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Scuola di uro Oncologia

Scuola di uro Oncologia. CONTROVERSIE ONCOLOGICHE L ’ oncologo risponde all ’ urologo: PRIMA LINEA DI TRATTAMENTO. G. Cartenì Direttore U.O.S.C. di Oncologia Medica A.O.R.N. A. Cardarelli Napoli. Roma, 12/13 Luglio 2013.

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Scuola di uro Oncologia

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  1. Scuola di uro Oncologia CONTROVERSIE ONCOLOGICHE L’oncologo risponde all’urologo: PRIMA LINEA DI TRATTAMENTO G. Cartenì Direttore U.O.S.C. di Oncologia Medica A.O.R.N. A. Cardarelli Napoli Roma, 12/13 Luglio 2013

  2. Quali criteri vengono utilizzati per scegliere il farmaco da utilizzare in prima linea ? • Come monitorizzare la terapia ? Criteri di successo/insuccesso • La gestione delle complicanze/effetti collaterali • Trattamento delle metastasi ossee • Associazione di farmaci ? terapie sequenziali ?

  3. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  4. Linee Guida EAU 2010

  5. First-line treatment guidelines for clear cell mRCC: ESMO 2012 Escudier B, et al. Ann Oncol 2012;23(Suppl 7):vii65–71

  6. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  7. Randomized, Open Label, Phase III Trial of Pazopanib versus Sunitinib in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma (mRCC): Results of the COMPARZ Trial Robert Motzer1, T. E. Hutson2, James Reeves3, Robert Hawkins4, Jun Guo5, Paul Nathan6, Michael Staehler7, Paul de Souza8, Jaime R. Merchan9, Kate Fife10, Jie Jin11, Robert Jones12, Hirotsugu Uemura13, Ugo De Giorgi14, Ulrika Harmenberg15, Jinwan Wang16, David Cella17, Lauren McCann18, Keith Deen18, and Toni K. Choueiri19 1Memorial Sloan Kettering Cancer Center, NY, NY, USA; 2Baylor Sammons Cancer Center/Texas Oncology, Dallas, TX, USA; 3Florida Cancer Specialists, Fort Myers, FL, USA; 4University of Manchester and The Christie Hospital, NHS Foundation Trust, Manchester, United Kingdom; 5 Renal Cancer and Melanoma Unit, Peking University Cancer Hospital, Beijing, China; 6Mount Vernon Hospital, Middlesex, United Kingdom;7 Department of Urology, Interdisciplinary Centre on Renal Tumors, University of Munich, Munich, Germany; 8University of Western Sydney School of Medicine, MMRG, CRG, Sydney, Australia; 9 University of Miami, Sylvester Cancer Center, Miami, FL, USA:10 Oncology Centre, Addenbrooke's Hospital, Cambridge, United Kingdom; 11 Peking University First Hospital, Beijing, China; 12Institute of Cancer Sciences University of Glasgow, Glasgow, United Kingdom;13 Department of Urology, Kinki University Faculty of Medicine, Osaka, Japan; 14IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy; 15Department of Oncology, Radiumhemmet Karolinska University Hospital, Stockholm, Sweden; 16 Cancer Hospital, CAMS & PUMC, Beijing, China; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL , USA;18GlaxoSmithKline, Inc., Collegeville, PA, USA; 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

  8. COMPARZ: PFS (IRC-assessed) Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223) PP, per-protocol 1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38 (last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)

  9. COMPARZ: PFS (IRC-assessed) Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223) PP, per-protocol 1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38 (last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)

  10. COMPARZ: PFS (IRC-assessed) Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223) PP, per-protocol 1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38 (last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)

  11. COMPARZ study design:Phase III, open-label, non-inferiority trial Pazopanib 800 mg QDContinuous daily dosing • Enrolment criteria: • Locally advanced or mRCC • Clear-cell histology • No prior systemic therapy • Measurable disease (RECIST 1.0) • KPS ≥70 • Adequate organ function Randomised1:1 N=927 Sunitinib 50 mg QD Schedule 4/2 N=1,110 Study start: August 2008 VEG113078 Phase II (Asia)n=183 VEG108844 Phase IIIn=927 COMPARZ:1,110 patients KPS, Karnofsky Performance Scale; RECIST, Response Evaluation Criteria in Solid Tumors; Schedule 4/2, 4 weeks on treatment, 2 weeks off www.clinicaltrials.gov (NCT00720941; NCT01147822)

  12. Primary Endpoint: Progression-free Survival (independent review) Pazopanib Sunitinib

  13. Interim Analysis of Overall Survival Pazopanib Sunitinib

  14. COMPARZ: Timing of assessments Sunitinib Pazopanib Week 6 Week 6 Week 6 Disease assessments Mean change from baseline QoL assessments Week 4 Week 4 Week 4 Time QoL, quality of life Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8Cella D, et al. Presented at ASCO-GU 2012; Abstract 346

  15. Most Common Adverse Events (treatment-emergent)

  16. COMPARZ: Common AEs (treatment-emergent) *AE ≥30% in either arm; †2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEs ALT, alanine transaminase; AST, aspartate transaminase; HFS, hand–foot syndrome; NA, not applicable

  17. Treatment Duration and Dose Adjustments 1. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)

  18. Quality of Life Results (first 6 months1) 1Pre-specified analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of covariance (ANCOVA). 2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant

  19. Quality of Life Results (first 6 months1) 1Pre-specified analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of covariance (ANCOVA). 2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant

  20. Quality of Life Results: PISCES1Randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma Escudier BJ, et al.. J Clin Oncol 30, 2012 (suppl; abstr CRA4502) Cella D, et al. ESMO Congress 2012 poster 792PD Yellow Font: favors pazopanib P-value <0.05 is statistically significant

  21. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  22. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  23. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  24. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  25. How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…!

  26. Significantly more patients preferred pazopanib over sunitinib (primary endpoint)1 p<0.001 70% (n=80) Patients (%) 8% (n=9) 22% (n=25) Escudier B, et al. J ClinOncol2012;30 suppl: abstr CRA4502.

  27. Quali criteri vengono utilizzati per scegliere il farmaco da utilizzare in prima linea ? • Come monitorizzare la terapia ? Criteri di successo/insuccesso • La gestione delle complicanze/effetti collaterali • Trattamento delle metastasi ossee • Associazione di farmaci ? terapie sequenziali ?

  28. Valutazione dello stato di malattia in corso di trattamento con targeted therapies • Necessario fare riferimento a criteri: • Diagnostica strumentale • Clinici • Laboratorio

  29. La risposta parziale è definita come tumor shrinkage pari al 30% Un tumor shrinkage del < 30% è un risultato positivo per il paziente.Il controllo del tumore potrebbe essere un endpoint clinicamente più rilevante2  Potrebbe non essere appropriato per valutare la risposta alle targeted therapies (differente meccanismo d’azione)  Le targeted therapies possono determinare necrosi tumorale piuttosto che tumor shrinkage3 Criteri di risposta (RECIST) - Criticità Icriteri RECIST rappresentano lo standard di valutazione di risposta al trattamento in studi clinici su farmaci antitumorali1 • Si basa sulle risposte agli agenti antitumorali citotossici • Non si misurano le necrosi tumorali 1. Therasse P, et al. J Natl Cancer Inst 2000; 92:205–16 2. Nygren P, et al Acta Oncologia 2008; 47:316–293. Abou-Alfa G, et al. J Clin Oncol 2006;24:4293–300

  30. Revisione criteri di risposta (RECIST v. 1.1) • Principali modifiche proposte: • Numero delle lesioni valutabili; • Dimensioni dei linfonodi patologici; • Conferma della risposta; • Supporto FDG-PET per valutare le progressioni.

  31. Come valutare la risposta al trattamento nell’era delle targeted therapies? • I criteri RECIST e la loro più recente revisione non tengono conto di: • Tecniche di imaging funzionale come la PET o la RMN • Valutazione anatomica volumetrica del tumore • Necessità di nuove metodiche di immagine atte a studiare la vascolarizzazione e la necrosi tumorale FDG-PET DCE-US DCE-MRI

  32. Imaging funzionale con DCE-USValutazione della risposta a sorafenib • Abdominal lymph node from an RCC in a 37 year-old woman (good responder) treated with sorafenib DCE-US before treatment shows contrast uptake throughout the tumour estimated at 81% DCE-US after 3 weeks of treatment shows contrast uptake throughout the tumour estimated at 48% DCE-US after 6 weeks of treatment shows contrast uptake throughout the tumour estimated at 31% Lamuraglia et al.EJC 2006

  33. identifying patients with progression-free survival of >250 days CONCLUSION: Assessment of metastatic RCC target lesions on CECT for changes in morphology, attenuation, size, and structure by MASS Criteria is more accurate than response assessment by SACT Criteria, RECIST, or modified Choi Criteria. Furthermore, the use of MASS Criteria for imaging response assessment showed high interobserver agreement and may predict disease outcome in patients with metastatic RCC on targeted therapy Smith AD, Shah SN, Rini BI, Lieber ML, Remer EM. Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol. 2010 Jun;194(6):1470-8

  34. Valutazione dello stato di malattia in corso di trattamento con targeted therapies • Necessario fare riferimento a criteri: • Diagnostica strumentale • Clinici • Laboratorio

  35. Criteri clinici • Esame obiettivo • Performance status • Sintomi tumore-correlati • Perdita di peso • Consumo di analgesici • Qualità di vita del paziente

  36. Criteri di laboratorio • Emocromo completo • Funzionalità epatica • Funzionalità renale • LDH • Calcemia Tossicità o progressione di malattia?

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