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Limpiego di nab-paclitaxel nel trattamento terapeutico del carcinoma mammario metastatico (in prima/seconda linea) Dr. Salvatore Bonura ASS 5 Bassa Friulana Ospedali di Latisana e Palmanova (UD)

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2005 Mastectomia sinistra + protesi K duttale inf. G2 pT2 N+ (1/16 N ) ER 90% PgR 70% HER 2 neg FEC x 6 adiuvante > Analogo LH/RH + TAM 2009 rec sottocutanea sin (QQII diam. 1,5 cm) Asportazione K duttale inf. G3 ER 95% PgR 5% Mib 1 30% HER 2 neg LETROZOLO Sesso F Et 43 anni Premenopausa

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FEBBRAIO 2012 recidiva periprotesica (sottocutaneo) sin ( 0,5 cm) Ca duttale infiltrante scarsamente differenziato ER > 95% PgR neg Mib1 40% HER 2 neg Citologia + su LNF iuxtaclaveare PET/TC (marzo) linfoadenopatie in sede mediastinica-claveare sx compatibili con localizzazioni secondarie di malattia

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Intervento APRILE 2012 inizia CHT Nab Paclitaxel 260 mg / mq /Q3W (1 ciclo) Nab Paclitaxel 125 mg / mq / settimana (Schedula 3 w on/ 1 w off) (2 cicli: 6 sedute) Dopo 3 cicli: Buona RP

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Eventi avversi Tossicit ( Q3W ): nausea G2, stomatite G2, artralgie-mialgie G3 (7-10 giorni) Tossicit ( QW ): nausea G1 Terapia impegnativa per la frequenza (impegno mentale) Leffetto peggiore stato lalopecia

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Ha ripreso il trattamento QW x 2 cicli (Paziente estremamente motivata ) Nausea-stomatite G1 - Artralgie scapolo-omerali G1 In attesa di rivalutazione

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Riepilogo caso clinico - Fasi del trattamento ed evoluzione clinica corrispondente PeriodoTrattamentoEvoluzione clinica 2005 Mastectomia (protesi)+LAD sx PT2 N+ (1/16) G2 RO++ HER 2 neg FEC x 6 adiuvante 2006 Tamoxifene + LH-RH ASSENZA DI MALATTIA 2009 Tamoxifene Recidiva sottocutanea sx (diam. 1,5 cm) K G3 RO+- Mib1 30% HER2 neg 2009 > 2012 (ASPORTAZIONE LETROZOLO) Assenza di malattia Febbraio-Marzo 2012 Letrozolo Recidiva sottocutanea sx (diam. 0,5 cm) K G3 RO+- Mib1 40% HER2 - PET/TC: LNFpat mediast-clav sin Aprile-Maggio-Giugno 2012 NAB-P x 3 cicli (1 > Q3W 2-3 > QW ) Remissione parziale di malattia Agosto-Settem. 2012 NAB-P x 2 cicli - QW In rivalutazione

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Spunti di discussione: Scelta del trattamento Scelta della schedula Come proseguire

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5-Year Survival Rates by Stage Stage 0 (95%) Stage I (88%) Stage II (66%) Stage III (36%) Stage IV (7%) http://www.nlm.nih.gov/medlineplus/ency/article/000913.htm

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Advances in Treatment 198019851990199520002005 Capecitabine Bevacizumab Paclitaxel CMF Gemcitabine Albumin-Bound Paclitaxel Trastuzumab Lapatinib Doxorubicin Epirubicin Mitoxantrone Vinorelbine Docetaxel HER2+ Aromatase Inhibitors Tamoxifen ER+ or PR+ Ixabepilone Fulvestrant

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Need for Better Therapies and Patient Selection to Improve Survival Drug resistance is associated with >90% treatment failures in patients with metastatic cancer 1 5-year survival of patients diagnosed with MBC is approximately 26%, 2 despite considerable therapeutic advances over the past 20 years 3 Improved selection of patients for response to available therapies will result from genomic and proteomic analyses 3 1.Longley and Johnson. J Pathol. 2005;205:275. 2. American Cancer Society. Cancer Facts & Figures 2007. Atlanta: American Cancer Society; 2007. 3. Seidman. Oncology (Williston Park). 2006;30:983.

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First-Line MBC Single-Agent Response Rates TreatmentORR (%) Docetaxel 1 (75-100 mg/m 2 )40-68 Paclitaxel 1 (175-250 mg/m 2 3-24 h)32-62 Doxorubicin 4 43 Capecitabine 3 3030 Vinorelbine 2 35-53 Gemcitabine 2 18-37 Cyclophosphamide 4 36 Fluorouracil 4 28 Methotrexate 4 26 Mitoxantrone 4 27 1.Seidman AD, Clin Cancer Res 2.Vogel and Nabholtz. The Oncologist. 1999;4:17. 3.OShaughnessy et al. Ann Oncol. 2001;12:1247.4.Sledge. Cancer Control. 1999;6:17.

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Taxanes as Adjuvant Therapy in BC Taxanes used in stage I-III BC significantly improves DFS Recurrence is still a substantial problem Emergence of molecular resistance to taxanes: Increases population requiring alternate therapy Decreases efficacy to other chemotherapies by cross-resistance

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Clinical Challenges in the Management of MBC Individualizing treatment to specific cancer biology Reducing and managing toxicity of chemotherapies Understanding and then overcoming resistance to chemotherapy and hormone therapy Impact in metastatic and adjuvant settings Increasing disease control and survival

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Rationale for New Agents MBC remains an important medical problem Anthracyclines and taxanes are the standard of care Increasing use in the adjuvant setting Drug resistance Need for new agents Capecitabine approved for use after failure of anthracyclines and/or taxanes ORRs 9% to 14% in phase III studies 1,2 Limited efficacy of other agents used in MBC 1.Miller et al. J Clin Oncol. 2005;23:792. 2.Geyer et al. N Engl J Med. 2006;355:2733.

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Le Linee-Guida: NAB-paclitaxel e altri taxani Paclitaxel viene raccomandato in prima linea in monoterapia o in associazione a bevacizumab Raccomandato anche lutilizzo di NAB-paclitaxel alla posologia di 100-150 mg/m 2 ev ai giorni 1, 8 e 15 ogni 28 giorni, o alla posologia di 260 mg/m 2 ev ogni 21 giorni Terapia di prima linea con paclitaxel settimale in monoterapia, paclitaxel associato ad antraciclina (doxorubicina, epirubicina), a gemcitabina, vinorelbina o carboplatino. Le Linee-guida ESMO suggeriscono anche limpiego del nuovo farmaco NAB-paclitaxel Nellaggiornamento 2010 delle linee guida AIOM NAB-paclitaxel stato inserito tra i farmaci molto attivi in monoterapia; si sottolinea infatti che NAB-paclitaxel ha dimostrato di migliorare significativamente la percentuale di risposte obiettive, TTP e OS nelle donne con carcinoma mammario metastatico rispetto a paclitaxel convenzionale disciolto in solvente

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NCCN: Linee-guida MBC Trastuzumab Exposed Anthracyclines Doxorubicin Pegylated Liposomal Doxorubicin Epirubicin Taxanes Paclitaxel Albumin-bound Paclitaxel Docetaxel Anti- metabolites Gemcitabine Capecitabine Combo/Other Vinorelbine FAC/CAF FEC AC AT CMF DC GP Other First Line (Trastuzumab Nave) Trastuzumab + Paclitaxel +/- Carboplatin Trastuzumab + Docetaxel Trastuzumab + Vinorelbine Trastuzumab + Capecitabine Capecitabine + lapatinib Trastuzumab + Capecitabine Trastuzumab + lapatinib Trastuzumab + HER2- recommended therapy HER2 + HER2 - Relatively clearer guidance for HER2+ patients 16 preferred single agents/combinations listed with no sequencing guidance Bevacizumab No compelling evidence that combination regimens are superior to sequential agents

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Representative Single Agents Chemotherapy Regimens for MBC 2007 NCCN Recommendations Doxorubicin Epirubicin Pegylated liposomal doxorubicin Paclitaxel Docetaxel Capecitabine Vinorelbine Gemcitabine Albumin-bound paclitaxel CAF/FAC (cyclophosphamide/doxorubicin/ fluorouracil) FEC (fluorouracil/epirubicin/cyclophosphamide) AC (doxorubicin/cyclophosphamide) EC (epirubicin/cyclophosphamide) AT (doxorubicin/docetaxel; doxorubicin/paclitaxel) CMF (cyclophosphamide/methotrexate/fluorouracil) Docetaxel/capecitabine GT (gemcitabine/paclitaxel) F = fluorouracil; A = doxorubicin; C = cyclophosphamide; E = epirubicin; T = paclitaxel; M = methotrexate. National Comprehensive Cancer Network. Breast Cancer. Clinical Practice Guidelines in Oncology v.2.2007. Combination Regimens

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NCCN: NAB-paclitaxel tra le monochemioterapie raccomandate in prima linea

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Sequential preferred Taxanes