Presentación de PowerPoint - Foro de Debate en Oncologia
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Presentación de PowerPoint - Foro de Debate en Oncologia
Cáncer de Ovario Avanzado Importancia de la 1ª decisión Dra Belén Ojeda Epithelial ovarian carcinoma is not a single disease Tratamiento del Cáncer de Ovario Avanzado Quimioterapia Cirugía Citorreducción primaria máximo esfuerzo (ER=0) Carboplatino + Paclitaxel • Histologia • Estadio FIGO • Debulking óptimo 1ª DECISION: La cirugía citorreductora de máximo esfuerzo es la columna vertebral del tto. del Cáncer epitelial de ovario avanzado Todas las pacientes diagnosticadas de un cáncer de ovario deberían de ser sometidas a una lapaotomia de estadificación completa, para una información precisa de la enfermedad e histologia Es importante para predecir el pronostico y la decisión del tratamiento post-cirugía Basandose en los resultados publicados, se recomienda que la cirugía primaria sea realizada por un ginecólogo oncologo Treatment of ovarian cancer: Optimal Debulking Surgery Stuart, et al. Int Gynecol Cancer 2011; 21:750-5 The impact of residual tumour on outcome in advanced ovarian cancer Data from an individual patient meta-analysis of three randomised phase III trials with 3,126 patients 5-year survival rate 100% HR (95% CI) Overall survival (%) 75% 1–10mm vs 0mm: 2.70 (2.37, 3.07) >10mm vs 1–10mm: 1.34 (1.21, 1.49) log-rank: p<0.0001 50% Med OS: 99,1m. 0mm 25% Med OS: 36,2 m 0% 0 12 24 36 48 60 72 84 Time (months) du Bois A, Reuss A, Pujade-Lauraine E, et al. Cancer 2009;15:1234–44 96 1–10mm >10mm Med. OS: 29,6 m. 108 120 132 144 Optimal Debulking Surgery in advanced ovarian cancer Complete surgical debulking improves prognosis in any FIGO stage Du Bois A, Reuss A, Pujade-Lauraine E, et al. Cancer 2009; 15:1234-44 Cáncer de Ovario Avanzado Cirugía Citorreductora Máxima (no enfermedad Residual) Paciente: • PS/edad • NS (BMI/caquexia) • Comorbilidades • Cirugías previas Biológial Tumoral Cirujano: • Motivación • Patrones de crecimiento • Conocimientos • Diseminación • Experiencia • Comorbilidad • Equipo multidisciplinario 4th Ovarian Cancer Consensus Conference June 25 – 27, 2010 UBC Life Sciences Institute, Vancouver, BC A4: What role does surgery play today? • Surgical staging should be mandatory and should be performed by a gynecologic oncologist. • The ultimate goal is cytoreduction to microscopic disease. There is evidence that reduction to ≤1 cm macroscopic disease is associated with some benefit. • The term “optimal” cytoreduction” should be reserved for those with no macroscopic residual disease. • Delayed primary surgery following neoadjuvant chemotherapy is an option for selected patients with advanced stage IIIC and IV ovarian cancer as included in EORTC 55971. Stuart, et al. Int J Gynecol Cancer 2011;21:750–5 N Engl J Med 2010;363:943-53. Ovaria, Trompa, Peritoneo Stage IIIC-IV R Cirugía de Debulking primaria Neoadjuvant Chemotherapy QT neoadyuvante CT x 3 ciclos CT x 3 ciclos Cirugía de Intervalo (no obligatorio) Interval surgery (if no progression) CT > 3ciclos CT > 3 ciclos • Aumenta la Citorreducción Optima: 21% 53% • Menos complicaciones: Mortalidad 2.7% 0.6% Sepsis 8 % 2% % Optimal Surgery (42% PDS vs 80% IDS) OS PFS OS PDS 29 m 12 m PDS (RD:0) 45 m NACT 30 m 12 m NACT (RD:0) 38 m La Cirugía Primaria (ER:0) Es el factor pronostico independiente más importante Vergote I., et al. N Engl J Med 363:10, 2010 How to select patients? Sistemic therapy : Advanced stages Conventional Chemoterapy The current therapeutic strategy is optimal cytoreductive surgery followed by 6 cycles of paclitaxel and carboplatin. According to the 4th Ovarian Cancer Consensus Conference the standard treatment should include paclitaxel (175 mg/m2) and carboplatin (AUC 5–7.5) every 3 weeks for 6 cycles. [I, A] Carboplatino +PLD : Alternative for patients not eliglible to taxol. ¿Qué se ha hecho para intentar mejorar los tratamientos? • Sustituir Paclitaxel por otra droga - SCOTROC (docetaxel); - MITO-2 (DLP) • Tratamiento de mantenimiento/consolidación - SWOG 9701 • Añadir una 3ª droga: (6 ensayos GCIG ≈10,000 p.) GOG 182-ICON5 QT intraperitoneal: GOG 172…. Densidad de dosis: Estudio NOVEL Antiangiogénicos: Bevacizumab Limitations and Complications GOG-172 • QoL by FACT-O worsened at the end of cycle 3 and 6. • Only 42% of patients completed the 6 cycles scheduled Sistemic therapy : Advanced stages Intraperitoneal chemoterapy IP CT is another standard option in the management of patients with stage lll and RD <1 cm despite of technical issues and toxicity which limits its routine use [I,A] Because of these difficulties may be an option only for selected patients and centers Dose-dense regimen NOVEL trial: New OVarian ELaborate trial FIGO stage II-IV epithelial ovarian, primary peritoneal or fallopian tube cancer RANDOMIZE Conventional TC (cTC) 320 pts Dose dense TC (ddTC) 317 pts Paclitaxel 180 mg/m2 d1 Carboplatin AUC 6 d1 Paclitaxel 80 mg/m2 d1,8,15 Carboplatin AUC 6 d1 Every 21 days for 6-9 cy Every 21 days for 6-9 cy Katsumata et al. Lancet 2009 Sistemic therapy : Advanced stages Dose-dense regimen Not formal recommendation of this strategy until definitive data in the Caucasian population. 2 European trials ongoing: MITO7 and ICON 8 Sistemic therapy : Advanced stages Antiangiogenic Therapy: Bevacizumab GOG218 GOG-0218: Schema Sub-óptimo Arm Carboplatin (C) AUC 6 Front-line: epithelial OV, PP or FT cancer ● Stage III optimal (macroscopic <1 cm) ● Stage III suboptimal ● Stage IV N=1873 R A N D O M I S E Stratification variables GOG performance status Stage/debulking status I Paclitaxel (P) 175 mg/m2 Placebo 1:1:1 Carboplatin (C) AUC 6 II Paclitaxel (P) 175 mg/m2 Bev 15 mg/k Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Bevacizumab 15 mg/kg Cytotoxic (6 cycles) OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab (CPP) Maintenance (16 cycles) (CP + Bev) III (CP+Bev Bev) 15 months N Engl J Med 365;26,2011 Antiangiogenic Therapy: Bevacizumab GOG 218: Primary endpoint results PFS 1.0 Median PFS (months) I CP + Pl Pl (n=625) II CP + Bev15 Pl (n=625) III CP + Bev15 Bev15 (n=623) 10.6 11.6 14.7 0.89 (0.78–1.02) 0.70 (0.61–0.81) 0.0437* <0.0001* Stratified analysis HR (95% CI) 0.8 PFS estimate p value one-sided (log rank) 0.6 0.4 0.2 CP + Pl Pl (Arm I) CP + Av15 Pl (Arm II) CP + Bev15 Bev15 (Arm III) 0 0 24 30 PFS analysis determined using RECIST, global deterioration or Time (months) CA125 progression p value boundary = 0.0116 6 12 18 36 42 48 Burger et al N Engl J Med2011 GOG 218- Significant PFS improvement, censored for CA-125 events and non-protocol therapy 1.0 CP + Bev15 Bev15 CP + Pl Pl (n=625) (n=623) 0.8 Median PFS (months) 12.0 18.2 0.62 PFS estimate Stratified analysis HR (95% CI) 0.6 (0.52–0.75) p value one-sided (log rank) <0.0001* 0.4 0.2 CP + Pl Pl CP + Bev15 Bev15 0 0 6 12 18 24 PFS (months) 30 36 42 48 *p value boundary = 0.0116 Data cut-off date: September 29, 2009 N Engl J Med 365;26,2011 ICON-7: diseño del estudio Epithelial ovarian, primary peritoneal or fallopian tube cancer ● High-risk stage I–IIA (grade 3 or clear cell) ● Stage IIB–IV n=1528 Carboplatin AUC 6* (C) CP Paclitaxel 175 mg/m2 (P) R 1:1 C P CPB7.5+ (Dec 2006 to Feb 2009) Bevacizumab 7.5 mg/kg q3w 12 months Stratification variables: • Stage I–III debulked ≤1 cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III • Intent to start treatment ≤/> 4 weeks after surgery • GCIG group Perren et al, N Engl J Med 365;26, 2012 ICON7: final OS high-risk (n=502) Stage III suboptimally debulked , any stage IV or no debulking surgery Control Research Total ∆ Non-proportionality test: p=0.0072 1.00 Deaths (%) 174 158 332 (66) Proportion alive 0.75 HR (95% CI) 0.78 (0.63–0.97) 0.50 0.25 9.4 BEV exposure 0 0 Number at risk Control 254 Research 248 6 30.3 12 208 224 18 24 30 36 Time (months) 156 180 101 135 39.7 42 48 82 95 54 60 21 27 Oza, et al. ECC 2013 (LBA6) 36 ICON7: Final OS by risk groups Interaction: p=0.01 1.00 Non-high risk HR 1.14 (0.93–1.40) 37% events Proportion alive 0.75 Control Research 0.50 Control Research 0.25 BEV exposure 0 0 6 12 Research High risk HR 0.78 (0.63–0.97) 66% events 18 24 30 36 Time (months) 42 48 Control 54 60 Oza, et al. ECC 2013 (LBA6) Bevacizumab added to initial chemotherapy followed by a maintenance period of bevacizumab should be served for patients who, following standard surgery, are found to have macroscopic residual disease.[I,A] First-line systemic treatment options in advanced ovarian cancer OVARIAN CANCER STAGES III and IV Stage III with out macroscopic residual disease Stage III with macroscopic residual disease < 1cm Stage III-IV with residual disease >1cm • Intraperitoneal CT* [I,A] • Intraperitoneal CT* [IA] • Carbo-paclitaxel – bevacizumab (I,A) • Carbo-paclitaxel (three-weekly [I.A] vs dense –dose [I.B]) • Carbo-paclitaxel – bevacizumab (I,A)** • Carbo-paclitaxel (three-weekly [IA] vs dense –dose [I,B] • Carbo-paclitaxel (three-weekly (I,A ) or weekly (IB)) *Treatment recommended in patients who meet selection ** Only for patients with macroscopic residual disease. Strategies for future in ovarian cancer Efrectuar estudios por grupos de pacientes según nueva clasificación histológica y alteraciones moleculares Investigar para encontrar marcadores predictivos de respuesta para seleccionar el tratamiento adecuado a cada paciente Una prioridad debería de ser conocer los mecanismos de resistencia a las nuevas drogas Aclarar temas pendientes como la duración de tratamientos, con nuevas moleculas Muchas gracias Bevacizumab: Questions to be answered Is PFS a valid end-point? Dose selection of bevacizumab? Optimal duration of bevacizumab? Other important questions: Role of bevacizumab in second line when it was used in first line Pharmaco-economic analysis Validation of Predictive biomarker: Strategies for future in ovarian cancer Bevacizumab: Questions to be answered Is PFS a valid end-point? Dose selection of bevacizumab? Optimal duration of bevacizumab? Other important questions: Role of bevacizumab in second line when it was used in first line Pharmaco-economic analysis Validation of Predictive biomarker: Methodology in clinical trials 2010 CGICG Consensus Statement Appropiate endpoints should reflect the achievement of clinical benefit: Toxicity, time without symptons, PRO, PFS, OS. Cost effectiveness should be evaluated when feasible. Early disease/ adyuvant trials: RFS(recurrence free survival) is a valid surrogate for OS. Advance disease – First line: PFS is a valid surrogate for OS in chemotherapy trials. » PFS preferred because of confounding effect of post-progression therapy » When possible the study should be powered to allow proper assesment of both PFS and OS – Platinum-sensitive relapse if PFS primary endpoint , OS co-primary endpoint, otherwise OS is the preferred primary endpoint – Platinum resistant refractory: Composite endpoints involving QoL » PFS is the preferred endpoint and ORR is not a validated with new agents. » Secondary endpoints: RR, % survival at 6 months, Health related QoL, PRO, time without symptoms or toxicity, pharmacoeconomic asnalyses Treatment of ovarian cancer: Optimal Debulking Surgery Stuart, et al. Int Gynecol Cancer 2011; 21:750-5 Neoadjuvant chemotherapy vs primary debulking surgery CHORUS TRIAL ASCO 2013 Conclusion: NACT “not inferior to primary debulking surgery”