Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan Gauthier Bouche, Nicolas André, Shripad Banavali, Frank Berthold, Alfredo Berruti, Guido Bocci, Giovanni Brandi, Ugo Cavallaro, Marco Colleoni, Giuseppe Curigliano, et al.

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Gauthier Bouche, Nicolas André, Shripad Banavali, Frank Berthold, Alfredo Berruti, et al.. Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan. Ecancer medical science/Ecancermedicalscience - http://www-ncbi-nlm-nih- gov.gate2.inist.fr/pmc/journals/899/ - http://www.ecancer.org/ecms, Bristol, UK : Cancer Intelli- gence (10.3332/ecancer)., 2014, 8, pp.463. ￿10.3332/ecancer.2014.463￿. ￿inserm-01867014￿

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HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 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, Marco Colleoni9, Giuseppe Curigliano10, Teresa Di Desidero11, 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, 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, France 3Tata Memorial Centre, Mumbai, India 4Department of Paediatric Oncology, University of Cologne, Germany 5Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Azienda Ospedaliera Spedali Civili, Brescia, Italy 6University of Pisa, Italy 7Department of Experimental, Diagnostic and Specialty Medicine University Hospital S. Orsola-Malpighi Bologna, Italy 8Molecular Medicine Programme, European Institute of Oncology, Milan, Italy 9Division of Medical Senology, European Institute of Oncology, European Institute of Oncology, Milan, Italy 10Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy 11University of Pisa, Italy 12Cancer Institute ‘I. Chiricuta’, Cluj-Napoca, Romania 13Unit of Gastrointestinal and Neuroendocrine Tumours, European Institute of Oncology, Milan, Italy 14Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Canada 15Nature Reviews Clinical Oncology, London, UK 16Department of Mathematics and Statistics, Southern Illinois University, Edwardsville, USA Report Conference 17Elisabetta Munzone, Division of Medical Senology, European Institute of Oncology, Milan, Italy 18Tumour Biology and Targeting Programme, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, Australia; Metronomics Global Health Initiative, Marseille, France; & Centre for Research in Oncobiology and Oncopharmacology, INSERM UMR911, Marseille, France 19Jefa Sección Oncología Experimental, Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Argentina 20Rappaport Faculty of Medicine, Technion, Haifa, Israel 21Brno School of Medicine, Brno, Czech Republic 22INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier, France & Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France 23Laboratory of Haematology-Oncology, European Institute of Oncology, Milan, Italy

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

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1 chemotherapy 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: 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 chemotherapies. 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

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Conference Report also was context broader a in community oncology medical the for chemotherapy metronomic of potential under-highlighted. The are that published in 2010 was that this was a highly cited article and thus was popular among the journal’s readership, as well as coverage of topics [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 cyclophosphamide metronomic the evaluating trial II phase non-randomised a in evaluating the weekly paclitaxel 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 sign , published online a couple of weeks before the Milan meeting. Part of the motivation for commissioning an update of the first article first the of update an commissioning for motivation the of Part meeting. Milan the before weeks of couple a online published , stimulating • suppressing • inhibiting • targeting • affecting •

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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, paediatriccancer, 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 potentialofmetronomicchemotherapybycancercommunity. of scepticism general a behind reasons key the and approach, therapy this of success the action, of mechanisms the repositioning, drug with chemotherapy, similarities metronomic the of advantages the emphasising by talk her continued She editorial. recent a in discussed observed inpatientstreatedwithbevacizumabandtrastuzumab. [10] [11 . 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 . ] 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 [8, 9] [8, . In this new experiment the best approach to control tumour growth was growth tumour control to approach best the experiment new this In . 4

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Conference Report inflammatory response. suggest a reduced survival in patients with intense angiogenic activity (as reflected by highmedian valuelevels were associated ofwith significantly a CEP improvedand overall viablesurvival (OS). CECs)These data, ifconfirmedand inlargerIL-8-mediated series ofpatients, 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 circulatingonendothelialstudy circulating(CEC),cells surrogateendothelial predictive asprogenitorCPP biomarkers 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 vinorelbine 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-methotrexate 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 cance [12] . The IBCSG 22-00 trial has just completed recruitment and randomised breast cancer patients [70% of 5

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Conference Report 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 etoposide, celecoxib, Oral vitamin D, (Combined COMBATfenofibrate, and the retinoic with acid, and results the conclusion their of audience the reminded He is ongoingandshouldaddress thisquestion. (EUDRACT2012-000072-42) conclusion. 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,abenefitwhichwas howeverstilllimited. 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 He have patients These NB. high-risk NB. with patients 246 on of analysis retrospective a focus from data presented a with experience his reported Germany) Cologne, of University Oncology, Paediatric of (Department Berthold Frank (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 in childrenattheEuropeanUnion(EU) He listed some of the inherent problems of paediatric oncology and insisted on the very limited number of phase I trial happening every year 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 ment inOS. in patients with Child-B disease, their experience also seems promising, but in comparison with historical data showed only moderate improve- 15.6 months which compared favourably to matched untreated controls from the ITA.LI.CA. database (of eight months) of OS median a gave and tolerated well was capecitabine metronomic first-line the performed, they trials the to Moving response. complete of alone capecitabine from their own experience with metronomic chemotherapy alone. In 2010, they published a dramatic responseHe had inidentified onesix patienttrials, testing a withmetronomic metronomicchemotherapy regimen in HCC, three of them in combination with sorafenib. He presented data 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 ture wasstronglyenrichedforstromathatclearlyhighlightedtheimportanceoftumour-stromacrosstalkprogressionIBC. environment. signa- remodeling This stroma pre-existing a by enhanced seems bevacizumab to (CDKN2A). response regulation The cycle partial respone from those that had no response. A supervised clustering identified 75 genes involved in matrix remodeling (MMP1) and cell forresponse IBCinwith lymphangitic spread thetochest wall. Theyidentified 160genes thatclearly separated patients thathad achieved To date, no molecular feature reliably predicts the response to bevacizumab. Using DNA microarrays, they searched for multigene predictors

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Conference Report 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 Societyclinician ofin thoseMedical countriesOncology is (ESMO)a manager or of Nationalscarce resources.Comprehensice The 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 butwith new innovativeaffordable approachesandnotasacheaprescuestrategy.come to chance a as seen be should Metronomics cancer. the of dying of risk 90% have you world, the in percentile?> 25th The numerous, and he illustrated this with the horrible fact that, as a child with cancer in one of the 25% poorest country LMICs in repurposing) drug and chemotherapy (metronomic metronomics of use the was talk their of topic the and India, of Banavali Shripad and Oncology 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 level of plasma VEGF view,of thepoint is pharmacodynamics chemotherapy a metronomic From from benefit of validated—biomarker not used—but most the patients. Indeed,arecentpilotstudysuggestedthatVEGFSNPs(i.e.,VEGF-634C/G)maybepredictiveofPFSbenefits UFT ronomic patients manner cancer treated concentration-dependent in and time a in expression their increase TSP-1, as such genes, some that showed he chemotherapy, metronomic includes an extensive PK study and will provide further information. Regarding the pharmacogenomic markers of metronomic MOMA study, a phase II trial of 222 colorectal cancer patients, randomised between bevacizumab alone and bevacizumab + capecitabine benefit. survival a The of predictive was administration first very the after µg/ml 0.5 than higher disease. Cmax progressive 5-FU with The maximal concentration (Cmax) of 5-FU (the active metabolite of UFT) in plasma was higher in patients with stable disease than in patients studies, metronomic irinotecan in these colorectal cancer 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 Basic • Maximum • Enhanced • Limited • [26] Department, Children'sHospitalofLaT

level

. 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 . [22] level

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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 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. worldwide networkandsupporttheimplementationoftrials withmetronomicsapproaches. a create to launched was which Initiative Health Global Metronomics the of framework the in LMIC in investigators with collaboration of survival whencomparedtomatchedcontrolsinpatientswithadvanced,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 (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,acutemyelogenousleukaemia(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 ( Dervan com in TataMemorial of centre outreach rural the in situation the Mumbai, in situation the to Compared Oncology Nicolas André (Metronomics Global Health Initiative; Aix Marseille Université, Inserm, CRO2 UMR_S 911; & Paediatric Haematology and high-income countriesusingchemotherapyaswellautologous stem cellt prevent may maintenance some of these oral relapses. In comparison with results months from other groups, the 12 disease free survival is similar that to what has been suggest observed in which therapy, who stopping patients of 18 months the six of within Out relapsed 45%. patients around 12 was it relapsed, where controls historical to favourable compared 25% of rate relapse The months. six Finally, in AML, after induction and consolidation, patients received a maintenance treatment with oral etoposide and 6-thioguanine for lower • lower • oral • ) 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

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Conference Report 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 indicatein findings including recent trials, cancer in tested extensively being is Metformin in bothimmunocompetentandimmunosuppressedmice.In theseexperiments,phenforminwasparticularlyeffective. cancer and cells. both They cells tested that progenitor endothelial found of they apoptosis 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 is setbypharmaceuticals. This mightexplainsomeoftherecentissuesincludingskyrocketingcostdrugs. 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 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 the includes 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,with52patientsnowtreatedtotal. 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

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Conference Report 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 chemotherapy experience tumourin his low-/intermediate-grade andneuroendocrine shared tumours ensure(NETs)Italy) goodMilan, Oncology, quality of Institute of European lifeTumours, withNeuroendocrine a and sequenceGastrointestinal of of medical(Unit Fazio Nicola cells or T cells.Metronomicchemotherapycouldalsoincreasethisimmuneresponse Their work also suggests that combining DCA or metformin could improve the immune response induced by immune cells cell transfer,cancer e.g., NK in expression I class (MHC) complex histocompatibility major inducing was DCA that indicating data provided also He doxorubicin incellswithwild-typep53. This interestingapproachiscurrentlybeingtested 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 ofinteresttoactonleukaemiacellswithcompoundsexertingtheireffect viaotherangles. 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 progression (TTP)wasninemonths study. 50.0%). PFS (two-year protocol is USD COMBAT102 of cycle modified per cost a starting with cost-effective, of considered compared be also time can It series. disease—at Peyrl’s with favourably residual compared outcomes gross These to opposed (PR)—as remission was significantly was age median the treated, been have nine years, that patients 51 the For protocol. this received had who amend- PNET and after MB and high-risk upfront glioma, ment medulloblastomas pontine diffuse relapsed upfront with and patients ependymoma, relapsed all (PNETs), tumours of nectodermal done primitive was relapsed retrospective (MB), A tumours. CNS most with associated changes epigenetic of protocol COMBAT a role [36] for to where they used an intensive protocol with rather high toxicity and no dramatic clinical improvement. As opposed to the original such and 5948 the metronomic better USD [37] median i te oiid OBT rtcl eeoi ws elcd ih oim apot cnieig h importance the considering valproate sodium with replaced was celecoxib protocol COMBAT modified the in , (excluding for patients number maintenance cost who tookatleastthree for of of cycles the entire intrathecal therapy received group, for drugs) all was and patients for months two. the two-yearPFS Peyrl’ Grade with 11 s of treatment protocol. Thesdata

high 3 toxicity risk embryonal and (two-year was [40] OS [39] mainly . In patients with metastatic low-/intermediate-grade were . in vivothelabofFrancescoBertolini. helped In vitro, DCA is able to stop cell proliferation, but brain tumours, PFS 32.2% stomatitis 40.7%) to generate and and and 55%, which the hypothesis, those cheilitis. respectively they ecancer who had plan The www.ecancer.org to median . The 2014,8:463 whether prospectively CR or outcome time partial there [38] to .

Conference Report be aberrantly expressed in cancer and inflammatory vasculature L1 is dysregulated in some tumours and is for instance involved in chemoresistance in ovarian cancer cells. Unexpectedly, L1 was 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. central nervous system, could have a role in tumour vascularisation. They focused on L1, a prototypic member of the neural Ig-CAM family, the in identified initially Ig-CAM), (Neural Cell Molecules Immunoglobulin-like Adhesion Neural that hypothesis 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 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 cytokines. 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 3 clide therapy(PRRT) with radionu- receptor peptide with radio-sensitising as combined been has capecitabine data). metronomic (unpublished them lomide Among In IEO’s experience, more than 70 patients have been treated with metronomic capecitabine so far, and very few with metronomic temozo- 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 [42] 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 The same group reported in 2014 results with another Italian multicentric phase II trial of 45 patients with NETs from mixed primary sites 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. adverse , 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 event. The TTP ofall29patients 177 Lutetium inaround20patients(unpublisheddata). [41] reported the use of 5-FU combined with octreotide long acting repeatable (LAR) in a phase II study [46] was 22.6 inwhichpatientsevenseemedtohaveacceleratedprogressionwiththiscombination. months [45] . Alfredo Berrutialso mentioned three case reports with benefit after multiple after benefit . with reports case three mentioned Berrutialso Alfredo (range, [47] 12 and its expression was induced by pro-angiogenic and inflammatory

2.7–68.5), while themedian in vitro results with paclitaxel and sorafenib [43] [44] in a consecutive series of 15 patients. OS wasnotreached.Thereno . In case of metastatic disease or disease metastatic of case In . 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 were 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. and VEGF/TSP-1weresignificantlyassociatedwithTTPcouldbeconsideredpotentialpredictorsofresponse metasta- 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. ses, the evidence supporting the potential of mebendazole 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 (docetaxel+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 released soon. be will and accepted been have manuscript The PFS. 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 prostate cancer (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 increas [51] .Looking for biomarkers of response, they could find that the baseline values of serum levels of the ratios VEGF/sVEGFR-2 ed the median ecancermedicalscience survival time, havinglowtoxicityinboth , the peer-reviewed scientific journal of [49] have been available since July 10 2014. He concluded by listing other potential 13

tumour models ecancer et al.JCI2014). [50] . Also, . A policy paper she reported observed that vascular L1 vascular that observed al et [48] and the article reviewing [52] ecancer that . www.ecancer.org the combination 2014,8:463 of

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 with metastatic/recurrentHNSCCpatientspresentlyat TMH. i metronomic chemotherapy leading to a 33% improvement in PFS than cisplatin. In addition,and101 and 249 in metronomicArmB,respectively, chemotherapywith valuepa of0.014led and 0.02, torespectively. an improvement Thus the primary endpoint ofthe study was met with Also, disease. advanced or relapsed locally had most and cancers cavity oral had patients the of Most cycles). six maximum times days 21 every (Arm B: Methotrexate 15 mg/m 15 Methotrexate B: (Arm 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 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 n OS;italso most had had [53, 54] received fewer , which costs approximately 10 USD, they undertook this randomised study to compare oral metronomic chemotherapy side prior effects, withmaintenance treatment 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 with radiotherapy of QOL.Oral and /or chemotherapy metronomic 14

chemotherapy . The median has thusbecome PFS and OS were a standard 66 ecancer and www.ecancer.org 152 of care 2014,8:463 days for in patients Arm A 2

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