Patienten mit Lebermetastasen

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1 Universitätsklinikum Carl Gustav Carus Universitätskrebszentrum / Medizinische Klinik I Dresden Patienten mit Lebermetastasen Welche perioperativen Therapiestrategien? Welche Konversionstherapie? Gunnar Folprecht

2 Offenlegung potentieller Interessenkonflikte 1. Anstellungsverhältnis oder Führungsposition Universitätsklinikum Carl Gustav Carus, Dresden 2. Beratungstätigkeit Merck, Roche, Lilly, Sanofi-Aventis, Bayer, Ipsen 3. Aktienbesitz keiner 4. Honorare Merck, Amgen, Sanofi-Aventis 5. Finanzierung wissenschaftlicher Untersuchungen Merck, 6. Gutachtertätigkeit keine 7. Andere finanzielle Beziehungen keine

3 ja Resektabel? nein

4 Überhaupt? Welche? Wann? ja Resektabel? nein

5 EORTC 40983: Liver met. +/- periop. FOLFOX Progression free survival Overall survival p=0.068 p=0.34 Nordlinger Lancet Oncol 2013

6 EORTC 40983: Liver surg. +/- FOLFOX HR 95% CI p interaction NO NEOADJUV CEA > NO NEOADJUV Performance status Body mass index < Sorbye Ann Surg 2012

7 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? Wann? ja Resektabel? nein

8 New EPOC : FOLFOX +/- Cetuximab Progression free survival Overall survival p=0.03 p=0.16 Primrose Lancet Oncol 2014

9 Resections and Margins in New EPOC 100% 90% Not operated: other 100% 90% 80% 70% 60% Not operated: PD Not resected 80% 70% 60% Missing or not applicable (CR) Margin 1cm 50% Ablation 50% Margin <1cm 40% 30% 20% Resection: Wedge/1 segment Resection: > 1 segment 40% 30% 20% Positive margin 10% 0% + Cetux Resection: multiple resect. 10% 0% + Cetux Data: Primrose et al, Lancet Oncol 2014

10 New EPOC discussion

11 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Resektabel?

12 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Resektabel?

13 Resectable metastases wt R FOLFOX/Cet OP FOLFOX/Cet OP FOLFOX/Cet wt R FOLFOXIRI/Bev OP FOLFOXIRI/Bev OP FOLFOX

14 Resected metastases CapOX HEPATICA OP R closed, 79 pts CapOX/Beva BLP-25 LICC OP R control

15 Resectable metastases EORTC BOS2 wt FOLFOX OP FOLFOX R FOLFOX/Beva OP FOLFOX/Beva FOLFOX/Pani OP FOLFOX/Pani FOLFOX/Pani PARLIM OP R planned 111 pts FOLFOX

16 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein Welche?

17 Response and resection rates within the trials Trials with neoadjuvant focus Trials in met. CRC Jones, Folprecht Eur J Cancer 2014

18 EGFR vs. VEGF plus chemo RAS wt n RR PFS OS FOLFIRI/Cetux % FOLFIRI/Beva % Heinemann, Lancet Oncol 2014 HR 0.93 HR 0.70 p=0.017 FOLFOX/Pani 88 64% FOLFOX/Beva 82 61% Schwartzberg, JCO 2014 HR 0.65 HR 0.63 p=0.058 /Cetux % /Beva % Lenz, ESMO 2014 p<0.01 HR 1.1 HR 0.9

19 Pooling the data (RAS wild type) Response rate Overall survival favors anti-vegf favors anti-egfr favors anti-egfr favors anti-vegf Khattak et al, Clinical Colorectal Cancer 2015

20 EGFR vs. VEGF plus chemo KRAS exon 2 wt n RR PFS OS FOLFIRI/Cetux % FOLFIRI/Beva % Heinemann, Lancet Oncol 2014 p=0.18 HR 1.06 HR 0.77 p=0.017 FOLFOX/Pani % FOLFOX/Beva % Schwartzberg, JCO 2014 HR 0.84 HR 0.62 p=0.009 /Cetux % resected: 82 pts (14.2%) /Beva % resected: 50 pts (8.9%) Venook, ASCO/WCGIC/ESMO 2014 p<0.02 p<0.01

21 FOLFOXIRI combinations in first line therapy n RR PFS OS FOLFOXIRI/Bev % FOLFIRI/Bev % Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 FOLFOXIRI % FOLFIRI % Falcone, JCO 2007 p< HR 0.63; p<0.01 HR 0.80;p=0.032 FOLFOXIRI/Bev 41 81% 18.6 FOLFOX/Bev 39 62% 11.5 Gruenberger, Ann Oncol 2015 Δ19[-2-40]% HR 0.43 [ ]

22 CELIM 2 CELIM2 study (random. phase II) Non-resectable liver metastases RAS Status RAS wt RAS mut BRAF mut Cet./FOLFOXIRI Cet./FOLFIRI Beva./FOLFOXIRI FOLFOXIRI Resection Non-resectable liver metastases: technically non-resectable (< 30%) >= 5 metastases local MDT decision for other reasons PS 0-1 No severe comorbidity pts planned to be randomized Response rate Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months [email protected]

23 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein Welche? - EGFR-AK + X - FOLFOXIRI ± X

24 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein RFA? Welche? - EGFR-AK + X - FOLFOXIRI ± X

25 CLOCC R RFA + FOLFOX(/Bev) FOLFOX(/Bev) Ruers, ASCO 2015 #3502 Progression free survival Overall survival p=0.025 Ruers, Ann Oncol 2012

26 CLOCC: Progression free survival HR = % CI ( ) P = (Log-rank test) Median (95% CI) (Months) 9.92 ( 9.07, 12.85) CT (11.01, 21.88) RF+CT 5-year PFS: 5.9% CT 24.2% RF+CT 8-year PFS: 2.0% CT 22.3% RF+CT (years) O N Number of patients at risk : Treatment CT RF+\-resection+CT Ruers et al, ASCO 2015

27 CLOCC: Long term Overall Survival HR = % CI ( ) P = (Log-rank test) Median (95% CI) (Months) (27.50, 47.67) CT (30.32, 67.75) RF+CT 5-year OS: 30.3% CT 43.1% RF+CT 8-year OS: 8.9% CT 35.9% RF+CT (years) O N Number of patients at risk : Treatment CT RF+\-resection+CT Ruers et al, ASCO 2015

28 CLOCC vs. EPOC: Long term Overall Survival EPOC-trial CLOCC-trial (years) O N Number of patients at risk : Treatment CT RF+\-resection+CT Ruers et al, ASCO 2015 / Nordlinger Lancet Oncol 2013

29 Radiofrequency RF + (N=57) Treatment by RF 30 (52.6%) RF + resection* 27 (47.4%) RF procedure laparotomy 51 (89.5%) Type of resection (N=27) laparoscopically 1 (1.8%) percutaneously 4 (7.0%) unknown 1 (1.8%) atypical resection or wedge 16 (59..3%) 2 or more segments 11 (40.7%) Mean time in hospital *1 patient with resection only 4.8 days

30 Radiofrequency RF + (N=57) Treatment by RF 30 (52.6%) RF + resection* 27 (47.4%) RF procedure laparotomy 51 (89.5%) Type of resection (N=27) laparoscopically 1 (1.8%) percutaneously 4 (7.0%) unknown 1 (1.8%) atypical resection or wedge 16 (59.3%) 2 or more segments 11 (40.7%) Mean time in hospital *1 patient with resection only 4.8 days

31 CLOCC N RR PFS OS R RFA + FOLFOX(/Bev) FOLFOX(/Bev) mo mo HR 0.57 HR 0.58 p=0.005 p=0.01 Progression free survival Overall survival Ruers, ASCO 2015 #3502

32 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

33 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Was ist das? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

34 Technical Resectability Remaining functional liver tissue Invaded structures/segments

35 Prognostic factors - Disease free interval - Number / size of metastases - Tumor markers - Nodal status Technical Resectability Remaining functional liver tissue Invaded structures/segments

36 Prognostic factors - Disease free interval - Number / size of metastases - Tumor markers - Nodal status Technical Resectability Remaining functional liver tissue Invaded structures/segments

37 Prognostic factors Conversion chemotherapy ( adjuvant ) Staged resections Portal vein embolisation Combination with ablation Conversion chemotherapy (tumour shrinkage) Technical Resectability Mobidity Risk of complications No of resections

38 FP+Oxal + Beva 24 weeks SD/PR/CR R FP/ Beva Beva Observ. 1 st progression FP+Oxal + Beva 2 nd progression AIO0207 Arnold #3503 CAIRO3 Koopman #3504 PFS1 B vs A: HR=1.21 [ ]; p=0.13 C vs A: HR=2.06 [ ]; p<0.001 C vs B: HR=1.57 [ ]; lp<0.001

39 6 Monate Leber 1 Leber 2 Lunge Conversion chemotherapy ( adjuvant ) B vs A: HR=1.21 [ ]; p=0.13 C vs A: HR=2.06 [ ]; p<0.001 C vs B: HR=1.57 [ ]; lp<0.001

40 Screening MDT discussion Overall survival Study design CELIM3 Resection (± ablation) progressive disease therapy* Patients with mcrc - technically resectable - poor prognostic factors* - therapy ( 4 months) R 1:1 therapy** i.e. further response Resection/ablation Quality of life mo. * > 10 metastases, DFS after the last resection <6 months and > 3 metastases, Basingstoke score 20 ** therapy is given as investigators choice

41 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

42 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X + SIRT?

43

44 Study Design Design: Prospective open-label RCT Primary endpoint: Progression-Free Survival Eligible Patients Non-resectable liveronly or liver-dominant mcrc No prior chemo for advanced disease WHO performance status 0 1 Stratified by Presence of extrahepatic metastases Degree of liver involvement Intended use of bevacizumab Institution Randomized 1:1 SIRT n = 530 n = 263 enrolled mfolfox6 (+ bevacizumab) (1) n = 267 enrolled mfolfox6 (+ bevacizumab) (1) SIRT ANZ: 280 (53%) EME: 191 (36%) US: 59 (11%) 1. Bevacizumab allowed at investigator s discretion, per institutional practice ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; US: United States Gibbs et al, ASCO 2015

45 Proportion Not Progressing Progression-Free Survival at Any Site n Events Median PFS FOLFOX (+ bev) months FOLFOX (+ bev) + SIRT months HR: 0.93 (95% CI: ), p= Time from Randomization (months) Number at risk FOLFOX FOLFOX + SIRT Gibbs et al, ASCO 2015

46 Tumor Response Rate Hepatic Resection Rate Objective Response Rate (ORR) ORR at Any Site ORR in the Liver Hepatic Resection CR + PR: 68.1% 76.4% p= % 78.7% p= % 80% 70% 70% 60% 60% 50% 40% PR: PR: PR: PR: 66,5% 71,9% 66,9% 72,7% 50% 40% 30% 30% 20% 10% CR: CR: CR: CR: p= ,5% 4,5% 1,9% 6,0% p= % 10% 13.7% 14.2% p= % FOLFOX (n = 263) FOLFOX + SIRT (n = 267) FOLFOX (n = 263) FOLFOX + SIRT (n = 267) 0% FOLFOX (n = 263) FOLFOX + SIRT (n = 267) CR: Complete Response; PR: Partial Response. Gibbs et al, ASCO EUA-0615

47 Gibbs et al, ASCO 2015

48 HAI vs iv Disease free survival Overall survival 3y 5y HAI 75% 54% IV 62% 52% >= 4 liver mets Goere et al, Ann Surg 2013

49 HAI vs. systemic chemo Progression free survival Overall survival Kerr et al, Lancet2003

50 HAI vs. systemic chemo Hepatic progression free survival Overall survival Kemeny et al, JCO 2006

51 Bisher negativ. OS abwarten. Gibbs et al, ASCO 2015

52 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X + SIRT? Bisher negativ. OS abwarten.

53 Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X + SIRT? Bisher negativ. OS abwarten.