation the of Part meeting. Milan the before weeks of couple a online published [5], 2010 in one first reviews—the two publishing includes which chemotherapy, metronomic of topic of Editor Chief Hutchinson, Lisa the for responsible mechanisms molecular and cellular the define further antitumour effects ofmetronomicchemotherapyregimens. to need the stressed also He guide. a as toxicity low-grade using possibly scheduling, and dosing individualised of benefit or requirement possible a and treatments, combination optimal settings, chemotherapy,metronomic treatment of optimal dose the optimal the on questions open chemotherapy.highlighting by concluded Kerbel metronomic of studies clinical continuing for rationale a provide trials two together,these taken Thus, patients. cancer breast metastatic in bevacizumab with combination in regimen UFT plus metronomic the evaluating trial II phase non-randomised a in evaluating the weekly plus bevacizumab regimen, amd the toxicity in the experimental arm was greater than previously observed considered negative. Kerbel pointed out that the toxicity seen in the standard arm was less than in the corresponding E2100 phase III trial was trial this endpoint, primary the was toxicity since and standard the to compared arm experimental the in greater actually was toxicity of weekly paclitaxel plus bevacizumab. The efficacy results were virtually identical between the two arms, which is encouraging. However, The experimental arm consisted of metronomic cyclophosphamide plus capecitabine and bevacizumab whereas the standard arm consisted as first-line therapy (called SAKK-24-09). However, the number of patients enrolled in this trial, made it more like a randomised phase II patients cancer breast metastatic in Switzerland, resection. in of undertaken time trial. was the trial at III metastases phase completed Another synchronous had and resected, been had tumour primary whose those e.g., patients, certain in benefit survival overall that indicated also in benefit progression-free significant survival (PFS), a especially showed after arm the treatment maintenance maintenance treatment, the but also in after patients retreatment The with regimen. CAPOX-B. CAPOX-B Subgroup upfront analysis original the with retreated then were they arm, either in relapsed only.patients observation When or regimen maintenance the to randomised were they therapy upfront one week off, using higher daily doses), combined with oxaliplatin and bevacizumab (CAPOX-B). If patients showed a response to the initial after they had received a standard regimen of chemotherapy involving capecitabine given in a more conventional schedule (two weeks on/ patients, cancer colorectal metastatic first-line in therapy maintenance follow-up a as bevacizumab, with combined regimen, capecitabine metronomic of efficacy and safety the chemotherapy evaluate regimens. to One trial, designed called CAIRO3, were run that by the trials Dutch Colorectal III Cancer phase Group, evaluated completed a continuous recent lower-dose some daily oral summarised then Kerbel disease forinvestigationaltherapeutics,incontrasttothemoretraditionalapproachofusingmicethatonlyhaveprimary tumours. metastatic of models mouse using of benefits the highlight also results The angiogenesis. inhibiting by circumstances certain in work not may chemotherapy metronomic that implies regimen. This same the with treated were tumours primary with mice when case the not was this whereas survival, prolonged experienced disease metastatic with Mice drugs. chemotherapy oral cyclophosphamide-two plus (UFT) Tegafur-uracilchemotherapy,e.g., metronomic using line, tumour same the with mice treating when observed was pattern opposite The setting. this in active was drug the that indicated tumours primary established with mice treating chemotherapy.contrast, with In or alone sunitinib of trials clinical III phase randomised previous with correlated chemotherapy.This standard with combined when even survival, prolonging of terms in activity no showed drug the cancer, breast metastatic advanced with mice in sunitinib testing when example, For when treating mice with advanced metastatic disease. This is in contrast to regimens chemotherapy certain metronomic various other of impact therapies, promising the including showing group, targeted his from anti-angiogenic findings recent highlight drugs. to on went Kerbel These effects candependheavilyonthenatureofchemotherapydrugstudied. action describedintheliteraturetoaccountforantitumoureffects ofmetronomicchemotherapy. These include: circumstance this change significantly stimulatingtheimmunesystem. • affecting tumourcellsdirectly, possiblyincludingcancerstemcells • suppressinghypoxia-induciblefactor1-apha(HIF1-alpha) • inhibitingmobilisationordirectlytargetingpro-angiogenicbonemarrowderivedcellpopulations(BMDCs) • targetingendothelialcellsofthetumourneovasculature • Nature Reviews Clinical Oncology Clinical Reviews Nature , was invited to explain the reasons behind the journal’s interest in the in interest journal’s the behind reasons the explain to invited was , 3 and a very recent update in 2014 in update recent very a and [4] ecancer www.ecancer.org 2014,8:463

Conference Report with it be encouraging, also trastuzumab are agents targeted with chemotherapy metronomic of Experience population. various in and combinations His group had performed several trials in the metastatic setting and results indicate a clinical benefit rate (CBR) of 60% or more with various Overall, about 15% of patients with targeted metastatic to breast cancercompared derived when a long empirical term quite benefit as (for now more the than until on 12 months) performed approaches, withlownumbers,andwererarelyrandomised. overview of trials metronomic the comprehensive approaches. a described He gave cancer. Italy) breast Milan, in Oncology, experience of metronomic Institute European Senology, Medical of (Division Colleoni Marco Session 2:Breastcancer, paediatric cancer, andmodels published. be can it before validation and replication further need the and infancy its in colonising still is work This tested. population be can which microenvironment, cell tumour different many represent nicely could analysis Spade and technology (CyTOF) Cytometry Mass Flight of microenvironment tumour the impact may Timea using that suggested therefore (TAM),He macrophages which others. associated T-regs,such and tumour therapy fibroblasts, following cells of subtypes the Specifically, therapy. following microenvironment tumour the at detected increased metastasis, whereas the pure metronomic regimen resulted in a very slow growth of the tumour with minimal metastasis lesions and regrowth rapid a by followed therapy the following response complete initial an in resulted regimen MTD the comparison, In survival. the chemo switch regimen which not only reduced the tumour growth and controlled it, but also it inhibited metastasis and increased mouse 2005 in Hanahan and Kerbel by proposed initially regimen this of superiority the confirming regimen, chemo-switch the with treated were they when survival, the extended model tumour pancreatic orthotopic an bearing mice period. which treatment in the lab ‘chemo-switch’his during This from results recent the explain could regimen MDSCs of levels low keeping thus gemcitabine, metronomic to treatment the switching a levels by blocked MDSC be can in gemcitabine MTD rebound following the that showed He regimen). metronomic (representing gemcitabine daily to compared when regimen) MTD (representing gemcitabine weekly with treatment following mice bearing non-tumour of blood the GR1+/CD11b+in markers surface the In a recent study, Shaked’s lab found that similar to EPCs there is also an increase in myeloid derived suppressor cells (MDSCs) expressing focusing onEPCs,distinguishingbetweenthelevelsofCEPsfollowingMTDcyclophosphamideandmetronomiccyclophosphamide. acceleration of metastasis. He mentioned that experiments from Bertolini published already in 2003 and tumour primary the from dissemination cell tumour to lead also can effects chemotherapy host MTD these following that showed also He angiogenesis. and re-growth tumour promote may turn in which factors growth of storm a generates regimen, MTD acute to response were also induced in the plasma in response to paclitaxel chemotherapy but not in response to gemcitabine. He concluded that the host, in (VEGF) factor growth endothelial vascular not but (SDF1) factor derived cell stromal and (GCSF) factor colony-stimulating granulocyte as drug anti-angiogenic an with treatment upfront an ‘blunted’by was which effect an blood, the in (EPCs) cells progenitor endothelial in induction an is there that showed he gemcitabine), not (but paclitaxel of dose bolus with treated mice bearing non-tumour Using regimen. chemotherapy metronomic is to environment compared when tumour regimen the chemotherapy (MTD) whether dose was tolerated maximum addressed during he changed question first The chemotherapy. metronomic to of hypotheses effect new therapeutic preclinical the describing of explain task the had Israel) Technion,Haifa, the at Medicine of Faculty (Rappaport Shaked Yuval is editoriallyindependentandalsotheimportanceofstayingintouchwithfieldbyattendingconferences,suchasthisone. Review’s journals. She highlighted the professionalism and expertise of of the team team leading the journal,editorial as wellthe as emphasisingon that the elaborated journal she Importantly, the generalscepticismofpotentialmetronomicchemotherapywithincancercommunity. behind reasons key the and approach, therapy this of success the metronomics, of therapy,action of mechanisms the repositioning, drug chemo- metronomic of advantages the emphasising by talk her continued She editorial. recent a in discussed also was context broader a cover topics that are under-highlighted in the literature. The potential of metronomic chemotherapy for the medical oncology community in observed inpatientstreatedwithbevacizumabandtrastuzumab. . However, Shaked stressed that focusing on one or two cell types does not allow a systemic view of the changes occurred changes the of view systemic a allow not does types cell two or one on focusing that stressed However,Shaked [10]. [11 ] or with bevacizumab and/or trastuzumab in the BEX/BEXET trial, even though some coronary heart disease (CHD) was was (CHD) disease heart coronary some though even trial, BEX/BEXET the in trastuzumab and/or bevacizumab with or , its editorial processes, and those of the Nature the of those and processes, editorial its Oncology, Clinical Reviews Nature . In this new experiment the best approach to control tumour growth was growth tumour control to approach best the experiment new this In 9]. [8, 4 [7] demonstrated similar results when ecancer www.ecancer.org . Factors such Factors [6]. 2014,8:463

Conference Report circulatingonendothelialstudy circulating(CEC),cells surrogateendothelial predictive asprogenitorCPP and(CEP),showed They used IBC as a model disease to investigate biological changes associated with an antiangiogenic agent as bevacizumab.studies. clinical and preclinical both in The examined biologicalfurther be to need will it although IBC, for approach therapeutic reasonable a be would system signalling VEGF-C/VEGF-D/VEGFR-3 the through Targetinglymphangiogenesis IBC. in specifically not IBC to in IBC than contribute in non-IBC tumour may samples. Several treatments targeting it lymphangiogenesis have been IBC; investigated in cancer in in general, but common is Lymphangiogenesis spread. Higher expression of capecitabine. lymphangiogenic factors (VEGF-C, VEGF-D, and VEGFR-3, Prox-1, and fibroblast growth factor 2) are detected to concurrent or before bevacizumab using wall chest the to spread lymphangitic with (IBC) cancer breast inflammatory recurrent with patients in trial a from results presented Italy) Milano, Oncologia, di Europeo Istituto Therapeutics, Experimental of (Division Curigliano Giuseppe cancer, breast in Continuing The roleofmetronomicchemotherapyseemsparticularlypromisingintheneoadjuvantandmaintenancesettings. positioned. be could chemotherapy metronomic where places suggesting and landscape cancer breast the at looking by concluded She and cyclophosphamide, vinorelbine, presentation, andpreliminaryresultswerepresented. of her of time combination the at planned the patients metastatic 146 of the of 59 role recruited already had the trial metronomically.The administered capecitabine evaluating 2010-024266-21) (EUDRACT trial VEX drugs), other the with seven and including capecitabine with (ten regimen metronomic with trials ongoing 17 identified she setting, metastatic the In chemotherapy. This regimenwasassociatedwithahighPCRrateandlowtoxicityin TNBC patients. (FEC) cyclophosphamide and epirubicin (5FU), Fluorouracil by followed paclitaxel/cyclophosphamide/capecitabine metronomic with results In the neoadjuvant/post-neoadjuvant setting, she identified seven trials. She also highlighted that Masuda recently reported receptor negativepatients. hormone in therapy adjuvant standard after maintenance cyclophosphamide- for testing (NCT00022516) trial 22-00 IBCSG receive will arms four patients the where the TNBC intervention (NCT01112826) in group of receive trial one year of two SYSUCC-001 metronomic capecitabine maintenance the after standard where adjuvant exercise), therapy, +/- and (NCT00925652) the intervention diet trial (plus ABCDE bevacizumab the with as cyclophosphamide metronomic such trials adjuvant interesting most She chemotherapy. the metronomic of positioning some for listed settings interesting be to also seemed settings adjuvant and neoadjuvant The benefit. clinical of markers surrogate reliable and biomarkers at looking on be should trial chemotherapy metronomic designing in directions New whole treatmentperiod,whichindicatesamorecomplexandpotentimmunomodulationofmetronomiccyclophosphamide. patients that Tregs were only transiently depleted during metronomic cyclophosphamide but tumour reactive T-cells were increased for the the number of Tregs, or an inhibition of the function of Tregs. A 2012 paper by Ge and Domschke in decrease a especially and immunity the on effect an including actions of mechanisms possible New future. the on view breast a with about cancer discussion the continued Italy) Milan, Oncology, of Institute European Senology, Medical of (Division Munzone Elisabetta relevant clinically most the of choice and combination, the endpoints. of could choice the trials for the of rationale design better the future, selection, the patient For better (QOL). with life of improved be quality on impact and toxicity limiting while patients of proportion large a in and is has activity shown able to the disease control chemotherapy that metronomic it is Overall, experience from clear the cancer breast definitive any making precluded randomisation conclusion. of absence the and numbers, limited in but rates (PCR) response complete pathologic response of terms in arm metronomic the and arm standard the between difference any show not did trial randomised a setting, neoadjuvant the In triple-negative breastcancer(TNBC)]betweenCMmaintenanceandobservationfirstresultsshouldbereleasedinspring2015. reported in 2009 by Watanabe trial Japanese the in as observed been have regimen metronomic a and regimen MTD [13] Ohr xeine dig ernmc rtcl o tnad eajvn ceohrp rgmn hwd interesting showed regimen chemotherapy neoadjuvant standard to protocol metronomic adding experience Other . [12]. The IBCSG 22-00 trial has just completed recruitment and randomised patients [70% of 5 [14] showed in metastatic breast cancer ecancer www.ecancer.org [15] 2014,8:463 encouraging

Conference Report (CR) paediatricpatientsarestillnottranslatedintocurrent practice. remission complete first high-risk very for maintenance as metronomics bring to attempts setting, relapsed in results encouraging Despite medulloblastoma. 13 of six and sarcoma, NB, high-risk high-grade 22 of one five only tumours, low-grade with patients 13 of out 12 find we regimen, this of survivors long-term the at looking that COMBAT is a feasible, effective, and low-toxicity treatment option for patients with relapsing/refractory malignancies relapsing/refractory with patients for option treatment low-toxicity and effective, feasible, a COMBATis that Treatment) regimen, Antiangiogenic which included low-dose Biodifferentiating daily temozolomide, Metronomic , celecoxib, Oral vitamin D, (Combined COMBATfenofibrate, and the retinoic with acid, and results the conclusion their of audience the reminded He year in2008–2013. per oncology adult in trials I phase 200 than more to compared ten than (EU)—fewer Union European the in cancer with children in year He listed some of the inherent problems of paediatric oncology and emphasised the very limited number of phase I trials happening every Response EvaluationCriteriaInSolid Tumours (RECIST)formetronomicchemotherapy. emission tomography (FDG-PET), highlighting that PET Response Criteria in Solid Tumours (PERCIST) 18-Fluoro-deoxyglucoseon seenpositron only wereresponse the of somemedulloblastoma.emphasised thatwithpatients He three and astrocytoma,anaplastic with patient one approach,metronomic a frombenefited and to responded who patients of cases fourdescribed Jaroslav The twofinalpresentationsofthefirstdaywerereportedexperiencesinpaediatriccancers. metronomic capecitabine/sorafenibtosorafenib/metronomiccapecitabineinadvancedHCCpatients. everolimuswith metronomic capecitabine in HCC/OLT patients at high risk of relapse; the second is a phase III randomised trial comparing They have now designed two trials for which they are currently assessing funding opportunities. The first is a pilot study on the association of comparison withhistoricaldatashowedonlymoderateimprovementinOS. ITA.LI.CA. the from controls untreated matched to months) favourably eight (of compared database which months 15.6 of OS median a gave and tolerated well was capecitabine metronomic first-line the performed, they trials the to Moving response. complete of confirmation histological with one He sorafenib. with one in combination response in dramatic a alone them capecitabine published metronomic with they of patient 2010, In three alone. HCC, chemotherapy in metronomic with regimen experience own their chemotherapy from data metronomic presented a testing trials, six identified had He interesting candidateforthisdisease. of because an drug chemotherapy metronomic make HCC in found cells the progenitor endothelial of level high the and stop effects. angiogenesis side strong The to having patients of 30% approximately with toxicity, some and benefit limited has which sorafenib on relies mainly treatment systemic population, this In (HCC). carcinomas hepatocellular with patients to cancer breast with patients from us took Italy) Bologna, Orsola-Malpighi S. Hospital University Medicine Specialty and Diagnostic Experimental, of (Department Brandi Giovanni signature wasstronglyenrichedforstromathatclearlyhighlightedtheimportanceoftumour-stromacrosstalkprogressionIBC. This environment. remodeling stroma pre-existing a by enhanced seems bevacizumab to response The (CDKN2A). regulation cycle cell and (MMP1) remodeling matrix in involved genes 75 identified clustering response. Asupervised no had that those from respone partial for response in IBC with lymphangitic spread to the chest wall. They identified 160 genes that clearly separated patients that had achieved To date, no molecular feature reliably predicts the response to bevacizumab. Using DNA microarrays, they searched for multigene predictors inflammatory response. suggest a reduced survival in patients with intense angiogenic activity (as reflected by highmedian valuelevels wereassociated ofwithsignificantly a CEP improved and overall viablesurvival (OS). CECs)These data, confirmedifand largerin IL-8-mediatedseries patients,of might vessel stabilisation). On the other hand, baseline counts of CEPs, of viable CECs, and of the inflammation-related chemokine IL-8 below the thatbaseline,at responders hadsignificantly higher countsCEC subpopulationaof expressing VEGFR2 andCPPsof(possibly involved in Štěrba (Brno School [17] of Medicine, . In second-line and in patients with Child-B disease, their experience also seems promising, but in in but promising, seems also experience their disease, Child-B with patients in and second-line In . Brno, [16] Czech and he presented two other unpublished cases with impressive response, including including response, impressive with cases unpublished other two presented he and Republic) set 6 the scene of metronomic chemotherapy [18] may be a better endpoint than in paediatric ecancer www.ecancer.org 2014,8:463 oncology. [19] . When . He

Conference Report activitycetuximabofpanitumumaboflackand biomarkers, broadenedcoloncancer).also of viewin He the mentioning different the types review 2010 their Guido Bocci (University of Pisa, Italy), gave a presentation about biomarkers. Starting with the definition from Marc Buyse and colleagues in Session 3:Biomarkersandrepositioning followed bymetronomicwithatime-varying,feedback-type dose. tumour the microenvironment (vasculature, immune system). Once nor any of these aspects are included heterogeneity into the model, the the optimal protocols were MTD neither account into take not did which models in effective was alone therapy MTD the Summarising, directions, shewouldliketoworkonthemodelofchaotictherapyproposedincollaborationwithNicolas André andEddyPasquier. future the in pointed also tumour.She the eradicate actually to need no with growth tumour the on depending dose the adjusting require She concluded by saying that the ideal approach to reach the good equilibrium would be a feedback dose or adaptive therapy. This would boundary andgotowardsthegoodequilibrium the boundary with the good region. However, it was then necessary to switch to metronomic chemotherapy to be able to actually cross this and bad regions, respectively. In this model, the MTD approach (bang-bang control) brought the point from the bad region close to crossing and the other with strong growth and depressed immune system (the bad equilibrium). Each of them has its region of attraction called good the describe to model. used Basically,was portrait this model phase has called two main representation points of geometrical equilibrium, a one with interactions, no system growth and immune a the competent immune adding system model, (the good last equilibrium), the In followed byarestperiod. The singularpartistheoneresponsibleformajorofshrinkingtumour[21] controlsingular the to switch to then vasculatureand the effecton an have to order in bang)(bang dose full with start toimportant was it heterogeneous cancer cells, the Chemo-Switch was the most effective. In a more comprehensive model taking into account the vasculature, In a model of homogeneous cancer cells, an MTD approach works best, whereas the singular approach was less effective tumour microenvironment,andamodeltakingintoaccounttheimmunesysteminteractions. the of compartment vasculature the account into taking a model cells, cancer of populations heterogeneous with a model cells, cancer of (first Chemo-Switch bang-bang followed by or singular). To singular), do (called this, she used chemotherapy four different contexts: a metronomic model with a bang), population homogeneous bang (called MTD meeting: this during discussed approaches main three chemotherapeutic the team compare to her models with mathematical analysed works have They USA) approaches. biomedical Edwardsville, describe that University, models mathematical Illinois on Southern Statistics, and Mathematics of (Department Ledzewicz Urszula (MTD approach)thanfromthecurrentmetronomicstudy. children could be treated in an the outpatientphase. assess All next the to to setting.move to allowed patients which responses Thesome 15 as well myelodepressiveas in observed were toxicities done 3 grade sidesome first that showed effectsand was feasibility study resultedpilot Averyendpoint. likelyprimary morethe fromas the(EFS) precedingsurvival event-free chemotherapywith patients 26 in and methotrexate cyclophosphamide, celecoxib, using tested and implemented being now is trial 2012 METRO-NB the 2010, in Marseille in Meeting Metronomic Second the Following responses. some with NB in studies pilot five in drugs other with combination in tested been has Since NBs express high levels of cyclooxygenase-2 (COX-2) and preclinical data have confirmed the potential of COX-2 inhibitors, celecoxib is ongoingandshouldaddressthisquestion. (EUDRACTconclusion. 2012-000072-42) trial any BEACON making the precluded Atrial, which randomised patients, European of larger for candidate good a anti-angiogenic NB treatment if makes bevacizumab This works angiogenesis. well of in makers other of levels high and VEGF high have NB high-risk or advanced with He explained that NB is a prototypical highly vascularised tumour. In addition, vessels are immature and of embryonic type in NB. Patients transplantation hadanincreasedsurvival,abenefitwhichwashoweverstilllimited. cell stem allogeneic second a undergo could who patients Only data. his by shown as outcome, the on impact no has chemotherapy and recurrence after survival poor very a have He patients These NB. high-risk NB. with patients 246 of on analysis retrospective a focus from data presented a with experience his reported Germany) Cologne, of University Oncology [23] , he showedvalidatedthathe , predictive oncologybiomarkerstheinfield few(e.g.,very areK-rasmutation predictive of [22]. in vivo models. The four small pilot studies in NB only included a very limited number 7 ecancer . www.ecancer.org [20] 2014,8:463 . In a model of

Conference Report Society of Medical Oncology (ESMO) or National Comprehensice Cancer Networkthat his(NCCN)] interest cannot stems befrom implementedthe Breast as Healthsuch Globalin limitedInitiative resource(BGHI), Alexandruan initiative Eniu (Cancerwhich Institutestarted ‘I.Chiricuta’,because the Cluj-Napoca,current guidelinesRomania) explained[e.g., he Europenahad limited experience with metronomic chemotherapy but and notasacheaprescuestrategy. approaches affordable innovative new with come to chance a as seen be should cancer. Metronomics the of dying of risk 90% have you numerous, and he illustrated this with the horrible fact that, as a child with cancer living in one of the 25% poorest countries in the world, LMICs in repurposing) drug and chemotherapy (metronomic metronomics of use the was talk their of topic the and India, of Banavali Shripad and Children’s Oncology Department, Hospital of La Timone, France) Marseille, the introduced next two speakers, Alexandru Eniu of Romania Nicolas André (Metronomics Global Health Initiative; Aix Marseille Université, Inserm, CRO2 UMR_S 911; & Paediatric Haematology and (to documentCss)andaneedofPK-PDmodels. nisms are involved and need to be explored. For the future, there is a need of a therapeutic drug monitoring of metronomic chemotherapy could be used as predictive indicators of efficacy. Plasma VEGF and VEGF gene polymorphisms may be a starting point but more mecha- He concluded that PK study needs to be done in metronomic chemotherapy trials as they are very informative and because PK parameters cyclophosphamide wherehighplasmaVEGFwasassociatedwithlowerPFS[29] level of plasma VEGF view,of thepoint is pharmacodynamics chemotherapy a metronomic From from benefit of validated— not used—but most the patients. Indeed,arecentpilotstudysuggestedthatVEGFSNPs(i.e.,VEGF-634C/G)maybepredictiveofPFSbenefits [27]. metronomic UFT manner in treated cancer patients metronomic chemotherapy, he showed that some genes, such as TSP-1, increase their expression in a time and concentration-dependent capecitabine metronomic includes an extensive PK study and will provide further information. Regarding the pharmacogenomic markers of survival a of predictive was + bevacizumab and alone bevacizumab administration between randomised patients, MOMAbenefit. cancer The colorectal 222 study,of first trial II phase a very the after µg/ml 0.5 than higher Cmax in 5-FU than disease The disease. stable progressive with with patients patients in higher was plasma in UFT) of metabolite active (the 5-FU of (Cmax) concentration maximal the cancer colorectal in studies, irinotecan metronomic these by provided information of tumours paediatric in wealth cyclophosphamide or vinorelbine with the 2006 in Stempak and by reported studies regimen the as such metronomic with performed studies PK of examples cited then He tyrosine as kinase inhibitorsortherapeuticantibodies. such drugs, other with negative) or (positive interactions PK possible any on information precious add could knowledge PK is required compared to conventional regimen, since most doses used are rather empirical with no consensus on the best dose. Moreover, constant optimal, an reach and important information that the PK study would give on metronomic chemotherapy is the possibility to find the correct dose reduction which know to important is it chemotherapy, metronomic of concentration of the drug, concept or its active metabolites over the time, which he called concentration in at a steady state (Css), that believes is effective. Further one if Because then? important this be is Why regimen. would this support to markers study PK no (PK) is there cyclophosphamide, pharmacokinetic mg 50 ‘simple’classical the for maybe instance, For interesting. that important as underlined he chemotherapy, metronomic to back Coming following: the are biomarkers for challenges main under-highlighted.the Tousuallyhim, were methods, imaging like some, that and biomarkers of theneedofcooperationbetweenindustryandacademia. • thevalidationpart • thequalityofagoodassay:quick,reliable,inexpensive,andeasy • theneedofmultipletestingmethods • theavailabilityofbiologicalmaterial • [30] . As we enter the 21st century, cancer has become a global disease. The challenges for good cancer care in LMICs are are LMICs in care cancer good for challenges The disease. global a become has cancer century, 21st the enter we As . [26]. The personalisation of metronomic chemotherapy could be obtained through a pharmacogentic analysis of candidate [28] . . This was in with also observed treated metronomic clearly tumours a canine model of metastatic spontaneous [25]. Moreover, CD133 gene expression has been proposed as a potential pharmacogenomic marker of and Allegrini in 2012 in Allegrini and [25], 8 with metronomic UFT in gastrointestinal cancers. In the latter, the In cancers. gastrointestinal in UFT metronomic with [26] . , Allegrini in 2008 with 2008 in [24], Allegrini ecancer www.ecancer.org 2014,8:463

Conference Report Moving tothemetronomicapproach,helistedadvantagesoftreatmentintheselimitedresourcescountries: specialists; thechoiceofdrugstherewasnotdrivenbyindicationbutavailability. theresources were extremely limited inthecountryside. Theyrealised that some ofthecore issues were theabsence ofmedical oncology He then illustrated the situation in Ghana, where chemotherapy and hormone therapy could be provided in Kumasi teaching hospital but that for resourcestratificationandproposedguidelineswithfourlevels. BGHIpublishes guidelines and organises global summits. Itsoon found that there isno one size that fits all (heterogeneity) with requirement countries, and therefore other guidelines were required. He underlined that a clinician in those countries is a manager of scarce resources. The for trastuzumab at their centre, only 4% of non-trial patients received trastuzumab, the majority of them paying from their pocket their from paying them of majority the trastuzumab, received patients non-trial of 4% only centre, their at trastuzumab for eligible patients cancer breast HER2+ of cohort large a in that showed He LMICs. in patients most for reach of out is treatment such of of understanding various molecular cancers and of development many therapies, targeted of the are responses short and lasting, the cost of advent the with changing is paradigm the though Even all. at if improvement minimal is there others many for tumours, solid some in outcome improved have we though strategy Tolerated chemotherapy Maximum the based using (MTD) that Dose showing by started He with experience metronomic chemotherapy. Indian the about talked who India, Mumbai, in Centre TataMemorial the of Banavali Shripad was speaker next The that oneyearofcyclophosphamide-methotrexatemaintenancecosts12euroinRomania. stating, forinstance, of drugs, accessibility support but also research fund could which Fund Metronomic a Global to setup suggested He in Madrid. older drugs, as indicated by a recent survey that they carried out and which will be presented at the ESMO conference in September 2014 World the on drugs therapy hormone Health Organisation (WHO) essential medicines list to increase the number of and possibilities. Europe is being affected by a drug shortage of chemotherapy some adding on working force task the of importance the mentioned also He It doesnotmeantherearenoissues—forinstance,vinorelbineneedstobestoredinacoldplace. survival whencomparedtomatchedcontrolsinpatientswith advanced,operableH&Ncancers increased with associated was month) a USD 15 than less cost (which celecoxib and methotrexate of combination the cancers, H&N In 50% atfiveyears[30] (which costs less than 25 USD a month) gave durable responses. Compared to the literature, the 49In patientsrelapsed, had favourablerefractory, OS of more and/orthan metastatic Ewing and rhabdomyosarcoma, the combination of oral tamoxifen, etoposide,in sarcoma,headandneck(H&N)cancers,acutemyelogenous leukaemia(AML). and cyclophosphamide or recurrence; peri-operative; and in the maintenance setting. As examples in these settings respectively, he reported of their experience highest the of relapse therefore settings: in clinical different three interesting is is especially chemotherapy in this type of of interest region. metronomic The interest chemotherapy Metronomic therapies. standard give to infrastructure limited is there and disease, advanced (www.walawalkarhospital. Dervan com in TataMemorial of centre outreach rural the in situation the Mumbai, in situation the to Compared lower • Maximumlevelcorrespondstowhatisavailableinrichcountries. • Enhancedlevelarethirdtierresources. • Limitedlevelaresecond-tierresources. • Basiclevelarecoreresources(e.g.,operatingroom). • lower cost,solesscostforthepatientandbettercompliance. • oraltreatment,sononeedofinfusionfacilitiesandpossibleinadistributedhealthcaresystembutissuesensuringcompliance • ) is typical of the rural challenge in India. Issues are not only financial but also clinical, as patients present with poor nutritional status, status, ) with poor nutritional present as is of in are but Issues patients typical not also the India. clinical, only challenge rural financial toxicities

toxicity

and .

therefore

better

compliance,

less

frequent

visits, 9

potentially

fewer

blood

tests, [32].

and

no

special ecancer

equipment www.ecancer.org 2014,8:463

for

following [31] .

Conference Report is setbypharmaceuticals. This mightexplainsomeof therecentissuesincludingskyrocketingcostofdrugs. drug development is that, in the past, the agenda of drug development was mainly driven by academia. It is no more in him the to problem main drugs. The old into case look to lab their as of interest recent the explaining the by session this concluded agenda Bertolini Francesco scheme fromtheEuropeanResearchCouncil. work, extending his original methodology to other refractory cancers, and will do it in Marseille, France, as part of the Marie Curie fellowship 235 genes potentially involved in drug resistance in NB, 84 of which correlated significantly with patient survival. He is now continuing this of identification the to led then analysis chemotherapy.Bioinformatics to cells drug-resistant re-sensitise to able were that hits 68 found and NB for screened compounds active 3600 of screening high-throughput a out carried He failure. of risk the lower and cost the reduce time, development the shorten can repositioning drug that known well is It siRNA. and drugs approved of screening high-throughput relies on that development drug for approach unconventional an proposes He funding. competitive attract to enough sexy not is cancer treatment for drugs old of use the that is idea His repositioning. drug ‘next-generation’ about was talk Pasquier’s Eddy of part second The dramatic response,whichlastedtwoyears,underthisexperimentalregimen. The planistostartaclinicaltrialassoonpossible. regimen methotrexate a had and angiosarcoma multi-focal a and had patient presented. This were patients five these of one of Images vinblastine, it. to responded have all and propranolol, of Shripad combination Dr metronomic by a treated with Mumbai, been Centre, have Memorial Tata angiosarcoma the at metastatic Banavali or relapse with patients five Interestingly,further was spheroids. vinblastine tumour and in propranolol between confirmed synergism The doxorubicin. and paclitaxel as such angiosarcoma of treatment the in used commonly drugs chemotherapeutic with not but lines, cell these against vinblastine with synergistically interacted Propranolol vitro. cells these that found team his expressed and Pasquier Eddy are lines, treatments cell endothelial effective transformed more and immortalised and with Starting failed, needed. repeatedly urgently counter-intuitively have TKI anti-angiogenic and bevacizumab angiosarcoma, In Two othergroupsrecentlyconfirmedthepotentialofβ-blockersintreatmentNB and microtubule-targetingdrugs,suchaspaclitaxelvincristine. of chemotherapy use the with lab his from findings Sydney,presented Institute, Cancer Australia Children’s the from Pasquier Eddy talk, his of part first the In low-grade opticpathwaygliomastestsfluvastatinwithcelecoxib(NCT02115074) basedonpreliminaryandpreclinicalevidence combination acid in valproic 18 and cohorts of etoposide, children cyclophosphamide, with a either with a trial relapsing/refractory tumours II or phase a metronomic very a advanced Morocco initiated disease. In Hessissen France, In Laila a Pr trial protocol. and in children Kababri with El ibuprofen–cyclophosphamide-methotrexate Maria Pr an treatment. with metronomic treatment a metronomic includesthe in which included programme been pilot have care patients palliative 29 a launched Hospital Children’s Cabral Reid Robert the from He also mentioned two other initiatives recently started in Central America and Morocco. In Dominican Republic, Dr Wendy Gómez García metronomic approachisstillusedinMalibytheinvestigator, with52patientsnowtreatedintotal. patients seven the of out noted were responses partial two and regimen this to acid valproic added protocol Mali-02 Metro The them hadalongstabilisationafterstudydiscontinuation of three and disease, stable had treated patients 12 the of out seven but response, any experienced patients the of various None types. of tumour cancer refractory with children to given was regimen vincristine/cyclophosphamide/methotrexate a trial, Mali-01 Metro the In worldwide networkandsupporttheimplementationoftrialswithmetronomicsapproaches. a create to launched was which Initiative Health Global Metronomics the of framework the in LMIC in investigators with collaboration of experience his reporting by LMIC the on part this concluded France) Marseille, Timone, La of Hospital Children’s department, Oncology Nicolas André (Metronomics Global Health Initiative; Aix Marseille Université, Inserm, CRO2 UMR_S 911; & Paediatric Haematology and high-income countriesusingchemotherapyaswellautologousstemcelltransplant(ASCT)whereindicated. prevent may maintenance some of these oral relapses. In comparison with months results from other groups, the 12 disease free survival is similar that to what has been observed suggest in which ther of β-blockers high levels in vitro in cancer of and in animal models of TNBC β1- treatment. and β2-adrenoreceptors His work showed and [36] and NB [33]. that that β-blockers propranolol, 10 [37]. were In particular, a able non-selective to increase strong [38, 39]. synergism β-blocker, the anti-angiogenic was could observed inhibit ecancer and their between www.ecancer.org anti-tumour proliferation 2014,8:463 β-blockers [35]. [34] activity . The . in

Conference Report T cells.Metronomicchemotherapycouldalsoincrease thisimmuneresponse[43] work also suggests that combining DCA or metformin could improve the induced by immune cell transfer, e.g., NK cells or He also provided data indicating that DCA was inducing major histocompatibility complex (MHC) class I expression in cancer cells doxorubicin incellswithwild-typep53. This interestingapproachiscurrentlybeing tested as such drugs activating p53 with cooperate to able DCAwas mechanism. dependent p53 a via act and cells the kill not does actually it to cytosol) the in glycolysis oxidation of pyruvate in of mitochondria and decreases the conversion of pyruvate product to lactate. the DCA increases PDK1, (a inhibiting By cycle. acid pyruvate citric the energy,in produce to converts mitochondria the in oxidised PDH then is which acetyl-coA, phosphorylation. by (PDH) dehydrogenase pyruvate enzyme the inactivates which enzyme kinase a (PDK1), kinase1 dehydrogenase pyruvate enzyme the DCAinhibit conditions. to and known factors is external of because time over rely they which on metabolism the change will cells Cancer homogeneous. not is metabolism cell tumour Warburgthe on acts which lab their in (DCA) dichloroacetate However,of cells. effectuse cancer the all reported almost He for described be ofinteresttoactonleukaemiacellswithcompoundsexerting theireffect viaother angles. could schedule metronomic the But leukaemia. in importance of really not is angiogenesis as leukaemia acute in approaches metronomic Montpellier, Montpellier, France) focused on tailored metronomic approaches for acute leukaemia. It could be surprising at first sight to use Biotherapy,CHU and Medicine Regenerative for Institute & Médecine UFR 1, Montpellier de Université U1040, (INSERM Villalba Martin Session 4:Moretypesofcancerandselectedpresentations in 2012 poor outcomes. They wanted to assess the role of COMBAT in high risk CNS tumours, in comparison with the outcomes reported by Peyrl known with tumours embryonal with trial clinical a in tested group his COMBATthat modified protocol the about talked Banavali Shripad Kamen, apaediatriconcologistwhopioneeredlow-dosechemotherapyandwasanuntiringadvocateofmetronomicchemotherapy. The prize was given by Ruth Kamen, Barton Kamen’s wife, to Shripad Banavali after a very touching speech in memory of the late Barton role?’. a there tumours—is brain malignant paediatric prognosis poor in therapy treatment) antiangiogenic biodifferentiating metronomic The first Barton Kamen-MGHI Prize has been awarded to Prof. Shripad Banavali for his abstract entitled ‘Modified combat (combined oral Barton Kamen–MGHIPrize and metformin of potential biological its interestasadrugrepositiontotreatsomecancers. the confirms This mice. of lifespan the increase to able would and radiotherapy with combination in beneficial be chemotherapy,could of efficacy the increase possibly to shown been has which fasting replace could metformin that Variousgroup. their by trial preoperative one in indicateincluding findings trials, recent cancer in tested extensively being is Metformin in bothimmunocompetentandimmunosuppressedmice.Intheseexperiments,phenforminwasparticularlyeffective. cancer cells. and both They cells tested that progenitor endothelial found of they induce as to metformin active were into market) looking the from started withdrawn they (now phenformin lab, and own metformin their In aspirin. is drug old interesting an of example typical The for suchmetronomicmaintenancetherapyallpatientswithhighriskembryonalbraintumours,whichtheyplantoprospectively study role a is there whether hypothesis, Peyrl’sthe for generate drugs) to protocol. intrathecal helped of data cost These (excluding USD 5948 These 50.0%). partial PFS or (two-year CR protocol COMBAT had outcomes compared favourably with modified Peyrl’s series. It who can also be considered cost-effective, starting with a cost per cycle of 102 those USD compared to of and time 40.7%) disease—at residual PFS gross (two-year to treatment opposed of (PR)—as months remission three least at took who to patients time for median better The significantly cheilitis. and stomatitis mainly was toxicity 3 Grade two. progression (TTP) was was nine received months for cycles the nine entire of was group, age and number median the median the two-year PFS treated, the and been OS and have were that 32.2% years, and patients 55%, 51 respectively.the For The protocol. outcome was this received had who PNET and MB high-risk upfront (PNETs),tumours nectodermal primitive relapsed (MB), diffuseupfront and amendment ependymoma, after relapsed and glioma, pontine epigenetic changes associated with most CNS tumours. A retrospective analysis was done of all patients with relapsed medulloblastomas COMBATprotocol [40] where they used an intensive protocol with rather high toxicity and no dramatic clinical improvement. As opposed to the original in vivo combinations of metformin and phenformin with aspirin and betablockers and found that the effect was synergistic , in the modified COMBAT protocol celecoxib was replaced with sodium valproate considering the importance of importance the considering valproate sodium with replaced was celecoxib COMBATprotocol modified the in [41], 11

. in vivothelabofFrancescoBertolini. In vitro, DCA is able to stop cell proliferation, but ecancer www.ecancer.org 2014,8:463 [42] . Their .

Conference Report In IEO’s experience, more than 70 patients have been treated with metronomic capecitabine so far, and very few with metronomic metronomic with few very radionuclide therapy(PRRT) with and far, so capecitabine receptor peptide with metronomic radio-sensitising as combined been has with capecitabine metronomic them treated data). Among (unpublished been temozolomide have patients 70 than more experience, IEO’s In study, animpressive64%responserate(PR+CR)wasobserved,withanine-month TTP (range2–15). Koumarianou’sO-6-methylguanine-DNAovercomeIn resistance.methyltransferase (MGMT)-relatedto reported been has temozolomide of schedule metronomic multiforme, glioblastoma as such tumours, other continuously.In mg/day 100 at orally given Temozolomidewas Koumarianou reported the use of metronomic temozolomide with octreotide LAR and bevacizumab with patientoutcome. (4%), and renal toxicity (2%). Proteinuria (all grades) was correlated with longer PFS (p = (11%), proteinuria 0.017). VEGF syndrome polymorphisms were hand/foot not associated included toxicities 3 Grade observed. were (SD) disease stable 64% and PR continuously.18% A [46] sites primary mixed NETsfrom with patients 45 of trial II phase multicentric Italian another with results 2014 in reported group same The significant decreaseincirculatingvascularepithelialgrowthfactor(VEGF)overtime. 3 adverse event. The median TTP of all 29 patients was 22.6 months (range, 2.7–68.5), while the median OS was not reached.There was no cytokines. vasculature inflammatory and cancer in expressed aberrantly be L1isdysregulated insome tumours and isfor instance involved inchemoresistance inovarian cancer cells. Unexpectedly, L1was found to which is also expressed in non-neural tissue, for example in immune cells such as dendritic cells where they favour intra- and extravasation. centralnervous system, could have rolea intumour vascularisation. Theyfocused onL1, prototypica member ofthe neural Ig-CAM family, the Immunoglobulin-likeNeuralidentifiedinitiallyinIg-CAM), hypothesis(NeuralthatMolecules CellAdhesion the made they lab, their In tumours, helistedtheplethoraofpossibleplayersatmolecular level,VEGFontopofthislist. affect to way possible a as vascularisation tumour the of normalisation of concept the and through going players vasculature. After tumour new in targets potential suggesting lab his from findings presented Italy Milan, Oncology, of Institute European the of Cavallaro Ugo that couldnotbeconfirmedinaclinicaltrial regarding the translation from preclinical results to clinical results as caution their of group note found a promising on concluded chemotherapy,he metronomic to added agents anti-angiogenic of effect potentiating the to respect With metronomic schedulemaybeabetteroptionforpatientswithadvanceddisease. a with chemotherapy of lines sequential of use the Second, line. fifth the or fourth the until it make cannot who patients the than disease pretreated heavily in indolent work more a have treatment regimen systemic of line another metronomic for eligible still are a and lines five or did four receive did who why patients First, patients? is: cases these in mind to comes that question The chemotherapy. of lines capecitabine oral with or infusion continuous in 5-FU with together gemcitabine using trial a in 1PR) and 1CR (including rate benefit clinical 46% the in demonstrated as interest of seems regimen Metronomic low. very remains OS but administered also is mitotane) and cisplatin doxorubicin, (etoposide, regimen EDP-M the relapse operated radically patients in mitotane with survival recurrence-free in benefit a 2007 in reported group his after setting adjuvant in used increasingly is and disease advanced for treatment standard the is mitotane cancer, rare this In cancer. adrenocortical for chemotherapy metronomic of potential the of summary a presented Italy) Brescia, Civili, Spedali Ospedaliera Brescia, Azienda of University Health, Public Sciencesand Radiological Specialties, Surgical and Medical of (Department Berruti Alfredo GEP NET withaD(low)levelofevidence. tumors (GEP NETs), metronomic chemotherapy has been included as an option (amongBased others) on forthe advancedaforementioned well-differentiated data in slow-growingthe AIOM/ITANET 2013 Italian guidelines for the management of gastroenteropancreatic neuroendocrine 200 mg/m of29 patients with metastatic or locally advanced well-differentiated NET from different primary sites. Themetronomic schedule of 5-FU was with metronomic chemotherapy. Brizzi NET in trials clinical published three only identify could He interesting. be could schedule metronomic toxicity,a low with possibly therapies, NET with a high tumour burden, where the therapeutic goal is to stabilise of metronomic the experience chemotherapy tumourin his low-/intermediate-grade andneuroendocrine shared tumours ensure(NETs)Italy) goodMilan, Oncology, qualityof Institute of European lifeTumours, withNeuroendocrine a and sequenceGastrointestinal of of medical(Unit Fazio Nicola , this time with metronomic capecitabine and bevacizumab combined with octreotide LAR. Capecitabine was given orally at 200 mg/day 2 per day as a intravenous protracted continuous infusion through an elastomeric pump. Four patients experienced at least one grade 177 Lutetium inaround20patients(unpublisheddata). [45] reported the use of 5-FU combined with octreotide long acting repeatable (LAR) in a phase II study [50] inwhichpatientsevenseemedtohaveacceleratedprogression withthiscombination. . Alfredo Berrutialso mentioned three case reports with benefit after multiple after benefit [49]. with reports case three mentioned Berrutialso Alfredo [51] 12 and its expression was induced by pro-angiogenicexpressioninducedinflammatoryby itswasand and [44] . In patients with metastatic low-/intermediate-grade in vitro results with paclitaxel and sorafenib [47] . In case of metastatic disease or disease metastatic of case In [48]. in a consecutive series of 15 patients. ecancer www.ecancer.org 2014,8:463

Conference Report papers to be published in five first the in covered drugs the be will which itraconazole, and clarithromycin, cimetidine, namely,nitroglycerin, them, mebendazole, of evidence of activity. The main reason of this discrepancy is the absence of commercial value of these—often generic—drugs. He listed five could be summarised by the fact that the most interesting drugs are not or limitedly tested in trials whereas they have a rather high level of organisations based in Brussels, Belgium, and Boston, USA respectively. Gauthier Bouche presented the rationale behind the project which non-profit two Cures, Global the and between Fund collaboration Anticancer a is project trials. This clinical in use their support to order in activity anticancer possible a have which drugs non-anticancer on evidence scientific the summarise to is project ReDO the of goal The project. ReDO or project Oncology in Drugs Repurposing the presented Strombeek-Bever,Belgium) Fund, (Anticancer Bouche Gauthier The sessioncontinuedwithsevenpresentationsselectedbythescientificcommittee. of context the in perspectives therapeutic new approaches. open might vessel-normalising L1 and/or targeting anti-angiogenic that possibility the stressing by talk his concluded Cavallaro reduced tumourgrowthandangiogenesiswhileenhancingvesselnormalisation(Magrini antibody L1-blocking an with mice tumour-bearing of treatment the concerned, was L1 targeting as far As normalisation. vessel tumour promoted L1 endothelial of ablation the Furthermore, architecture. junctional and permeability vascular regulated and cells endothelial in promotes tumour growth and dissemination. Looking at the vessels in the tumour, they concluded that L1 induced an angiogenic phenotype Cavallaro vasculature, the in L1 of ablation specific the with model mouse cancer pancreatic a Combining OS of4.6months. The regimenwaswelltolerated. 5-FU to 5-DFUR from conversion occurs enzymatic mainly as in the expected tumour be and to not in was the which normal tissues. The metabolites clinical results other of the this to trial were compared a median low PFS respectively. very of of 2.1 was months ingestion, level and after a 5-FU median concentration hours 2 and maximal hours, 1.5 The hour, 1 hour, 5-FU). 0.5 observed finally were 5-FU and finally 5-DFUR and 5-DFUR, (5-DFCR, 5-DFCR, capecitabine, metabolites its and capecitabine of analyses) level chromatography plasma liquid the high-pressure describe (i.e., to methods elaborated with study pharmacokinetic a on focused trial This patients. Teresa Di Desidero (University of Pisa, Italy) presented results or metronomic capecitabine and cyclophosphamide in colorectal cancer of level the increase evidence infavourofthisregimen. to required now is chemotherapy) metronomic and (+prednisonevs.docetaxel+prednisone patients 159 of toxicity.trial favourable Arandomised a with patients mCRPC in treatment line first as effective is combination this conclusion, a As gov/pubmed/25111199). (http://www.ncbi.nlm.nih.released been now has article PFS. The longer indicated (bFGF) factor growth fibroblast basic as well as VEGF high as counter-intuitive were response with associated Biomarkers months. 33 was OS median and months 15 was PFS Median profile. case as 87% of the patients were free of progression at six months with an impressive waterfall plot in terms of response and good toxicity the actually was This months. six at progression of free patients 37 the of more or 24 having as success defined they trial, the designing prednisone, oral metronomic cyclophosphamide, and celecoxib in metastatic castration-resistant (mCRPC) patients. When docetaxel, line first of trial II phase arm single a of results the time first the for present to back came Italy) Pisa, of (University Bocci Guido and VEGF/TSP-1weresignificantlyassociatedwith TTP andcouldbeconsideredpotentialpredictorsofresponse[56] seen were response (7%, 1/15), with a clinical benefit of 47%, and median partialOS one of and 6/15)45 (40%,disease weeks;stable prolonged neitherwere responses main gradecelecoxib.The cyclophosphamideand III/IVofcombination a toxicities with nor changes in the quality of life trialperformedtheyreportedphasetalkIIadvancedher in aof breastpart last cancer The patients progressed standard tochemotherapy cyclophosphamide andmetforminwasabletomoderatelydecreasetumourgrowthincreasethesurvivalofmice. tases, and increased the median survival time, having low toxicity in both tumour models tumour both in toxicity low having time, survival median the increased and tases, metas- lung decreased growth, tumour inhibited doxorubicin + cyclophosphamide or celecoxib + cyclophosphamide with chemotherapy for chemotherapy metronomic with experience the on talk breast cancer a in the preclinical and clinical settings. gave They worked with two murine mammary adenocarcinoma Argentina) tumour models. Metronomic Rosario, of University (National Scharovsky Graciela O drugs ofinterestandemphasisingthatrepurposedareagreatuntappedsourcepossibleactive,safe,affordable drugs. the evidence supporting the potential of mebendazole [55] .Looking for biomarkers of response, they could find that the baseline values of serum levels of the ratios VEGF/sVEGFR-2 ecancermedicalscience , the peer-reviewed scientific journal of [53] have been available since July 10 2014. He concluded by listing other potential 13 ecancer et al.JCI2014). . Also, she reported that the combination of combination the that reported she [54]. Also, . A policy paper observed that vascular L1 vascular that observed al et [52] and the article reviewing ecancer . www.ecancer.org 2014,8:463

Conference Report want totestthisinaphaseIIIrandomisedtrial. they and patients, TNBC of prognosis poor the negate may chemotherapy metronomic Thus, (p=0.000). 52.6% and 45.6% versus 100% the excellent event-free survival (EFS) and OS for patients receiving metronomic chemotherapy versus those not receiving was 100% and chemotherapy.metronomic received 33 and chemotherapy metronomic no received had 20 patients, months, 36 of follow-up median a At phase II, which consisted of daily oral metformin and cyclophosphamide and weekly methotrexate for one year. Of the 53 evaluable TNBC by followed was this weeks; 12 times cisplatin weekly with along cyclophosphamide and celecoxib oral daily was I Phase phases: two of of outcomes the of TNBC patients who did not analysis receive metronomic chemotherapy,retrospective and of those who received the a same. Metronomic chemotherapy consisted of were presented results The radiotherapy. +/- surgery,chemotherapy, (CAF) fluorouracil cyclophosphamide/doxorubicin/ oral included which therapy standard after patients TNBC all to therapy maintenance giving started they centre, outreach rural the at TNBCs, in outcome metronomic poor using the considering results Thus, TNBCs. good recurrent/metastatic with with patients experience, in chemotherapy of lot a gained had team TMH The 68%). approximately of OS (three-year CR logical patho- a achieve not do who patients for especially poor, is prognosis the chemosensitivity,and increased of spite in relapse of chance higher a have TNBCs course. aggressive particularly a carries and women younger in seen is disease where India, including LMICs, in patients of (30%) percentage higher a in occurs TNBC TMH. of centre outreach rural the Dervan, Hospital, WalawalkarBKL the at done ‘Metronomic titled Mumbai, was TMH, work This from analysis’. (TNBC): Aretrospective Cancer Banavali Breast Negative TripleShripad with patients Prof. in relapses prevents by therapy maintenance presented paper interesting very a was meeting the of talk last The for care of standard a become thus has chemotherapy patients withmetastatic/recurrentHNSCCpresentlyat TMH. metronomic Oral QOL. of maintenance with effects, side fewer had also it OS; in metronomic chemotherapy leadingwith tomet wasa study33% the improvementofrespectively.endpoint primary0.02,the and Thus0.014in ofPFS value thanp respectively, cisplatin.aB, withArmin 249 In andaddition, 101 metronomic chemotherapy led to an improvement Also, most had received prior treatment with radiotherapy disease. advanced and/oror relapsed locally had chemotherapy.most and cancers cavity oral had patients the of Most cycles). Thesix maximum times mediandays 21 every PFS and OS were 66 and 152 days in Arm A and should alwaysbeseenasachancetocomeupwithnewinnovative affordable approachesandnotasacheaprescuestrategy. safety. and approaches efficacy demonstrating on substantial and compromising undisputable without improvement, money especially in save populations to with the LMICs greatest as unmet However, well needs. another solution to Metronomics as deal with the issue countries of practice change high-income is to perform in well-designed clinical trials opportunity services of metronomic major and health repurposing a represents national which for cost, low their is approaches metronomic of favour in argument strong Ainterest. commercial of a of benefit the demonstrating trials III lack the be to seems practice. reason clinical main in The used barely were approaches those that admitted phase was it approach, metronomic few the of impact the at Looking issues. general important highlighted also meeting The tumour environmentcompartments. Another importantlessonistheneedforPK/PDstudiestoadjustdosesandimproveoutcomes. Recent data and new research tools will allow researchers to look into the details of the effect of metronomic chemotherapy on the different The meeting gave new directions for a better understanding of the role of a metronomic schedule in inducing tumour response or stabilisation. Conclusion mg/m 15 Methotrexate B: (Arm chemotherapy by only 1–2% of patients in LMICs. Even combination palliative chemotherapy is ill afforded. Thus, with their experiencethese developed with oral recurrences. metronomic Cetuximab-based combination palliative therapy, which is standard of care inin Indiahigh-income and affects countries mainly is peopleafforded from poor socio-economic background. Nearly two-thirds presented cancers all of with9–10% for accounts advancedTatathe HNSCC at Mumbai. done in was Hospital stages,study Memorial This (HNSCC)’. region neck andand head 40–60% of oralmetronomic therapy with intravenous chemotherapy in patients with metastatic, relapsed, or inoperable squamous cell carcinoma of the Prof. Shripad Banavali (Mumbai) combined the next two free papers to give his talk titled ‘A prospective randomised phase II study comparing [57, 58] , which costs approximately 10 USD, they undertook this randomised study to compare oral metronomic chemotherapy 2 once a week + celecoxib 200 mg bid everyday) with standard IV single agent cisplatin (Arm A: 75 mg/m 75 A: (Arm cisplatin agent single IV standard with everyday) bid mg 200 celecoxib + week a once 14 ecancer www.ecancer.org 2014,8:463 2

Conference Report References

16. 10. 15. 14. 13. 11. 12. 1. 5. 3. 2. 6. 4. 7. 8. 9. Klement G DOI: André N, Carré M and Pasquier E (2014) 7(8) pp455–65DOI:10.1038/nrclinonc.2010.8 angiogenesis inmice Hanahan D, Bergers G and Bergsland E (2000) cancer CancerRes T Browder regression withoutoverttoxicity Shaked Y Pasquier E, Kavallaris M and André N (2010) N André and M Kavallaris E, Pasquier pp 1785–7DOI:10.1126/science.112759 Bertolini F giogenic, producing objective responses and survival benefit in a mouse model of cancer of model mouse a in benefit survival and responses objective producing giogenic, Pietras K and Hanahan D (2005) zation andviabilityofcirculatingendothelialprogenitorcells term chemotherapytreatmentstrategy YShaked 10.1200/JCO.2005.07.09 Brandi G 2487103 PMID: 2138807 expressing/ cancer receptor breast primary hormone HER2-negative low or triple-negative for chemotherapy preoperative as cil/epirubicin/cyclophosphamide Hasnis E Masuda N Masuda and clinicaloutcome Y Ge 1687773 nomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients cancer breast elderly in treatment systemic primary as cyclophosphamide oral nomic following weeklygemcitabinetherapy Bottini A, Generali D, Brizzi MP and Fox SB HER-2 positivemetastaticbreastcancer L Orlando Breast Cancer01Trial JCclinicOncol for Study Adjuvant Surgical National cancer: breast high-risk node-negative, with patients in chemotherapy postoperative T Watanabe 10.1038/nrclinonc.2014.8 et al et 2 0 et al et al et al et al et et al et al et et al (2012) et al et et al et t al et Durable complete response of hepatocellular carcinoma after metronomic capecitabine (2014) (2006) (2005) (2003) 0 (2000) (2006) (2014) (2000) Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects immunological patients: cancer breast metastasized in treatment cyclophosphamide Metronomic (2009) 60(7)pp1878–86PMID: Anti-bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobili Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long- effective an is cyclophosphamide bolus-dose intermittent with combined metronomic Low-dose JClinInvest105(8)pp1045–7DOI:10.1172/JCI987 Cancer ImmunolImmunother Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with patients in methotrexate and cyclophosphamide metronomic with combination in Trastuzumab A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluoroura- by followed paclitaxel/cyclophosphamide/capecitabine metronomic of study II phase A Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant experimental against efficacy improves chemotherapy of scheduling Antiangiogenic 3 rl rcl n tgfr oprd ih lsi ccohshmd, ehteae furuai as fluorouracil methotrexate, cyclophosphamide, classic with compared tegafur and uracil Oral 9 PMID: A multitargeted, metronomic, and maximum-tolerated dose ‘chemo-switch’ regimen is antian- The JCliniInvest105(8)ppR15–24DOI:10.1172/JCI882 27(9)pp1368–74DOI: 2491337 Metronomics: towards personalized chemotherapy? 2 PMID:1699054 Neoplasia Cancer Chemother Pharmacol Chemother Cancer Cancer Res et al (2006) BMC Cancer 1076617 2 PMID:2053138 Metronomic chemotherapy: new rationale for new directions new for rationale new chemotherapy: Metronomic Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor 4 16(6)pp501–10DOI:10.1016/j.neo.2014.05.01 61(3) pp353–62DOI:10.1007/s00262-011-1106-3 65(16)pp7045–51DOI: 5 Randomized phase II trial of letrozole and letrozole plus low-dose metro- 6p225DOI:10.1186/1471-2407-6-22 8 15 10.1200/JCO.2008.18.393 0 Cancer Res

(2) pp 229–38 DOI: 229–38 pp 74(2) 2 PMID: 63(15)pp4342–6PMID: 10.1158/0008-5472.CAN-05-076 1077264 9 9 8 PMCID:30084 5 PMID: Nat Rev Clin Oncol 10.1007/s00280-014-2492- J Clin Oncol Clin J 1 PMID: J Clin Oncol Clin J 1290760 1697840 Tumori 2495731 ecancer 2 (5) pp 939–52 DOI: 939–52 pp 23(5) 5 PMID:1610305 2 Nat Rev Clin Oncol Clin Rev Nat 0 PMCID:157923 www.ecancer.org Science 3623–8 PMID: 3623–8 24 96(6) pp 1028–30 11 9 2014,8:463 (7) pp 413–31

313(5794) PMID: y 0 1 -

Conference Report 32. 31. 27. 26. 25. 28. 18. 17. 33. 30. 29. 24. 23. 22. 19. 21. 20. HER2-, inatertiarycarecentreIndia Pai PS Pai J Ghosh pp. e239–48DOI:10.1016/S1470-2045(13)70056- s10456-012-9260- locally advancedoralsquamouscellcancers: A matched-pairanalysisIndianJCancer Orlandi P amide plus celecoxib in patients with advanced refractory gastrointestinal cancers G Allegrini cancer patientsBrJCancer98(8)pp1312–9DOI:10.1038/sj.bjc.660431 G Allegrini 08-331 cancer prostate hormone-refractory advanced in ethasone AFontana 2386052 Agrawal A Agrawal 18(12) pp1256–7DOI:10.1634/theoncologist.2013-009 G Brandi Oncol 33(1)pp31–4DOI:10.1097/MPH.0b013e3182018ab Traore(2011)F nr N (2013) N André study InvestNewDrugs V Marchetti cyclophosphamide metronomic with treated patients cancer mph.0000243657.64056.c vinblastine or cyclophosphamide in pediatric recurrent solid tumors pp 74–80DOI:10.4103/0972-3919.13028 Stempak D Stempak pp 309–17DOI:10.1038/nrclinonc.2010.4 M Buyse Immune DynamicsJMathBiol64557–77DOI:10.1007/s00285-011-0424- (2011)H Schaettler and M Naghneian U, Ledzewicz center experience D etal(2012) Zapletalova angiogenesis JTheoreticalBiol (2008) H Schaettler and U Ledzewicz 1142/S021833901440001 (2014) H Schättler and U Ledzewicz 7 PMID: et al et 6 PMCID:374957 et al et et al et al et t al et et al et et al et et al et et al et et al et et al et Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in care of standard existing to compared treatment therapy-based anticancer of scheduling metronomic Oral (2013) (n.d.) (2013) (2010) 1962258 Children treated with metronomic chemotherapy in a low-income country: METRO-MALI-01 country: low-income a in chemotherapy metronomic with treated Children (2009) (2014) (2012) (2008) (2006) (2012) a te ie oe o mtoois n o-noe n mdl-noe countries? middle-income and low-income in metronomics for come time the Has 6 PMID:2238258 Oncology Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of usage their and patients, of tumors breast in expression receptor HER2 and progesterone Estrogen, VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study II phase a patients: carcinoma hepatocellular advanced in capecitabine Metronomic imres n sroae n pit–h calne f ttsia validation statistical of challenge points–the end surrogate and Biomarkers Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexam- and celecoxib, cyclophosphamide, metronomic of evaluation pharmacodynamic and Clinical Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosph and UFT metronomic of evaluations pharmacodynamic and pharmacokinetic Clinical, Response assessment in metronomic chemotherapy: RECIST or PERCIST? or RECIST chemotherapy: metronomic in assessment Response A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal metastatic in irinotecan metronomic on study pharmacodynamic and pharmacokinetic A A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic low-dose and celecoxib of study biomarker antiangiogenic and pharmacokinetic pilot A 30(4)pp1725–30DOI: 4 First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumours: a pilot a tumours: canine spontaneous of model metastatic a in chemotherapy metronomic First-line 4 3 PMID:1711495 Metronomic chemotherapy with Metronomic chemotherapytheCOMBAT regimeninadvancedpediatricmalignancies:amulti- 0 82(5)pp249–60DOI:10.1159/00033648 252295–312DOI:10.1016/j.jtbi2008.02.01 5 PMCID:333891 On optimal chemotherapy for heterogeneous tumors heterogeneous for chemotherapy optimal On Optimal and suboptimal protocols for a class of mathematical models of tumor anti- tumor of models mathematical of class a for protocols suboptimal and Optimal 5 PMID: 3 PMID: 8 10.1007/s10637-011-9672- 1 PMID:2363932 2476105 2036872 Optimal Response to Chemotherapy for a Mathematical Model of Tumor-of Model Mathematical a for Chemotherapy to Response Optimal 2 3 PMID:2423258 7 PMCID:399677 7 Indian JCancer 8 16 Clin Cancer Res Cancer Clin Br J Cancer J Br 4 3 PMID:2253836 J Pediatr Hematol Oncol 1 PMCID:386841 1 PMID: 48(4)pp391–6PMID:2229324 y 6 4 5

(4) pp 957–64 DOI: 957–64 pp 109(4) (15) pp 4954–62 DOI: 4954–62 pp 15(15) 1836294 Angiogenesis 3 8 0 PMCID:236170 50(2)pp135–41PMID: J Biological Systems Biological J 28(11) pp 720–8 DOI:

15(2) pp 275–86 DOI: 10.1038/bjc.2013.39 10.1158/1078-0432.CCR- a Rv ln Oncol Clin Rev Nat 9 Indian J Nucl Med 29(2) Nucl J Indian ecancer 3 act Oncol Lancet www.ecancer.org J Pediatr Hematol Pediatr J 2397920 2014,8:463 1–21 DOI: 1–21 22 10.1097/01. Oncologist 10.1007/ PMID: 8 5 14(6) 7(6) -

Conference Report 34. 36. 35. 37. 39. 38. 43. 42. 41. 40. 44. 45. 49. 48. 47. 50. 46. country: Metro-Mali-02IndianJCancer Traore F Pasquier E Pasquier pilocytic astrocytomaActaNeuropatholCommun S Mercurio in neuroblastoma Pasquier E implication inbreastcancertreatmentOncotarget2(10)pp797–809PMID: 5(1) pp161–72PMID: Wolter JK 48(12) pp2460–5DOI:10.1016/j.jpedsurg.2013.08.02 Xu T Villalba M 10.1016/j.biocel.2012.04.02 illa M Villalba study pilot single-center 1687401 children: in tumors solid relapsed J Sterba Cancer Peyrl A Peyrl Cancer Treat Rev36(Suppl3)ppS87–94DOI:10.1016/S0305-7372(10)70026- N Fazio pp 223–32PMID:2423722 Brizzi MP docrine carcinomas. A phase II trial of the Piemonte oncology network oncology Piemonte the of trial II phase Acarcinomas. docrine Sperone P Sperone NEJMoa06336 Terzolo M 325556 for malignant neuroendocrine tumoursEndocr-Relat Cancer Koumarianou A 24628963 PMID: 1988698 tical carcinomaEurJEndocrinolE Berruti A 0281 PMID: study II phase multicenter a carcinoma: adrenocortical advanced study XELBEVOCT the tumors: neuroendocrine differentiated Berruti A et al 59(3)pp511–7 DOI:10.1002/pbc.2400 6 t al et et al 4 et al et et al et al et al et (2013) PMCID:3996907 et al et al et al et al t al et et al et et al et al et et al et 2041017 (2013) (2012) (2014) (2012) (2010) (2014) 0 (2007) (2009) (2006) (2014) 7 PMCID:277660 et al et (2013) (2010) (2013) (2011) Antiangiogenic effect of propranolol on the growth of the neuroblastoma xenografts in nude mice (2013) Br JCancer108(12):2485–94DOI:10.1038/bjc.2013.20 Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocor- (2012) (2012) ninigncmtooi teay o cide wt rcret mroa ban tumors brain embryonal recurrent with children for therapy metronomic Antiangiogenic 4 Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas carcinomas neuroendocrine enteropancreatic advanced with patients in therapies targeted Biological Chemical metabolic inhibitors for the treatment of blood-borne cancers Adjuvant mitotane treatment for adrenocortical carcinoma N Eng J Med Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroen- Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in effective and feasible is therapy metronomic oral antiangiogenic and biodifferentiating Combined 2438928 Β-Blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in chemotherapy second-/third-line a as capecitabine or 5-fluorouracil metronomic plus Gemcitabine Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: chemotherapy of efficacy anti-tumor and effects anti-angiogenic the potentiates Propranolol rm uo cl mtbls t tmr mue escape immune tumor to metabolism cell tumor From Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in combination celecoxib/fluvastatin metronomic of effect synergistic and targets new for Evidence 1 4 PMID: Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide long-acting and bevacizumab temozolomide, metronomic with treatment Combination 7 PMCID:396019 4 166(3) pp451–8DOI:10.1530/EJE-11-091 2256893 50(3) pp.250–3DOI:10.4103/0019-509X.118741 0 6 8 1(1)p17DOI:10.1186/2051-5960-1-1 2 17 (1) pp L1–4 DOI: 10.1530/ERC-11-028 19(1)ppL1–4 BMC Cancer BMC Onkologie Endocr-RelatCancer 5 PMID: BMC Cancer BMC 2200658

8 (14) pp184 DOI: pp184 14(14) 7 p 381 DOI: 308–13 pp 29(7) 8 PMID: 2369502 n J ice Cl Biol Cell Biochem J Int 2 PMCID:324815 2112961 PMID:24061467 7 PMID:

pp 388 DOI: 388 pp 9

(2) pp 445–53 DOI: 445–53 pp 17(2) 2 PMCID:369422 Anticancer Agents Med Chem 7 356(23) pp 2372–80 DOI: 10.1186/1471-2407-14-184 2425268 10.1159/00009347 7 PMID:2223254 7 10.1186/1471-2407-9-388 9 PMCID:389346 ecancer 1 p 161 DOI: 106–13 pp 45(1) 9 www.ecancer.org 10.1677/ERC-09- 2014,8:463 eit Blood Pediatr Oncotarget J Ped Surg 2 PMCID: 10.1056/ PMID: 4 8 PMID: PMID: 14(2)

Conference Report 53. 52. 51. 55. 54. 58. 57. 56. science atira P Pantziarka Pantziarka P etal(2014)TheRepurposingDrugsinOncology(ReDO)Project J ExpMed206(3)pp623–35DOI:10.1084/jem.2008121 L Maddaluno advanced breastcancerpatients HAPerroud field Rico MJ Patil V V Patil Patil Vetal(2012)MetronomicchemotherapyinadvancedoralcancersJCancerResTher PMID: 23979202 chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer Perroud HA and Rico Clinic Oncol(RCollRadiol) Cancer Invest32(3)pp92–8DOI:10.3109/07357907.2013.87748 et al et 8pp443PMID:2507521 et al et al et (2013) (2014) (2014) al et et al et (2013) (2009) Oral metronomic chemotherapy in recurrent, metastatic and locally advanced head and neck cancers cancers neck and head advanced locally and metastatic recurrent, in chemotherapy metronomic Oral Comparative effectiveness of two metronomic chemotherapy schedules-our experience in the preclinical et al Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in celecoxib and cyclophosphamide with chemotherapy metronomic of effect therapeutic and Safety Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic eupsn Dus n nooy RD)mbnaoe s n nicne agent anti-cancer an as (ReDO)—mebendazole Oncology in Drugs Repurposing The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells dendritic of trafficking and migration transendothelial regulates L1 molecule adhesion The 25(6) pp388DOI:10.1016/j.clon.2013.01.002 7 PMCID:409602 Future Oncol9(3)pp451–62DOI:10.2217/fon.12.19 4 1 PMID: 18 1927362 0 PMID: 7 PMCID:266497 24499110 Ecancermedicalscience 6 5 8(Suppl1)ppS106–10 Indian J Cancer 8pp442 ecancer www.ecancer.org Ecancermedical 50(2) pp 115–21 2014,8:463 -

Conference Report