ESMO Preceptorship Program 27.-28. March Singapore Unresectable or boarderline resectable (Groupp 1) chemotherpy +/- targeted agents Claus-Henning Köhne Klinik für Onkologie und Hämatologie North West German Cancer Center (NWTZ)
ESMO approach: Grouping of patients Liver / Lung limited disease Curative approach resectable unresectable ESMO Group 0 ESMO Group 1 Supported by randomised trials
Resectable LLD but high risk of recurrence Age 51y Rectal Adeno-Ca: ct3, N+ Synchroneous LLD, ø 12 cm CEA 568 ng/ml >12cm
Resectable LLD but high risk of recurrence Fong Score Primary tumor N + DFI < 12 Monate > 1 Metastasis > 5 cm CEA > 200 ng/ml >12cm Age 51y Rectal Adeno-Ca: ct3, N+ Synchroneous LLD, ø 12 cm CEA 568 ng/ml High Fong Score Estimated survival @ 5y < 10%
Group 0 Resectable metastases Primary tumor N + DFI < 12 Monate > 1 Metastasis > 5 cm CEA > 200 ng/ml Fong score > 2 Disease specific survival (DSS)
Adjuvant systemic chemotherapy of CLM: Overall survival Combined analysis FFCD / EORTC trial 5-FU/FA Overall survival FOLFIRI 1.00 Treatment HR=0.89: 95%CI [0.66-1.19] Probability 0.75 0.50 0.25 1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51% 0.00 0 12 24 36 48 Months Number at risk LV5FUs 153 95 65 44 25 LV5FUs+IRI 153 114 70 41 22 LV5FUs adjusted Logrank p=0.43 LV5FUs+IRI Mitri et al. JCO 2008 Ychou et al. ASCO 2008
EORTC 40983: PFS irrespective of resection (usual definition), all patients, updated May25, 2009 Group 0 Resectable metastases 100 90 80 70 60 50 40 30 20 10 R FOLFOX -> OP -> FOLFOX OP Overall Logrank test: p=0.026 PFS = DFS? 0 0 1 2 3 4 5 6 7 8 (years) O N Number of patients at risk : Treatment 133 182 92 63 48 35 22 9 4 Surgery 123 182 123 81 62 49 29 14 4 Pre&Postop C
Progression-free survival in eligible patients 100 HR= 0.77; CI: 0.60-1.00, p=0.041 90 80 70 60 Periop CT +8.1% At 3 years 50 40 30 20 10 Surgery only 36.2% 28.1% 0 0 1 2 3 4 5 6 (years) O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5 Nordlinger et al. Lancet 2008
Progression-free survival in eligible patients 100 90 80 70 60 50 40 MOST LIKELY BENEFIT Borderline resectable pts? High proliferative tumors? MOST LIKELY NO BENEFIT Easily resectable? Fong score 0-2? 30 20 10 0 0 1 2 3 4 5 6 (years) O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5 Nordlinger et al. Lancet 2008
Group 0 Resectable metastases New EPOC study Neoadjuvant FOLFOX +/- Cetuximab in LLD Primrose et al. Lancet Oncol 2014
Liver limited diesase: Patient selection EPOC New EPOC Surgery Chemo Chemo Inclusion Definitely resectable Definitely and suboptimal resectable N Lesions Maximum 4 unlimited unresectable 10% 4% 12-19% Köhne JCO accepted for publication
Liver limited diesase: Patient selection Clearly resectable Chemotherapy adjuvant to surgery Borderline resectable Definitely NOT resectable Surgery adjuvant to chemotherapy
Potential disadvantage of effective neoadjuvant chemotherapy inresectable liver metastases CT/MRI prior chemo CT/MRI after chemo prior surgery Non - visible on CT/MRI, potentially visible during operation Visible on CT/MRI Köhne JCO accepted for publication
New EPOC is considered as a national embarrassment (Graeme Poston) The PFS difference in New EPOC is a most likely a nonrelevant and biased artefact. (Köhne JCO 2015 accepted) New EPOC is a failed trial of no relevance to the licensed indication for Erbitux (European Medicine Agency)
ESMO approach: Grouping of patients Liver / Lung limited disease Curative approach resectable unresectable ESMO Group 0 ESMO Group 1 Supported by randomised trials
Case: Male 44 y, sigmoid adenocarcinoma well until 4 months ago, PS 2 weight loss ~ 5 Kg within last 3 months grossly enlarged palpable liver abdominal US: difuse hypodensic liver leasons CT scans: Synchroneous diffuse liver metastases LDH elevated, WBC 12.000 /dl Bilirubin normal, LFT < 4x ULN
Case: Male 44 y, 05/06 Base line 05/06-11/06 FOLFIRI + Cetux 11/06-03/07 FOLFOX + Cetux PS 2 PS 0 liver mets operable primary tumor pcr + 5 kg mets not operable Patient died 02/15
Group 1 Potentially resectable metastase s Secondary liver resection rates and tumour response: 25 prospective studies 1998-2012 Folprecht G.Köhne CH et al. Ann Oncol 2005; 16: 1311-19 Jones R et al. Eur J Cancer, 2014 Pre-defined resectability R 2 = 0.62 p = 0.003 High response rate Patient selection Multidisciplinary team (MDT) Resectability defined Resectability not defined size of square denotes size of population studied 15/04/2015 Rates of secondary liver resection versus response to chemotherapy: Resectability clearly defined Resectability not clearly defined
FOLFIRI vs. FOFOXIRI Regimen N RR Author FOLFIRI 122 41% Falcone FOLFOXIRI 122 66% JCO 2007 FOLFIRI+Bev 256 53% Falcone FOLFOXIRI+Bev 252 65% NEJM 2015 FOLFOXIRI more effective than FOLFIRI Unproven role of bevacizumab
Secondary endpoint: Resection of Metastases The GONO experience FOLFIRI N=122 FOLFIRI + bev Arm A N = 256 FOLFOXIRI N=122 FOLFOXIRI + bev Arm B N = 252 P (comparison of bev arms) Secondary surgery with radical intent 21% 26% 0.210 R0 secondary surgery 8% 12% 15% 15% 0.327 Liver-only subgroup N = 46 N = 59 Secondary surgery with radical intent 41% 39% 1.000 R0 secondary surgery 12% 28% 36% 32% 0.823
Randomised trials of EGFR antibodies 1 st line k-ras exon 2 wt only European & Asian experience Trial Therapy ORR CRYSTAL (n=666) FOLFIRI +/- Cetux 40% vs. 57% Infusional Chinese * (n=138) FOLFIRI or FOLFOX+/- Cetux 40% vs. 57% 5FU PRIME (n=656) FOLFOX +/- Pani 48% vs. 57% OPUS (n=197) FOLFOX +/- Cetux 34% vs. 57% Bolus 5FU COIN (n=729) XELOX/FOLFOX +/- Cetux 57% vs. 64% Cape NORDIC (n=194) FLOX +/- Cetux 47 vs. 46% sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only
CRYSTAL: Resection rates by country Worked within MDTs No MDT working Country No. Pts Resections 106 4 103 3 89 9 85 2 80 3 73 1 64 6 58 1 58 4 54 7 54 1 49 1 32 5 32 2 27 1 10 1 Data on file
Group 1 Potentially resectable metastases Chinese randomized trial in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab Ye et al. JCO 2013
Group 1 Potentially resectable metastases CELIM: R0 Resection as a surgical maintenance therapy in the continuum of care Progression free survival Overall survival R0 resected: 15.4 95%CI: 11.3-19.5 Not R0 res.: 8.9 95%CI: 6.7-11.0 HR 2.10 [1.37-3.20] p<0.001 R0 resected: 53.9 95%CI: 35.9-71.9 Not R0 res.: 27.3 95%CI: 21.1-33.4 HR 2.25 [1.34-3.78], p=0.002 5y-OS: 45.8% few patients without relaps Update CELIM 12/2012, ASCO 2013
Group 1 Potentially resectable metastases Randomized trials in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab METHEP Chinese study CELIM OLIVIA FOLFIRI/F OLFOX ~30 FOLFOXIRI N=30 FOLFIRI/FOL FOX N=68 CT + Cet N=70 FOLFIRI/F OLFOX + Cet N=67 FOLFOX + Bev N=39 FOLFOXIRI + Bev N=41 RR ~60 73% 40% 57% 70% 62% 81% R0 resection ~23 30% 7% 26% 33% 31% 54% OS all pts (mo) OS resected pts (mo) ~29 48.8 21.0 30.9 35.7 32.2 NR - - 36.0 46.4 53.9 - - Ychou Ann Surg Oncol 2013; Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010; Gruenberger Ann Oncol 2015
CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % 62.3 60.4 64.0 60.0 Non-Caucasian, % 14.6 16.5 9.3 20.0 Achieve NED: FOLFOX, %* 73 74 77 81 Prior Radiation, %* 14.5 132 /180 13.7 8.0 6.7 Prior Adjuvant Chemotherapy, 8.9 9.0 6.7 9.5 %* Palliative intent, % 86.4 82.5 62.7 60.0 Primary in place, % 28 27 30 20 Liver metastases only, % 29.3 39.8 53.3 50.0 *Stratification Factor
CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Palliative intent, % 86.4 82.5 62.7 60.0 curative intent % 13.6% 17.5% curative intent N 76 101 Resected NED (R0) N Pat 45 66 45 66 Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % 28 27 30 20 Liver metastases only, % 29.3 39.8 53.3 50.0 *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132
CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm Chemo + Bev Chemo + Cetux N (Events) 50(15) 82(30) Median HR (95% CI) (95% CI) 67.4 (50.6-NA) 1.2 64.1 (0.6-2.2) (51.1-78.9) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy
Chemotherapy : Optimal timing? Clearly resectable Borderline resectable Chemotherapy adjuvant to surgery? Individual discussion Definitely NOT resectable Surgery adjuvant to chemotherapy
CELIM 2 Köhne JCO accepted for publication
CRC liver metastases a continuum of clinical presentation Resectable technically resectable unresectable (low risk) but high risk for relaps 2 cm single > 5 mets > 5 cm etc. Surgery peri-operative Ctx conversion CTx Neo/Adjuvant CTx? (CTx+/- Cetux?) (achieve high RR) FOLFOXIRI FOLFIRI+EGFR FOLFOX + EGFR (p)cr a problem? no wait until mets come back
CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % 62.3 60.4 64.0 60.0 Non-Caucasian, % 14.6 16.5 9.3 20.0 Achieve NED: FOLFOX, %* 73 74 77 81 Prior Radiation, %* 14.5 132 /180 13.7 8.0 6.7 Prior Adjuvant Chemotherapy, 8.9 9.0 6.7 9.5 %* Palliative intent, % 86.4 82.5 62.7 60.0 Primary in place, % 28 27 30 20 Liver metastases only, % 29.3 39.8 53.3 50.0 *Stratification Factor
CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % 62.3 60.4 64.0 60.0 Non-Caucasian, % 14.6 16.5 9.3 20.0 FOLFOX, %* 73 74 77 81 Prior Radiation, %* 14.5 13.7 8.0 6.7 Prior Adjuvant Chemotherapy, 8.9 9.0 6.7 9.5 %* Palliative intent, % 86.4 82.5 62.7 60.0 Primary in place, % 28 27 30 20 Liver metastases only, % 29.3 39.8 53.3 50.0 *Stratification Factor
CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Palliative intent, % 86.4 82.5 62.7 60.0 curative intent % 13.6% 17.5% curative intent N 76 101 Resected NED (R0) N Pat 45 66 45 66 Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % 28 27 30 20 Liver metastases only, % 29.3 39.8 53.3 50.0 *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132
CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm Chemo + Bev Chemo + Cetux N (Events) 50(15) 82(30) Median HR (95% CI) (95% CI) 67.4 (50.6-NA) 1.2 64.1 (0.6-2.2) (51.1-78.9) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy
Potential impact of type and duration of chemotherapy on surgery Mortality rate not increased Morbidity rate related to the number of cycles of CT Steatohepatitis Sinusoidal distention Karoui Nordlinger et al, Ann.Surg. 2006 Vauthey et al. JCO 2006
Impact of pathological response after chemotherapy on survival 1st line: 66% CPR: 29/738 (4%) FOLFOX: 6% Adam et al, JCO 2008 1st line: 100% CPR total : 25/271 (9%) FOLFOX : 12% FOLFOX + Bev: 8.6% Blazer et al, JCO 2008
Evaluation of ORR Primary analysis FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p ITT population (N= 592) 62.0 56.2 67.5 58.0 52.1 63.7 1.18 0.85-1.64 0.183 Assessable for response (N= 526) 72.2 66.2 77.6 63.1 57.1 68.9 1.52 1.05-2.19 0.017 p = Fisher s exact test (one-sided) Heinemann V- et al J Clin Oncol 31, 2013 (suppl; abstr LBA3506)
Evaluation of ETS Rate (Early Tumor Shrinkage) Rate of Early Tumor Shrinkage* CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 wt n= 493 62.3 55.8 68.5 47.9 41.6 54.2 1.80 (1.26-2.58) 0.0015 Final RAS wt n= 330 68.2 60.3 75.4 49.1 41.5 56.8 2.22 (1.41-3.47) 0.0005 *ETS: early tumor shrinkage 20% at 6 weeks p = Fisher s exact test (two-sided)
Evaluation of Depth of Response (DpR*) FOLFIRI + Cetuximab FOLFIRI + Bevacizumab median DpR % SE % SE p KRAS exon 2 wt n= 493-44.1 (±54.6%) - 32.9 (± 44.3%) 0.0003 Final RAS wt n= 330-48.9 (±54.8%) - 32.3% (± 42.3%) <0.0001 Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test) *DpR: percentage of maximal tumor shrinkage observed at the nadir compared with baseline SE = standard error; p = two-sided Wilcoxon test p
Rate of resection in LLD and no formal MDT prior chemo NO16966 N R0 CTx + bevacizumab 211 12.3% CTx + placebo 207 11.6% CRYSATL (KRAS wt) FOLFIRI+Cetuximab 316 13.2% FOLFIRI 350 5.6% Okines et al. BJC 2009 Köhne etal. WCGIC 2011
Colorectales - Ca R0 Resection of Metastases Controversy: Adjuvant Therapy? USA Yes (Kemeny NEJM 1999) Europa No (Lorenz NEJM 200)
Liver metastases: adjuvant HAI + i.v. CTX p=0.02 Median overall survival Fong 0-2 Fong 3-5 HAI+systemic 83.3 mo 60.0 mo (10y: 38.7%) systemic 82.8 mo 38.3 mo (10y: 16.3%) p=0.13 Kemeny et al NEJM 1999 and 2005
Adjuvant chemotherapy after liver resection Majo clinic regimen vs. Observation (n=171) FFCD ACHBTH AURC 9002 Trial Disease free survival Overall survival Cox multivariat Analysis p=0.028 n.s. Portier et al. JCO 2006
- Curative approach in k-ras wt tumors Arguments disfavouring CapeOX or VEGF antibodies : Higher RR for FOLFOX vs.capeox No increase in RR if Beva is added to FOLFOX or CapeOx Investigator report IRC data Chemo+ Chemo placebo + Bev FOLFOX+ FOLFOX placebo + Bev XELOX+ XELOX placebo + Bev 49% 47% 50% 47% 48% 46% p = 0.90 p = 0.88 p = 0.91 38% 38% 36% 38% 39% 37% p = 0.99 p = 0.49 p = 0.48 Potential bleeding and wound healing complications
Questions to CALGB 80405 in resected patients 1. Liver limited disease pts obviously only 50% of all resected pts. Which metastases were resected in the other half? Primary tumor +/- liver metastases? If so, this is not the usual patient with metastatic disease entering a trial to improve median survival 2. Number of pts with curative intent nearly equal those who were later resectable. Where these pts resectable upfront? And why have they not been resected? 3. How was curative intend defined? By investigator or by multidisciplinary team? 4. Curative intent at baseline higher for Cetuximab arm. 5. Discrepance of numbers: Resected NED =111 but Resected achieved NED=132
Group 1 Potentially resectable metastases Randomized trials in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab METHEP Chinese study CELIM OLIVIA FOLFIRI/ FOLFOX ~30 FOLFOXIRI N=30 FOLFIRI/FO LFOX N=68 CT + Cet N=70 FOLFIRI/F OLFOX + Cet N=67 FOLFOX + Bev N=39 FOLFOXI RI+Bev N=41 RR ~60 73% 40% 57% 70% 62% 81% R0 resection ~23 30% 7% 26% 33% 31% 54% OS all pts (mo) OS resected pts (mo) ~29 48.8 21.0 30.9 35.7 32.2 NR - - 36.0 46.4 53.9 - - OS non resected pts - - 19.6 25.7 27.3 - - Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010
Response rates = resection rates? CT CT + Erbitux Response (%) 80 70 60 50 40 30 20 10 0 p<0.001 71 44 80 70 60 50 p=0.016 76 80 70 60 50 70 40 40 39 30 Why? 39 30 20 20 10 10 0 0 80 70 60 50 40 30 20 10 0 79 R0 resection (%) p=0.125 5.6 13.2 p=0.21 4.3 16.0 60 50 40 30 20 10 33 60 50 40 30 20 10 60 CRYSTAL (KRAS wt) OPUS (KRAS wt) 0 CELIM (KRAS wt) 0 POCHER (ITT)* Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Folprecht G, et al. EMCC 2011 (Abstract 6009); Garufi C, et al. Br J Cancer 2010;103:1542 1547
Comparison of process and liver resection rates in Erbitux trials in liver limited kras WT studies Study CRYSTAL Who recruited? Entry by general oncologist % RR Erbitux arm Treatment with Erbitux RR 70% Who determined liver resectability? Decision on liver resection by general oncologist Liver resection rate Erbitux arm 13% OPUS Entry by general oncologist Treatment with Erbitux RR 75% Decision on liver resection by 16% general oncologist CELIM Entry by MDT with Liver Surgeon Treatment with Erbitux RR 70% Decision on liver resection by MDT 34% with Liver Surgeon POCHER Entry by MDT with Liver Surgeon Treatment with Erbitux RR 78% Decision on liver resection by MDT 60% with Liver Surgeon Liver surgeons MUST work with medical oncologists from the outset if these outcomes are to be reproduced