ESMO Preceptorship Colorectal Cancer Nov 2016 Barcelona Treating Liver Limited or Oligometastatic CRC Claus-Henning Köhne Klinik für Onkologie und Hämatologie North West German Cancer Center (NWTZ)
Learning objectives All patients with liver limited or oligometastatic disease have a potential chance for cure A multidisciplinary aproach is essential The clinical presentation may be considered as Resectable, boarderline resectable, potentially resectable after chemotherapy In resectable disease surgery alone or following chemotherapy are options In boarderline and unresectable disease the most effective and still tolerable chemotherapy according to the molecular profile should be used within a multidisciplinary context Even if surgery might not be curative it extends overall survival and can be considered as a further line of chemotherapy or a form of maintenance chemotherapy
Guidelines CRC mut mut
2016 - FIRE3: Blinded review for Resektability of CRC Metastases Neumann et al, ESMO 2016
Liver limited disease: Patient groups Clearly resectable Borderline resectable Definitely NOT resectable
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)
Probability 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] 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
Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases EORTC 40983 (EPOC) R FOLFOX -> OP -> FOLFOX OP RFS OS Nordlinger et al. Lancet Oncol 2013
Conclusions resectable & boarderline resectable disease Resectable : Perioperative Chemotherapy questionable Boarderline : no restrictions in Chemo regimens including use of EGFR
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
Response and resection rates within trials Trials with neoadjuvant focus Trials with palliative focus CRC Give the most active (RR) regimen still tolerable by the patient Folprecht G.Köhne CH et al. Ann Oncol 2005; Jones R et al. Eur J Cancer, 2014
Tumor load at Baseline Morbidity ESMO acknowledges response parameters like early tumor shrinkage (ETS) or depth of response (DpR) for conversion therapy Fire-3 data Lethal tumor load OS 70 60 50 40 30 20 10 0 No CT =<5 cycles 6-9 cycles =>10 cycles ETS Tumor nadir PFS Time since start of treatment Steatohepatitis Karoui Nordlinger et al, Ann.Surg. 2006 Sinusoidal distention Vauthey et al. JCO 2006
Arguments disfavouring CapeOX over infusional Doublets (FOLFOX or FOLFIRI)
Randomised trials Doublets vs. Triplets and Doublets +/- VEGF 1 st line RASwt and RASmut disease CTx +/- VEGF Trial Therapy ORR DOUBLET vs. TRIPLET Trial Therapy ORR NO16966 (n=700) FOLFOX +/- Beva 38% vs. 38% n.s. GONO (n=244) FOLFIRI +/- Oxaliplatin 41% vs. 66% (n=700) ITACA (n=376) EORTC request CAPOX +/- Beva FOLFOX or FOLFIRI +/- Beva FOLFIRI +/- Bev 38% vs. 38% n.s. 48% vs. 49% n.s. not done TRIBE (n=700) Austria (n=80) AIO (n=242) FOLFIRI / BEV +/- Oxaliplatin FOLFOX / Bev +/- Irinotecan FOLFOX / Bev +/- Irinotecan 53% vs. 65% 62% vs. 81% 60% vs. 79% Saltz et al. JCO 2008, Cassidy BJC 2007, Passardi Ann Oncol 2015 Van Cutsem NEJM,
Randomisierte Studien mit EGFR AK 1. Linie k-ras exon 2 wt Europäische & Asiatische Erfahrungen Trial Therapy ORR CRYSTAL (n=666) FOLFIRI +/- Cetux 40% vs. 57% Chinese * (n=138) FOLFIRI or FOLFOX+/- Cetux 40% vs. 57% Infusional 5FU PRIME (n=656) OPUS (n=197) FOLFOX +/- Pani FOLFOX +/- Cetux 48% vs. 57% 34% vs. 57% Bolus 5FU Cape Tailor (n=380) VOLFI all RASwt (n=99) 2:1 COIN (n=729) NORDIC (n=194) FOLFOX +/- Cetux 34% vs. 56% FOLFOXIRI +/- Pani 61% vs. 86% XELOX/FOLFOX +/- Cetux 57% vs. 64% FLOX +/- Cetxu 47 vs. 46%
Chinese randomized trial in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab Ye et al. JCO 2013
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
EORTC CLOCC trial Theo Ruers et al, ASCO 2015
EORTC CLOCC trial N=152 Arm Resection Resection +RFA CT 12% RFA only CT+RFA 47% 6% Theo Ruers et al, ASCO 2015
Clearly resectable Borderline resectable Liver limited / dominant diesase S U R G E R Y Chemotherapy? adjuvant to surgery Definitely NOT resectable C H E M O Surgery! Adjuvant to chemotherapy Maintenance or an additional line of chemotherapy to chemotherapy
OPEN QUESTIONS Right / Left RASmut BRAFmut
Overall response rate left & right JY Douillard & JP Pignon ESMO 2016
EVALUATION OF RESPONSE SIDEDNES ORR (%) 100 90 80 left 90,6 N=78 right N=18 OR 4.518 (1.29-15.71) P=0.0210 OR 2.500 (0.37-16.88) P=0.6372 70 60 50 68,0 60,0 40 30 37,5 20 10 mfolfoxiri + panitumumab FOLFOXIRI mfolfoxiri + panitumumab FOLFOXIRI 24 Geissler et al. ESMO 2017
Treatment for RASmut or BRAFmut Disease? Cremolini et al. Lancet Oncol 2015
Welches ist die beste therapie für RASmut Erkrankung? FOLFIRI/Bev +/- Oxaliplation FP/Bev +/- Irinotecan Triplette nicht besser als Doublette Group Events/No. OS (95% CI), months Doublette nicht besser als FP+Bev RAS/BRAF WT (Arm A) 51/79 25.2 (20.8-29.8) RAS/BRAF WT (Arm B) 40/79 32.2 (26.1-46.1) RAS MT (Arm A) 68/97 21.3 (19.6-23.0) RAS MT (Arm B) 65/97 23.2 (18.1-28.4) Cremolini et al. Lancet Oncol 2015 BRAF MT (Arm A) 11/12 12.4 (10.2-20.2) BRAF MT (Arm B) 8/10 7.8 (4.7-13.5) Modest et al. ESMO 2017
Prognosis of BRAFmut Disease Triplett +/- Panitumumab ORR (%) 100 90 80 super wild-type 86,0 BRAF mutation 70 60 64,7 71,4 50 40 30 20 22,2 10 mfolfoxiri + panitumumab FOLFOXIRI mfolfoxiri + panitumumab FOLFOXIRI Jones et al. et al. JCO 2017 Geissler et al. ESMO 2017
CELIM 2 PI Gunnar Folprecht Dresden
Clearly resectable Borderline resectable Liver limited / dominant diesase S U R G E R Y Chemotherapy? adjuvant to surgery Definitely NOT resectable C H E M O Surgery! Adjuvant to chemotherapy Maintenance or an additional line of chemotherapy to chemotherapy
Learning objectives All patients with liver limited or oligometastatic disease have a curative chance A multidisciplinary aproach is essential Clinical presentation may be considered as Resectable, boarderline resectable, potentially resectable after chemotherapy In resectable disease surgery alone or following chemotherapy are options In boarderline and unresectable disease the most effective and still tolerable chemotherapy according to the molecular profile should be used within a multidisciplinary context Even if surgery is not curative it extends overall survival and can be considered as a line of chemotherapy or a form of maintenance chemotherapy
Thank you for your attention!
Metastatic disease including locoregional treatment
FOXFIRE (n=1103, 3 Studies)
FOXFIRE (n=1103, 3 Studies) HR: 1.04 P=0.6 Slide 12 HR: 0.90 P=0.1 Presented By Ricky Sharma at 2017 ASCO Annual Meeting
FOXFIRE (n=1103, 3 Studies) Best radiological response by study Presented By Ricky Sharma at 2017 ASCO Annual Meeting
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, % Achieve 14.6 NED: 16.5 132 9.3 20.0 FOLFOX, %* 73 74 77 81 /180 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 *Stratification metastases Factor only, % 29.3 39.8 53.3 50.0
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 *Stratification metastases Factor only, % 29.3 39.8 53.3 50.0
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 N (Events) Median (95% CI) HR (95% CI) p Chemo + Bev 50(15) 67.4 (50.6-NA) 1.2 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than preop chemotherapy Chemo + Cetux 82(30) 64.1 (51.1-78.9) (0.6-2.2)
Resectable Colorectal Liver Metastases Presented By Jeanne Tie at 2016 ASCO Annual Meeting
2016 - FIRE3: Blinded review for Resektability of CRC Metastases Neumann et al, ESMO 2016
Patients treated with palliative Chemotherapy in a regional Center in UK Jones et al, BJS 2012
Guidelines CRC unresectable (LLD) mut mut
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
Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases EORTC 40983 (EPOC) and new EPOC R FOLFOX -> OP -> FOLFOX OP RFS OS Nordlinger et al. Lancet Oncol 2013 R FOLFOX -> OP -> FOLFOX +Cet -> OP -> +Cet RFS OS 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 2015
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 2015