Cáncer de Ovario Avanzado Importancia de la 1ª decisión. Dra Belén Ojeda

Transcripción

1 Cáncer de Ovario Avanzado Importancia de la 1ª decisión Dra Belén Ojeda

2 Epithelial ovarian carcinoma is not a single disease

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4 Tratamiento del Cáncer de Ovario Avanzado Cirugía Citorreducción primaria máximo esfuerzo (ER=0) Quimioterapia Carboplatino + Paclitaxel Histologia Estadio FIGO Debulking óptimo

5 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

6 Treatment of ovarian cancer: Optimal Debulking Surgery Stuart, et al. Int Gynecol Cancer 2011; 21:750-5

7 Overall survival (%) 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 100% 5-year survival rate HR (95% CI) 75% 1 10mm vs 0mm: 2.70 (2.37, 3.07) >10mm vs 1 10mm: 1.34 (1.21, 1.49) log-rank: p< % Med OS: 99,1m. 0mm 25% 0% 1 10mm >10mm Med. OS: 29,6 m Time (months) Med OS: 36,2 m du Bois A, Reuss A, Pujade-Lauraine E, et al. Cancer 2009;15:

8 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:

9 Cáncer de Ovario Avanzado Cirugía Citorreductora Máxima (no enfermedad Residual) Paciente: PS/edad NS (BMI/caquexia) Comorbilidades Cirugías previas Biológial Tumoral Patrones de crecimiento Diseminación Cirujano: Motivación Conocimientos Comorbilidad Experiencia Equipo multidisciplinario

10 4 th 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 Stuart, et al. Int J Gynecol Cancer 2011;21:750 5

11 N Engl J Med 2010;363:

12 Ovaria, Trompa, Peritoneo Stage IIIC-IV R Cirugía de Debulking primaria CT x 3 ciclos Cirugía de Intervalo (no obligatorio) CT > 3ciclos Neoadjuvant Chemotherapy CT x 3 ciclos Interval surgery (if no progression) CT > 3 ciclos QT neoadyuvante Aumenta la Citorreducción Optima: 21% 53% Menos complicaciones: Mortalidad 2.7% 0.6% Sepsis 8 % 2%

13 % Optimal Surgery (42% PDS vs 80% IDS) OS PFS PDS 29 m 12 m NACT 30 m 12 m PDS (RD:0) NACT (RD:0) OS 45 m 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

14 How to select patients?

15 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.

16 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

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18 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

19 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

20 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 Paclitaxel 180 mg/m2 d1 Carboplatin AUC 6 d1 Every 21 days for 6-9 cy Dose dense TC (ddtc) 317 pts Paclitaxel 80 mg/m2 d1,8,15 Carboplatin AUC 6 d1 Every 21 days for 6-9 cy Katsumata et al. Lancet 2009

21 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

22 GOG- 218 Sistemic therapy : Advanced stages Antiangiogenic Therapy: Bevacizumab

23 GOG-0218: Schema Sub-óptimo Front-line: epithelial OV, PP or FT cancer Stage III optimal (macroscopic <1 cm) Stage III suboptimal Stage IV N=1873 Stratification variables R A N D O M I S E GOG performance status Stage/debulking status 1:1:1 Bev 15 mg/k Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Bevacizumab 15 mg/kg Arm I (CPP) II (CP + Bev) III (CP+Bev Bev) Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab N Engl J Med 365;26,2011

24 PFS estimate Antiangiogenic Therapy: Bevacizumab GOG 218: Primary endpoint results PFS 1.0 I CP + Pl Pl (n=625) II CP + Bev15 Pl (n=625) III CP + Bev15 Bev15 (n=623) Median PFS (months) Stratified analysis HR (95% CI) 0.89 ( ) 0.70 ( ) p value one-sided (log rank) * <0.0001* CP + Pl Pl (Arm I) CP + Av15 Pl (Arm II) PFS analysis determined using RECIST, global deterioration or CA125 progression p value boundary = CP + Bev15 Bev15 (Arm III) Time (months) Burger et al N Engl J Med2011

25 PFS estimate GOG 218- Significant PFS improvement, censored for CA-125 events and non-protocol therapy CP + Pl Pl (n=625) CP + Bev15 Bev15 (n=623) Median PFS (months) Stratified analysis HR (95% CI) p value one-sided (log rank) 0.62 ( ) <0.0001* CP + Pl Pl 0 CP + Bev15 Bev PFS (months) *p value boundary = Data cut-off date: September 29, 2009 N Engl J Med 365;26,2011

26 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 (Dec 2006 to Feb 2009) R 1:1 Carboplatin AUC 6* (C) Paclitaxel 175 mg/m 2 (P) Stratification variables: 12 months 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 C P Bevacizumab 7.5 mg/kg q3w CP CPB7.5+ Perren et al, N Engl J Med 365;26, 2012

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31 Proportion alive ICON7: final OS high-risk (n=502) Stage III suboptimally debulked, any stage IV or no debulking surgery 1.00 Non-proportionality test: p= Control Research Total Deaths (%) (66) 0.75 HR (95% CI) 0.78 ( ) BEV exposure Number at risk Control Research Time (months) Oza, et al. ECC 2013 (LBA6)

32 Proportion alive ICON7: Final OS by risk groups Interaction: p=0.01 Non-high risk HR 1.14 ( ) 37% events Control Research BEV exposure High risk HR 0.78 ( ) 66% events Time (months) Control Research Research Control Oza, et al. ECC 2013 (LBA6)

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34 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]

35 Stage III with out macroscopic residual disease First-line systemic treatment options in advanced ovarian cancer OVARIAN CANCER STAGES III and IV Stage III with macroscopic residual disease < 1cm Stage III-IV with residual disease >1cm Intraperitoneal CT* [I,A] Carbo-paclitaxel (three-weekly [I.A] vs dense dose [I.B]) Intraperitoneal CT* [IA] Carbo-paclitaxel bevacizumab (I,A)** Carbo-paclitaxel (three-weekly [IA] vs dense dose [I,B] Carbo-paclitaxel bevacizumab (I,A) Carbo-paclitaxel (three-weekly (I,A ) or weekly (IB)) *Treatment recommended in patients who meet selection ** Only for patients with macroscopic residual disease.

36 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

37 Muchas gracias

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39 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:

40 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:

41 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

42 Treatment of ovarian cancer: Optimal Debulking Surgery Stuart, et al. Int Gynecol Cancer 2011; 21:750-5

43 Neoadjuvant chemotherapy vs primary debulking surgery CHORUS TRIAL ASCO 2013 Conclusion: NACT not inferior to primary debulking surgery