L’impiego 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)

Sesso F Età 43 anni Premenopausa 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

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

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

Eventi avversi Tossicità ( Q3W ): nausea G2, stomatite G2, artralgie-mialgie G3 (7-10 giorni) Tossicità ( QW ): nausea G1 “Terapia impegnativa per la frequenza (impegno mentale)” “ L’effetto peggiore è stato l’alopecia”

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

Riepilogo caso clinico - Fasi del trattamento ed evoluzione clinica corrispondente Periodo Trattamento Evoluzione 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

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

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

Advances in Treatment 1980 1985 1990 1995 2000 2005 Tamoxifen CMF Doxorubicin Mitoxantrone Epirubicin Paclitaxel Vinorelbine Aromatase Inhibitors Docetaxel Gemcitabine Capecitabine Fulvestrant Trastuzumab Albumin-Bound Paclitaxel Bevacizumab ER+ or PR+ Lapatinib HER2+ Ixabepilone

Need for Better Therapies and Patient Selection to Improve Survival Drug resistance is associated with >90% treatment failures in patients with metastatic cancer1 5-year survival of patients diagnosed with MBC is approximately 26%,2 despite considerable therapeutic advances over the past 20 years3 Improved selection of patients for response to available therapies will result from genomic and proteomic analyses3 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.

First-Line MBC Single-Agent Response Rates Treatment ORR (%) Docetaxel1 (75-100 mg/m2) 40-68 Paclitaxel1 (175-250 mg/m2 3-24 h) 32-62 Doxorubicin4 43 Capecitabine3 30 Vinorelbine2 35-53 Gemcitabine2 18-37 Cyclophosphamide4 36 Fluorouracil4 28 Methotrexate4 26 Mitoxantrone4 27 1. Seidman AD, Clin Cancer Res 2.Vogel and Nabholtz. The Oncologist. 1999;4:17. 3. O’Shaughnessy et al. Ann Oncol. 2001;12:1247.4. Sledge. Cancer Control. 1999;6:17.

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

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

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 studies1,2 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.

Le Linee-Guida: NAB-paclitaxel e altri taxani Paclitaxel viene raccomandato in prima linea in monoterapia o in associazione a bevacizumab Raccomandato anche l’utilizzo di NAB-paclitaxel alla posologia di 100-150 mg/m2 ev ai giorni 1, 8 e 15 ogni 28 giorni, o alla posologia di 260 mg/m2 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 l’impiego del nuovo farmaco NAB-paclitaxel Nell’aggiornamento 2010 delle linee guida AIOM NAB-paclitaxel è 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

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

Chemotherapy Regimens for MBC 2007 NCCN Recommendations Representative Single Agents Combination Regimens 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. 1. National Comprehensive Cancer Network. Breast Cancer. Clinical Practice Guidelines in Oncology – v.2.2006.

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

Taxanes Sequential preferred