Esquemas o ptimos de quimioterapia para la resecabilidad de la enfermedad potencialmente resecable

Transcripción

1 Esquemas o ptimos de quimioterapia para la resecabilidad de la enfermedad potencialmente resecable Dra E. González- Flores HMQ Virgen de las Nieves Granada

2 Nueva definición de resecabilidad: Todas las metástasis de hígado que se pueden extirpar completamente, dejando al menos 30% de hígado remanente... Incluso en casos con enfermedad extrahepática si es Más práctico que dogmático resecable Adam R et al. Gastrointest Cancer Res. 2009

3 Metástasis hepáticas de CCR Metástasis hepáticas CRC casos/año (Europa) 30% metástasis sincrónicas ~50% desarrollaran metastasis 30 35% Sólo serán hepáticas Resecable 20% a 25% No resecable 75% a 80% Localización Número Tamaño conversión Beneficio en SG 30% a 50% a 5 años 15% a 10 años Chu, et al. Clin Colorectal Can 2006; Kemeny, et al. NEJM 1999; Kemeny, et al. Oncologist 2007; Leichman. Surg Oncol Clin N Am 2007; Leonard GD, et al. J Clin Oncol. 2005;23: Resecable 10% a 20%

4 Selección de la estrategia óptima IRRESECABLES POTENCIALMENTE RESECABLES ALTO RIESGO RESECABLES BAJO RIESGO QT paliativa QT de conversión QT neoadyuvante seguida de cirugía Cirugía de entrada

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6 + Correlación tasa de resección de metástasis y tasa de respuesta,6,5,4,3,2,1 0,0,3,4,5,6,7,8,9 Response rate Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96, p=0.002) Studies including all patients with mcrc (solid line) (r=0.74, p=0.001) Phase III studies in mcrc (dashed line) (r=0.67, p=0.024) Folprecht G, et al. Ann Oncol (2005).

7 Median 5-year survival (range), % Resection of liver metastases improves survival R0 resected (16 studies) Simmonds PC, et al. Br J Cancer. 2006;94: % 32% Resected, R0/R1 unclear (19 studies) 7% Non-radical resection (11 studies) Surgical series published after % Not resected (6 studies) R0, resection with microscopically negative margins.

8 Survival probability An oncosurgical approach offers the chance of cure to a subgroup of initially non-resectable patients OS (n = 184) DFS (n = 184) year survival 10-year survival % 19% Time (years) Cure was achieved in 16% of CRC patients with liver metastases who became eligible for surgery after response to conversion chemotherapy 27% 15% Adam R, et al. J Clin Oncol 2009;27: Cure = disease-free 5 years after last hepatectomy/last resection of extrahepatic metastases. DFS, disease-free survival; OS, overall survival.

9 Aumento en la tasa de respuestas Qumioterapia ± Fármacos dirigidos Aumento de las resecciones hepáticas Aumento de la supervivencia

10 Elección de tratamiento? PEDRO, de 64 años HTA, DM DX ABRIL 2011: adenocarcinoma de sigma a 20 cm CEA 1.100, CA RAS NATIVO

11 EXISTE UNA QUIMIOTERAPIA DE ELECCIÓN EN ESTE PACIENTE?

12 FOLFOX VS FOLFIRI Author QT n RR Resec IFL % 1% Goldberg, 2004 FOLFOX % 4% IROX % 4% Colucci, 2004 Tournigand, 2004 FOLFIRI % FOLFOX % FOLFIRI % 9% FOLFOX % 22%

13 CPT-11 STEATOHEPATITIS > Infection complications increased 90-day mortality after hepatic surgery (14,7% vs 1,6%) Vauthey. JCO Karoui. Ann Surg 2006 OXALIPLATINO VASCULAR LESIONS Sinusoidal obstruction syndrome (SOS) Hemorrhagic centrilobular necrosis Nodular regenerative hiperplasia No increase perioperative mortality and morbility

14 TRIPLET TREATMENT: FOLFOXIRI CCR m con enfermedad metastásica irresecable N= 244 FOLFIRI N=122 FOLFOXIRI N= 122 N=244 FOLFOXIRI N=122 FOLFIRI N=122 P TR 60% 34% <0,0001 R0 15% 6% 0,033 R0 en sólo hepát. 36% 12% Toxicidad Neurotoxicidad % 0% < 0,0001 Neutropenia % 28% < 0,0001 Diarrea % 12% n.s. Falcone et al. J Clin Oncol 2007

15 SELECCIÓN DE ANTICUERPOS: ESCENARIOS CCR RAS MUTADO QT + BEVACIZUMAB CCR RAS NATIVO QT + ANTIEGFR QT+ BEVACIZUMAB

16 - LA MAYORÍA FASES II - FASES III NO DISEÑADOS PARA QX HEPÁTICA - POBLACIÓN HETEROGÉNEA - CRITERIOS DIFERENTES DE RESECABILIDAD FOLFOX XELOX FOLFOX BEVACIZUMAB FOLFOX PANITUMUMAB FOLFOX CETUXIMAB FOLFIRI FOLFIRI BEVACIZUMAB FOLFIRI PANITUMUMAB FOLFIRI CETUXIMAB FOLFOXIRI FOLFOXIRI BEVACIZUMAB FOLFOXIRI PANITUMUMAB

17 BEVACIZUMAB EN METÁSTASIS HEPÁTICAS Study Treatment Selected patients n TR (%) R0 (%) AVF 2107 NO B-IFL IFL B-FOLFOX B-XELOX No < 2 No First-BEAT B-CT (oxali/cpt) No (12/7) GONO B-FOLFOXIRI No BOXER OLIViA B- XELOX B- FOLFOX vs B- FOLFOXIRI non-resectable and borderline No resecables Gruenberger B-XELOX Resectable Hurwitz 2004, Saltz 2008, Masi 2010, Wong 2011, Gruenberger 2008

18 FOLFOX XELOX FOLFOX BEVACIZUMAB FOLFOX PANITUMUMAB BOXER GONO OLIVIA FOLFOX CETUXIMAB FOLFIRI FOLFIRI BEVACIZUMAB FOLFIRI PANITUMUMAB FOLFIRI CETUXIMAB FOLFOXIRI FOLFOXIRI BEVACIZUMAB FOLFOXIRI PANITUMUMAB

19 Pacientes irresecables - M. sincrónicas - > 4 metástasis - > 5 cm MET RESECABLES DE ALTO RIESGO DE RECAIDA - Dificultad de R0 por localización o distribución - Poco volumen hepático postqx

20 + FASE II OLIVIA: first-line treatment of mcrc with bevacizumab plus doublet or triplet chemotherapy mcrc patients with liver-only metastases clearly defined as unresectable (n=80) CRITERIOS DE IRRESECABILIDAD: - Imposibilidad de resecciones R0/R1 - <30% volumen hepático postqx - Contacto vasos R Bevacizumab + mfolfox6 (up to 12 cycles) Bevacizumab + FOLFOXIRI (up to 12 cycles) Gruenberg et a. Annals of Oncology 2015:

21 Variable (95% CI) Bevacizumab + FOLFOXIRI (n=41) Bevacizumab + mfolfox-6 (n=39) Difference p value Resection rate R0/R1/R2 61.0% ( %) 48.7% ( %) 12.3% ( %) R0/R1 51.2% ( %) 33.3% ( %) 17.9% ( %) R0 48.8% ( %) 23.1% ( %) 25.7% ( %) ORR (tumour) 80.5% ( %) 61.5% ( %) 18.9% ( %) PFS 18.8 ( %) 12.0 ( )

22 Tasas de Respuesta BEVACIZUMAB Bevacizumab + FOLFOXIRI Bevacizumab + FOLFOXIRI Bevacizumab + XELOX Response (%) GONO 1 (n=57*) OLIVIA (N = 41 BOXER 3 (n=45) Doi 4 (n=57*) ORR 44 (77) 33 (80,5) 35 (78) 41 (72) CR 7 (12) (9) 2 (4) PR 37 (65) (69) 39 (68) 1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO Wong, et al. Ann Oncol 2011; 4. Doi, et al. Jpn J Clin Oncol 2010

23 Tasas de Resección BEVACIZUMAB Estudio Rama experimental N R0 tasa de resección (%) BOXER BVZ + XELOX GONO BVZ + FOLFOXIRI OLIVIA BVZ+FOLFOXIRI 41 48,8 Tasas de resección R0 de 20 49% en pacientes con solo metástasis hepáticas

24 Resección tras tratamiento con FOLFIRI-aflibercept: experiencia española ORR: 45,4% o El 46.2 % de los pacientes ha recibido biológico previo. o ORR (overall response rate): RC+RP= 45,4% Presented By Andres Muñoz at 2015 SEOM Congress

25 FOLFOX XELOX FOLFOX BEVACIZUMAB FOLFOX PANITUMUMAB CRYSTAL OPUS CELIM POCHER NCT FOLFOX CETUXIMAB FOLFIRI FOLFIRI BEVACIZUMAB FOLFIRI PANITUMUMAB FOLFIRI CETUXIMAB FOLFOXIRI FOLFOXIRI BEVACIZUMAB FOLFOXIRI PANITUMUMAB

26 CETUXIMAB EN METÁSTASIS HEPÁTICAS TRIAL CT N RR (%) R0 (%) P-II trials LLD CRC patients CELIM FOLFOX + C FOLFIRI + C >5 lesions, tecnically non resectable POCHER crono-iflo >5cm, >4 lesions, hiliar P-III trials CRC, non selected KRASwt patients CRYSTAL FOLFIRI + C FOLFIRI LLD-CRC OPUS FOLFOX + C FOLFOX LLD-CRC META-ANALYSIS CT CT+anti-EGFR LLD-CRC Folpretch. Lancet 2010; Garufi. Br J Cancer 2010; VanCutsem. J Clin Oncol 2011, Bokemeyer, Ann Oncol 2011; Petrelli. Int J Colorectal Dis 2012

27 ESTUDIO CELIM Pacientes con CRC + metástasis hepáticas no resecables R Cetuximab + FOLFOX Cetuximab + FOLFIRI TR 70% R0 34% Terapia: 8 ciclos Evaluación de resecabilidad *Technically non-resectable/ > 5 liver metastases 70 pts K-RAS NATIVO TÉCNICAMENTE NO RESECABLES 4 ciclos más de quimioterapia TÉCNICAMENTE RESECABLES Resección Folprecht G, Gruenberger T. Lancet Oncol 2010; 11: Continuar QT por 6 ciclos

28 ESTUDIO POCHER CCR con M1 hepáticas no resecables* TR 79% R0 60% Crono-IFLO + cetuximab x 4 ciclos n:43 *Técnicamente no resecables >4 lesiones, >5 cm, hiliar, enfermedad extrahepática RP o EE: evaluación de resecabilidad No Resecable Resecable 80% K-RAS NATIVO OBJETIVO PRINCIPAL: tasa de resección Garufi et al. Br J Cancer 2010; 103: Continuar tratamiento hasta PE Crono-IFLO + cetuximab x 4 ciclos Resección Completar 6 meses de tratamiento

29 Ye et al. JCO 2013 N=138 QT + CETUXIMAB QT TR 57% RO 25.7% TR 29% RO 7.4%

30 FOLFOX XELOX FOLFIRI FOLFOX CETUXIMAB FOLFOXIRI FOLFOXIRI CETUXIMAB Fase II N= 30 R0 37% FOLFIRI CETUXIMAB Saridaki et al. British Journal of Cancer. 107(12):1932-7, 2012

31 PRIME FOLFOX XELOX FOLFOX BEVACIZUMAB PLANET TRIP FOLFOX PANITUMUMAB FOLFOX CETUXIMAB FOLFIRI FOLFIRI BEVACIZUMAB FOLFIRI PANITUMUMAB FOLFIRI CETUXIMAB FOLFOXIRI FOLFOXIRI BEVACIZUMAB FOLFOXIRI PANITUMUMAB

32 PRIME study post-hoc analysis (WT RAS and LLD) Updated analysis Updated analysis Panitumumab + FOLFOX4 FOLFOX4 Objective response,* n (%) 38 (81) 27 (66) Panitumumab + FOLFOX4 (n = 48) % difference (95% CI) 15.0 ( ) P-value FOLFOX4 (n = 41) Median PFS, months HR (95% CI) 0.75 ( ) P-value Median OS, months HR (95% CI) 0.71 ( ) P-value Douillard JY, et al. Eur J Cancer 2015;51: Descriptive P-value (Wald test).

33 Patients (%) PRIME study post-hoc analysis Resection rates (WT RAS and LLD) Updated analysis = 6.5% P = 0.644* 33% 27% Panitumumab + FOLFOX4 (n = 48) FOLFOX4 (n = 41) 31% = 14.2% P = 0.145* % Douillard JY, et al. Eur J Cancer 2015;51: Any resection Complete resection *Descriptive P-value (Fisher exact test).

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35 PLANET FASE II WT KRAS liveronly mcrc not suitable for initial surgery N=80 WT = 53 R 1:1 FOLFOX4 (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W)) 4 liver metastases at least 1 metastasis >10 cm in diameter Liver metastases technically not resectable (vascular compromise and/or location in which complete resection is impossible and/or 25-30% of healthy liver would not remain functional after resection) Response Rate, Resectability Rate, Safety, PFS,OS

36 PLANET study Response rate and resectability (WT RAS population) Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823 ORR: Objective response rate (not confirmed*); *patients resected before response confirmation

37 Proportion eventfree (%) PLANET study RAS analysis (interim results) OS and resectability (WT RAS) In the overall group, surgery was associated with longer OS HR = 0.20 (95% CI, ) Log-rank P = Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1 S810:abstract 2128 (and poster) Months 2 OS by resection status Median, months (95% CI) Surgery done 51.5 ( ) Surgery not done 26.5 ( ) 4 8 N/S, not significant.

38 TRIP RAS* WT / BRAF WT initially unresectable mcrc (n = 37) *RAS, KRAS, NRAS, and HRAS (codons 12, 13, and 61) Fornaro L, et al. Ann Oncol 2013; 24: Panitumumab + FOLFOXIRI All patients (n = 37) FOLFOXIRI # (Q2W) + panitumumab 6 mg/kg (Q2W) Patients with LLD (n = 12) ORR, ENFERMEDAD % EXTRAHEPÁTICA 68% 89 Resectability of metastases: assessed every 2 months - recommended when feasible Median PFS, months R0 resection, % irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, and folinate 200 mg/m 2 on day 1, followed byfluorouracil 3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks.

39 A meta analysis of resectability and outcomes with anti-egfr mab therapy (KRAS exon 2 WT, LLD) Comparison of first-line CT + / - cetuximab or panitumumb KRAS WT initially unresectable liver-limited mcrc Meta analysis of RCTs: Primary outcome: rate of R0 resection Secondary outcomes: PFS, OS and ORR Four RCTs involving 484 KRAS WT patients were included: PRIME, Douillard 2010 COIN, Maughan 2011 CRYSTAL, Van Cutsem 2011 OPUS, Van Cutsem 2011 Petrelli F, Barni S. Int J Colorectal Dis 2012;27: CT, chemotherapy; mcrc, metastatic colorectal cancer; LLD, liver limited disease; mab, monoclonal antibody; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

40 Proportion, % Impact of anti-egfr mab therapy on outcomes (KRAS exon 2 WT, LLD) Proportion, % Response rate P = R0 resection rate P = CT alone Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mcrc patients with unresectable liver-limited disease Petrelli F, Barni S. Int J Colorectal Dis 2012;27: CT+ EGFR mab 0 CT alone CT + EGFR mab CT, chemotherapy; mab, monoclonal antibody; R0, resection with microscopically negative margins.

41 SELECCIÓN DE ANTICUERPOS: ESCENARIOS CCR RAS MUTADO QT + BEVACIZUMAB CCR RAS NATIVO QT + ANTIEGFR QT+ BEVACIZUMAB

42 CALGB/SWOG Resected, n R0-resected, n N (Events) Median, months (95% CI) Bevacizumab + FOLFOX/FOLFIRI % 132 (45) 64.7 ( ) Erbitux + FOLFOX/FOLFIRI % 1. Venook A, et al. ESMO 2014 (Abstract LBA10), updated information presented at meeting

43 CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm N Median HR p (Events) (95% CI) (95% CI) Chemo + 50(15) 67.4 Bev (50.6-NA) Chemo + 82(30) 64.1 ( ) Cetux ( ) La mediana de SG es superior a los 64 m independientemente del biológico recibido en 1ª línea. Presented By Alan Venook at 2014 ESMO Annual Meeting

44 Phase 3 CAIRO5 study (DCCG, ongoing) 1 st -line treatment of initially unresectable, liver-limited, WT or MT RAS mcrc mcrc LLD Unresectable (N ~ 640) Stratification by resectability of liver metastases (potentially resectable vs permanently unresectable RAS/BRAF mutation R testing WT RAS MT RAS Panitumumab 6 mg/kg + FOLFOX or FOLFIRI (Q2W) Bevacizumab 5 mg/kg + FOLFOX or FOLFIRI (Q2W) Bevacizumab 5 mg/kg + FOLFOX or FOLFIRI (Q2W) Bevacizumab 5 mg/kg + FOLFOXIRI (Q2W) Huiskens J, et al. BMC Cancer 2015;15:365. ClinicalTrials.gov identifier: NCT (Accessed ). Primary endpoint: PFS Patients will not be selected for potential resectability. The (un)resectability status will be prospectively assessed by a central panel according to predefined criteria; Irinotecan 165 mg/m 2, followed by oxaliplatin 85 mg/m 2 and leucovorin 400 mg/m 2 over 2h, followed by 5-FU 3200 mg/m 2 CIV. CIV, continuous intravenous infusion. DCCG, Dutch Colorectal Cancer Group. WT RAS = WT KRAS exons 2/3/4 and NRAS exons 2/3.

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46 ESMO Draft mcrc treatment algorithm Presented at WCGIC NED Clearly resectable metastases Surgery alone; surgery with perioperative/ postoperative CT WT RAS Fit GOAL Doublet + anti-egfr Surgery Cytoreduction (shrinkage) MOLECULAR PROFILE MT RAS Combination + bevacizumab Re-evaluation/assessment of response Q2M GOAL Cytoreduction (shrinkage) Continue CLINICAL CONDITION OF THE PATIENT Progressive disease Unfit (but may be suitable) FP ± bevacizumab; reduced dose doublet; anti-egfr MT BRAF Triplet + bevacizumab Disease control Continue; maintenance; or pause WT RAS CT + biological agent Second-line Unfit BSC Disease control (control progression) MOLECULAR PROFILE MT RAS CT + bevacizumab MT BRAF Unusual, see text Re-evaluation/assessment of response Q2 3M Continue; maintenance; or pause Progressive disease Second-line

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48 Evolución PET_TAC CIRUGIA R0 OS: 5 AÑOS sin recaida

49 El objetivo fundamental en un paciente con M1 hepáticas potencialmente resecables es la resección R0/R1 de las mismas pues es lo que puede llevar a la curación del paciente. El esquema de tratamiento que más tasas de respuestas y de resecciones consigue es aquel que incluye las drogas más activas en el tratamiento del CCR metastásico asociado a terapias dirigidas No podemos decir que un agente biológico asociado a quimioterapia sea claramente superior a otro ni en ORR ni en tasa de resecciones R0. A la vista de los resultados de los estudios disponibles la combinación de quimioterapia + anti EGFR en RAS WT y FOLFOXIRI + BEVACIZUMAB representan una buena opción en esta población de pacientes consiguiendo alta tasa de respuestas, respuesta precoz y elevado porcentaje de resecciones