VISIÓN DEL ONCÓLOGO MÉDICO. Dr. Carles Pericay Oncologia Mèdica Hospital Universitari de Sabadell Corporació Sanitària Parc Taulí

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2 VISIÓN DEL ONCÓLOGO MÉDICO Dr. Carles Pericay Oncologia Mèdica Hospital Universitari de Sabadell Corporació Sanitària Parc Taulí

3 The multidisciplinary team Strategic choices determine the therapeutic options Surgeon Oncologist Collaboration is essential from diagnosis and adecuate treatment Radiologist Therapeutic Comitee Histopathologist Modificada de F Ciardiello

4 CRITERIOS DE IRRESECABILIDAD Evolución histórica de la indicación de cirugía de las metástasis. * Indicación metástasis pulmonares de otros primarios pero no del colon.

5 CRITERIOS DE IRRESECABILIDAD

6 Cáncer Colorrectal Metastásico: SG Probabilidad de Supervivencia Resección (n=340) QT regional (n=123) QT sistémica (n=70) No tratmiento (n=484) Años desde diagnóstico Stangl R et al. Lancet 1994;343:

7 LiverMetSurvey Diciembre de % 24% Years from diagnosis

8 Conversion CT + surgery for treatment of mcrc with unresectable liver metastases Single centre study of consecutive patients mcrc with unresectable liver metastases (n = 184) Conversion chemotherapy* Response evaluated every 2 months Surgery F O L L O W - U P Minimum follow-up 5 years Study objectives: evaluation of possibility of cure, determination of predictive factors of disease cure Adam R, et al. J Clin Oncol 2009; 27: *Last preoperative regimen, FL (18%), FOLFOX (62%), FOLFIRI (6%), FOLFOXIRI (9%), Other (5%)

9 EORTC intergroup study [EPOC] Surgery ± FOLFOX4 for resectable liver metastases from colorectal cancer Open label, phase 3 study mcrc with initially resectable LLD (n = 364) R 1:1 FOLFOX4 6 cycles None S U R G E R Y None FOLFOX4 6 cycles Study endpoints: PFS (1 ), OS, resectability, tumour response, safety ClinicalTrials.gov identifier: NCT Nordlinger B, et al. Lancet 2008; 371: ; Nordlinger B, et al. Lancet 2013; 14: mcrc metastatic colorectal cancer; LLD, liver limited disease; OS, overall survival; PFS, progression free survival.

10 EORTC intergroup study [EPOC] Progression free survival All eligible patients All resected patients Proportion eventfree (%) Proportion eventfree (%) Years HR (96% CI) = 0.77 (0.60, 1.00) P = Surgery + FOLFOX4 (n = 171) 3-year PFS, % 36.2 Surgery (n = 171) Years Surgery + FOLFOX4 (n = 151) HR (96% CI) = 0.73 (0.55, 0.97) P = year PFS, % 42.4 Surgery (n = 152) 33.2 Perioperative FOLFOX4 reduced the risk of PFS events by ~25% Nordlinger B, et al. Lancet 2008; 371: PFS, progression free survival.

11 EORTC update Lancet Oncology Volume 14, No. 12, p , November 2013 Results In all randomly assigned patients, median overall survival was 61 3 months (95% CI ) in the perioperative chemotherapy group and 54 3 months ( ) in the surgery alone group. 5-year overall survival was 51 2% (95% CI ) in the perioperative chemotherapy group versus 47 8% ( ) in the surgery-only group. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.

12 Metástasis técnicamente resecables: diferente riesgo diferente intención 1-4 Nódulos 5 o más nódulos u otros Factores de riesgo Neoadyuvante o Cirugía inicial Inducción o reducción Mejorar los resultados de la cirugía

13 Metástasis irresecables: obtener máxima respuesta y reconsiderar QT de conversión resecable

14 No se puede No mostrar se puede la imagen mostrar en la imagen este momento. este momento. No se puede mostrar No se la puede imagen mostrar en este la imagen momento. este momento. No se puede mostrar No se la puede imagen mostrar en este la imagen momento. este momento (%) Resección hepática de múltiples metástasis 63% 95% 92% Log Rank: p< postquimioterapia: SG 55% 44% 12% Downstaging : 58 Stabilization : 39 Progression : % 30% Ys Adam R et al. Ann Surg %

15 Hepatic toxicity and CHT regimen Vauthey et al JCO 24: , 2006 Toxicity% Sinusoidal dilation steatohepatitis 158 p No treatment 1,9 4,4 248 p neoadjuvant CHT 5,4 8,4 5FU+OXA 18,9 p<.001 5FU+IRI 20,2 p< day mortality no steatohepatitis steatohepatitis 1,6 14,7 p<.001 Pawlic et al: J Gastointestinal Surg 2007: Morris et al: Eur J Surg Oncol 2007.

16 70 Influencia del número de ciclos de QT en la morbilidad Morbilidad (%) No QT 5 ciclos 6 9 ciclos 10 ciclos Karoui et al. Ann Surg 2006

17 75% 56% 33% CR-MjR, índices de mejor supervivencia global (5 años) RP, basada en un estudio minucioso de la pieza, puede ser útil como factor pronóstico

18 Buena respuesta : 44% Mala respuesta : 66% 80% Strong RP 51% Weak RP OS Strong RP es un índice de mejor supervivencia global (5 años) RP tiene potencial pronóstico de supervivencia Necesidad de un protocolo estandarizado en el manejo de la pieza

19 85% 55% RP es un factor predictivo de supervivencia mediado por la fibrosis

20 Ann Surg Oncol 2011;18:

21 RESUMEN 1.-Resecar es mejor que no resecar 2.-QT perioperatoria mejor que sólo cirugía 3.-Convertir M1 irresecables en resecables 4.-Vigilar toxicidad de la quimioterapia 5.-Conseguir respuestas precoces radiológicas y patológicas 6.-Todo para mejorar el SCORE de riesgo de los pacientes

22 LiverMetSurvey Diciembre de % 39%

23 Incremental improvements in OS in mcrc over the past decade Saltz 1, FU/LV bolus 12.6 Douillard 2, 2000 Saltz 1, FU/LV infusion IFL Douillard 2, 2000 FOLFIRI (de Gramont or AIO) 17.4 Goldberg 3, 2004 Hurwitz 4, 2004 Saltz 5, 2008 FOLFOX IFL + bevacizumab XELOX/FOLFOX + bevacizumab Falcone 6, 2007 Van Cutsem 7, 2011 FOLFOXIRI FOLFIRI + cetuximab * Douillard 8, 2013 FOLFOX + panitumumab 23.8* Douillard 9, 2013 FOLFOX + panitumumab 26.0 # Overall survival (months) 1. N Engl J Med 2000; 343:905-14; 2. Lancet 2000; 355:1041-7; 3. J Clin Oncol 2004; 22:23-30; 4. N Engl J Med 2004; 350: ; 5. J Clin Oncol 2008; 26:2013-9; 6. J Clin Oncol 2007; 25:1670-6; 7. J Clin Oncol 2011; 29:2011-9; 8. J Clin Oncol 31, 2013 (suppl; abstr 3620, and poster); 9. N Engl J Med 2013;369: Informal comparison as these are not head-to-head clinical trials; *WT KRAS; # WT RAS, WT in KRAS & NRAS exons 2/3/4

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26 NO16966: BEV + CT significantly improves PFS but not RR or OS in combination with XELOX/FOLFOX4 (ITT) RR Response rate (%) Months Placebo + FOLFOX4/XELOX p= BEV + FOLFOX4/XELOX AVF2107g: Bevacizumab significantly improves RR, PFS and OS in combination with IFL (ITT) RR Response rate (%) Placebo + IFL p= BEV + IFL Months

27 CRYSTAL: Cetuximab + FOLFIRI significantly improves RR, PFS and OS vs FOLFIRI (KRAS wt) RR Response rate (%) p< FOLFIRI Cetuximab + FOLFIRI OPUS: Cetuximab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt) RR Response rate (%) p= FOLFOX4 Cetuximab + FOLFOX4

28 PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt) RR Response rate (%) p= FOLFOX Pani + FOLFOX

29 CELIM: Tasas de Respuesta y Resección R0 All patients Cetuximab + FOLFOX6 Cetuximab + FOLFIRI KRAS wt RAS wt n=106 n=53 n=53 n=67 N=67 CR/PR 62% 68% 57% 70% 79% 95% CI 52 72% 54 80% 42 70% 58 81% R0 resections 34% 38% 30% 33% 95% CI 25 44% 25 52% 18 44% 22 45% Folprecht G, et al. Lancet Oncol 2010; 11: Folprecht G, et al. EMCC 2011 (Abstract-Poster No. 6009)

30 (7 revisores) Cada escáner fue evaluado sin conocer los datos clínicos de los pacientes ni cuando fue hecho (si antes o despus de la Qt) Antes de Erbitux + QT Después de Erbitux + QT 00% % % 0% 50% non-resectable chemo preferred resectable exploration resectable non - resectable 50% 0% 50% 00% Patient 100% Patient 32% 60% Erbitux + CT incrementa los pacientes potencialmente resecables en un 28% p<0,01

31 Resumen cirugía R0 Estudio CELIM FOLFOX6/Cetuximab 38% 20/53 pts FOLFIRI/Cetuximab 30% 16/53 pts TODOS 34% 36/106 pts 5 o >5 METASTASIS 40% 19/48 pts conversión IRRESECABLES 28% 16/57 pts Folprecht et al. Lancet Oncol; Nov 25, 2009

32 Ann Oncol Feb 27. [Epub ahead of print] Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM-study).Folprecht G1, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, Hartmann JT, Stoehlmacher-Williams J, Lang H, Trarbach T, Liersch T, Ockert D, Jaeger D, Steger U, Suedhoff T, Rentsch A, Köhne CH. *p<0.001 A all B OS 35.7 m 29 m PFS 10.8 m 10.5 m R0 OS* No R0 OS 53,9 m ( ) 21,9 m ( ) R0 5y OS 46.2%

33 POCHER: Alta tasa de respuestas y resecciones Response rate R0 resection rate 2-year OS rate % Patients (%) Patients (%) % Patients (%) % Garufi C, Br J Cancer, 2010

34 PLANET study Panitumumab + FOLFOX4 or FOLFIRI in patients with WT KRAS exon mcrc, LLD (n = 77) Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P); ClinicalTrials.gov identifier: NCT R 1:1 mcrc and LLD Panitumumab 6 mg/kg (Q2W) + FOLFOX4 (Q2W) Panitumumab 6 mg/kg (Q2W) + FOLFIRI (Q2W) Treatment until progression or resectability achieved Response evaluation Q8W Study endpoints: ORR for entire panitumumab + CT treatment period (1 ), PFS, OS, liver metastases resection rate, time to resection, safety, peri-operative safety Exploratory endpoint: protocol predefined RAS analysis PD Or additional surgery PD Or additional surgery Follow-up Q3 ±1M after safety evaluation (up to 36M) Safety: 30±3 days after last study drug administration RAS ascertainment rate: 83.1%. WT RAS = WT KRAS/NRAS exons 2, 3, 4.

35 PLANET study RAS analysis ORR WT RAS Panitumumab + FOLFOX4 (n = 27) Panitumumab + FOLFIRI (n = 26) ORR, n (%) 21 (77.8) 19 (73.1) (95% CI) ( ) ( ) Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P). Not confirmed, patients resected before response confirmation.

36 WT RAS Percentage of patients (95% CI) 100% % 60% 40% 20% 0% 0 PLANET study RAS analysis Resectability 69.2% ( ) n = % 53.8% ( ) ( ) n = 28 n = % 37.0% ( ) n = % ( ) n = 7 Panitumumab + FOLFOX4 (n = 27) Panitumumab + FOLFIRI (n = 26) Total (n = 53) ( ) n = 21 Surgical resection Resection rate (R0 + R1) Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).

37 PLANET study Resection and OS (WT RAS population) Higher resection rates associated with ETS at Week 8: ETS 30% vs < 30% 64.5% vs 31.2%; P = ETS 20% < 20% 59.4% vs 30%; P = (N/S) In the overall group, surgery was associated with longer OS Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1 S810:abstract 2128 (and poster). Proportion event-free (%) OS by resection status HR = 0.20 (95% CI, ) Log-rank P = Months Median, months (95% CI) Surgery done 51.5 ( ) Surgery not done 26.5 ( ) N/S, not significant.

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40 NEOADJUVANT BEVACIZUMAB IN LIVER METASTASES Study Treatment Selected patients n TR (%) R0 (%) AVF NO B-IFL IFL B-FOLFOX B-XELOX No < 2 No First-BEAT 3 B-CT (oxali/cpt) No (12/7) GONO 4 B-FOLFOXIRI No (LLD) 57 (30) 77 (80) (26) TRIBE 5 LLD CRC patients b-folfoxiri FOLFIRI No (LLD) Hurwitz 2004, 2- Saltz 2008, 3- Okines 2009, 4- Masi 2010, 5- Falcone 2012, 6- Wong 2011, 7- Gruenberger 2008, 8- Gruenberger (32) 12 (28) Gruenberger 7 B-XELOX Resectable BOXER 6 B- XELOX non-resectable and borderline OLIVIA 8 B-FOLFOXIRI B-FOLFOX6 non- resectable disease % 23%

41 BOXER: Study in potentially resectable patients Technically unresectable liver-only metastases from CRC (n=46) Oxaliplatin 130mg/m 2 * (day 1) + capecitabine 850mg/m 2 * b.i.d. (days 1 14) + bevacizumab 7.5mg/kg (day 1) q3w Prospective, single-arm, phase II study Primary endpoint: overall response rate Secondary endpoints: safety, complete resection rate, peri-operative complications, PFS, DFS, OS *In patients aged 75 years: oxaliplatin 100mg/m 2 (day 1) + capecitabine 650mg/m 2 b.i.d. (days 1 14) + bevacizumab 7.5mg/kg (day 1) Defined as best radiological response, evaluated using RECIST criteria at least once every four cycles Imaging: CT CAP and MRI liver mandatory; PET recommended (performed in 91% patients)

42 BOXER: Response Rate Response, n (%) CAPOX + bevacizumab (n=45) Complete response 4* (9) Partial response 31 (69) Stable disease 7 (16) Progressive disease 3 (7) Overall response rate (CR + PR) [95% CI] 35 (78% [63 89]) *Patients also received chemoradiation to primary tumour

43 BOXER: Resections Rate/ R0 resections. Patients consort Eligible patients (n=45) Upfront resectable (n=15) Initially unresectable (n=30) Too early (n=2) No liver resection (n=4) Radiological CR (n=3) PD during CRT (n=1) Converted to resectable (n=10) Remain unresectable (n=20) Liver resection (n=9) Still on active treatment (n=5) Total liver resection: (n=16) R0 R1 R2 Patients, n (%) 9 (56) 5 (31) 2 (13) Liver resection (n=7) No liver resection (n=3) Radiological CR (n=1) No lesion identified at laparotomy (n=1) Not fit for anaesthetic (n=1)

44 F-II OLIVIA: BVZ + mfolfox6 vs BVZ + FOLFOXIRI in unresectable liver-limited mcrc Variable (95% CI) Resection rate Bevacizumab + FOLFOXIRI (n=41) Bevacizumab + mfolfox-6 (n=39) Difference p value R0/R1/R2 61.0% 48.7% 12.3% R0 48.8% 23.1% 25.7% ORR (tumour) 80.5% ( %) 61.5% ( %) 18.9% ( %) PFS Gruenberger, ASCO 2013

45 TRIBE: F-III FOLFOXIRI-B VS FOLFIRI-B irresectable metastatic CRC FOLFIRI + Bev (n=256) FOLFOXIRI + Bev (n=252) p Secondary surgery with radical intent (%) R0 secondary surgery (%) Liver-only subgroup n=46 n=59 Secondary surgery with radical intent (%) R0 secondary surgery (%) Falcone et al. ASCO 2013

46 WT RAS OS (primary endpoint) HR (95% CI) loghr logse Weight CALGB (n = 526) 0.90 ( ) FIRE-3 (n = 342) 0.70 ( ) PEAK (n = 170) 0.63 ( ) Total (fixed) 0.79 ( ) 100 Total (random) 0.77 ( ) Heterogeneity: Chi 2 = 2.87, df = 2, (P = 0.24), I 2 = 30%, Tau 2 = Favours anti-egfr + CTx Heinemann V, et al. Ann Oncol 2015;26(Suppl 4):abstract 150 (and poster). Favours bevacizumab + CTx Weight is relative weight (%) from the fixed effect model.

47 WT RAS ORR RR (95% CI) logrr logse Weight CALGB (n = 526) 0.78 ( ) FIRE-3 (n = 342) 0.91 ( ) PEAK (n = 169) 0.95 ( ) Total (fixed) 0.85 ( ) 100 Total (random) 0.86 ( ) Heterogeneity: Chi 2 = 2.81, df = 2, (P = 0.25), I 2 = 29%, Tau 2 = Favours anti-egfr + CTx Favours bevacizumab + CTx Heinemann V, et al. Ann Oncol 2015;26(Suppl 4):abstract 150 (and poster). RR is the relative risk, EGFRI + CTx/bevacizumab + CTx (%). Weight is relative weight (%) from the fixed effect model.

48 Venook, et al. ESMO 2014

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50 CONCLUSIONES La resección de las M1 es la única posibilidad de conseguir la curación El equipo multidisciplinar es fundamental para alcanzar este objetivo. Es necesario definir con precisión ante que tipo de paciente nos encontramos. La quimioterapia juega un papel de gran importancia en la estrategia de tratamiento: quimioterapia + cirugía es mejor que cirugía sola.

51 CONCLUSIONES Incluso en las metástasis irresecables la resección quirúrgica puede ser posible después de una quimioterapia efectiva. En esta situación, la poliquimioterapia con agentes biológicos es la indicada hasta el momento. Una combinación de quimioterapia con Anti-EGFR parece ser más activa en relación a SG, ORR, ETS, DoR,

52 CONCLUSIONES En los dos casos presentados, la quimioterapia se ajusta plenamente a los estándares de aplicabilidad de la mejor opción terapéutica para los pacientes tratados.

53 Gràcies