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Chemotherapy: when less is more?

Chemotherapy: when less is more?. Marina E Cazzaniga Director, Clinical research Phase 1 Centre ASST Monza & Milano Bicocca School of Medicine and Surgery. Chieti, 15 Giugno 2017. Il Network HERMIONE. Monza, 27 febbraio 2017. Perché la necessità di un Network?.

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Chemotherapy: when less is more?

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  1. Chemotherapy:when less is more? Marina E Cazzaniga Director, Clinical research Phase 1 Centre ASST Monza & Milano Bicocca School of Medicine and Surgery Chieti, 15 Giugno 2017

  2. Il Network HERMIONE Monza, 27 febbraio 2017

  3. Perché la necessità di un Network? • Vista la numerosità di studi di ricerca clinica indipendente promossi da singoli, si è creata la volontàe la necessitàdi ideare una piattaforma di collegamento fra i vari centri, che possa essere messa a disposizione di tutto il gruppo, ma anche di singoli Centri • HERMIONE si propone come strumento di collaborazione per la ricerca clinica INDIPENDENTE nel tumore della mammella metastatico HR+ • HERMIONEnon vuole replicare, o porsi come alternativa, a gruppi cooperatori già esistenti sul territorio nazionale

  4. Cos’è la piattaforma HERMIONE? • HERMIONE è una piattaforma interattiva, che funge da strumento di collegamento a diversi livelli: • Fra Centri diversi sul territorio nazionale • All’interno di un singolo Centro • All’interno di un gruppo di persone di un singolo centro, o di centri diversi • HERMIONE funge da repository di materiale bibliografico, slides, ecc • HERMIONE funge da Forum per lo scambio di opinioni fra clinici, discussione di casi clinici, ecc – diversi livelli di scambio

  5. DE-ESCALATION IN CHEMOTHERAPY TREATMENT Less number of drugs  poly-chemotherapy vs monotherapy Less patients treated  better selection of patients Less toxicity from the same drugs  changing in schedule and way of administration

  6. CHEMOTHERAPY vs ENDOCRINE THERAPY (Cardoso F, AnnOncol 2017) (Cazzaniga ME, ASCO 2017, #1057)

  7. POLYCHEMOTHERAPY vs MONOTHERAPY Adherence to International ESO-ESMO (ABC) guide-lines in HER2-ve metastatic breast cancer (MBC) patients (pts) – Preliminary results of the GIM 13 - AMBRA Study (Cardoso F, AnnOncol 2017) (Cazzaniga ME, submitted ESMO 2017)

  8. IMPROVEMENT IN PATIENTS SELECTION

  9. IMPROVEMENT IN PATIENTS SELECTIONDoes subclonality make the primary tumour a poor proxy for the metastatis seeding clone?

  10. IMPROVEMENT IN PATIENTS SELECTIONDoes subclonality make the primary tumor a poor proxy for the metastasis seeding clone?

  11. Metronomic chemotherapy(mCT) : definition CHANGEMENT IN SCHEDULE AND ADMINISTRATION “Indeed, metronomic chemotherapy may be better defined as a frequent, regular administration of drugdoses designed to maintain low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time without inducing excessive toxicities.” Bocci & Kerbel. NatRevClinOncolin press “Metronomic chemotherapy is defined as the minimum biologically effective dose of a chemotherapic agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumour activity ” Klement G.L & Kamen BA J Paediatr. Haematol. Oncol. 33,1-3, 2011 “The cumulative doses administered over the course of long-term metronomic treatments can be similar or even higher than those administered in conventional MTD regimens, making the terminology ‘low dose chemotherapy’ somewhat misleading.” Andre, Carry, Pasquier. NatRevClinOncol, vol 11, 2014

  12. Antivasculareffects of MTD & Metronomic CHT MTD regimens Metronomicregimens Increase of the antivasculareffects by blocking the recovery of new vascularizationwithoutincreasingadverseevents Vascularrepairactivityduring the drug-free periodsbecause of up-regulation of pro-angiogenicfactors Emmenegger U, Chou A, Bocci G. 2010, Springer

  13. mVRL significantly decreases pro-angiogenic genes expression and promotes anti-angiogenic genes PRO-ANGIOGENIC ANTI-ANGIOGENIC

  14. MDA RESULTS(MTT assay) MET STD (Cazzaniga ME, submitted)

  15. mCT: Depletion of Tregsand modulation of myeloid-derived suppressor cells (MDSC) Pere H et al. Oncoimmunology 2012 Andre N et al. NatRev 2014

  16. Single-agent or combination regimens of mCHT (Cazzaniga ME, Dionisio MR and Riva F, CancerLetters 2016)

  17. VICTOR-2 Study ORIGINAL ARTICLE METRONOMIC CHEMOTHERAPY WITH ORAL VINORELBINE (mVNR) AND CAPECITABINE (mCAPE) IN ADVANCED HER2-NEGATIVE BREAST CANCER PATIENTS: IS IT A WAY TO OPTIMIZE DISEASE CONTROL? FINAL RESULTS OF THE VICTOR-2 STUDY M.E. Cazzaniga1, L. Cortesi2, A. Ferzi3, L. Scaltriti4, F. Cicchiello1, M. Ciccarese M5, S. Della Torre6, F. Villa7, M. Giordano8, C. Verusio9, M. Nicolini10, A.R. Gambaro11, L. Zanlorenzi12, E. Biraghi13, L. Legramandi14, E. Rulli14 on behalf of the VICTOR Study Group 1 2 Primary end point • CBR=OR+SD≥24 weeks Secondary end points ORR=CR+PR DCR=OR+SD PFS, TTP Cazzaniga ME, Cortesi L, Ferzi A et Al. BreastCancer Res Treat, 2016

  18. VICTOR-2 Study Primary end pointCBR = OR+SD ≥ 6 months CBR=48.8% CBR=55.8% • Median time to response: 2.0 months Cazzaniga ME, Cortesi L, Ferzi A et Al. BreastCancer Res Treat, 2016

  19. VICTOR 2 Study – Efficacyresults PFS according to treatment line and hormonereceptor status • PFS rate at 1 year: 1st-line=24.3% - 2nd-line=22.2% Cazzaniga ME, Cortesi L, Ferzi A et Al. BreastCancerResTreat, 2016

  20. The median TTP was 25.1 months in the naïve group and 11.2 months (95% CI: 9.2e17.0) in the pre-treated group Montagna E et Al, 2017

  21. The betterstudiedregimenis CM (low-dose oralcyclophosfamide and methotrexate); otherregimens are beingevaluated(includingcapecitabine and vinorelbine)

  22. Patients’ selection for metronomicchemotherapy «The majority of these trials enrolledHR+vepatients, with indolentdisease or bone metastases, so far allthesediseasecharacteristicscould serve aspratical guide lines for patients’ selection» (Cazzaniga ME et Al, J CancerClinTrials, 2016)

  23. Take-home message & conclusion The ability to target angiogenesis, cancer stem cells and modulate the immune system provides an opportunity to overcome resistance and delay tumour progression • The way to reach a clear de-escalation of CHT in ABC patients is far from be defined • Lack of predictive biomarkers • Lack of clinical tools to select patients • Metronomic CHT could be considered a good example of CHT de-escalation: • Well tolerated • Administered orally • Relatively low cost CBR, clinical benefit rate; ORR, overall response rate

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