Unresectable or boarderline resectable disease

Transcription

1 ESMO Preceptorship Colorecatl Cancer July 2016 Prague, Czech Republic Unresectable or boarderline resectable disease Claus-Henning Köhne Klinik für Onkologie und Hämatologie North West German Cancer Center (NWTZ)

2 Learning objectives All patients with liver limited or oligometastatic disease have a potential curative chance 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

3 Guidelines CRC mut mut

4 ESMO Guidelines for resectable (liver) metastases

5 New ESMO Guidelines Conversion with best systemic therapy unresectable

6 Resectable LLD but high risk of recurrence Age 51y Rectal Adeno-Ca: ct3, N+ Synchroneous LLD, ø 12 cm CEA 568 ng/ml >12cm

7 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 5y < 10%

8 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)

9 EORTC 40983: PFS irrespective of resection (usual definition), all patients, updated May25, 2009 Group 0 Resectable metastases R FOLFOX -> OP -> FOLFOX OP Overall Logrank test: p=0.026 PFS = DFS? (years) O N Number of patients at risk : Treatment Surgery Pre&Postop C

10 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 [ ] Probability year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51% Months Number at risk LV5FUs LV5FUs+IRI LV5FUs adjusted Logrank p=0.43 LV5FUs+IRI Mitri et al. JCO 2008 Ychou et al. ASCO 2008

11 Resectable Colorectal Liver Metastases Presented By Jeanne Tie at 2016 ASCO Annual Meeting

12 EORTC 40983: Long term survival Nordlinger et al. Lancet Oncol 2013

13 Progression-free survival in eligible patients 100 HR= 0.77; CI: , p= Periop CT +8.1% At 3 years Surgery only 36.2% 28.1% (years) O N Number of patients at risk : Nordlinger et al. Lancet 2008

14 Progression-free survival in eligible patients MOST LIKELY BENEFIT Borderline resectable pts? High proliferative tumors? MOST LIKELY NO BENEFIT Easily resectable? Fong score 0-2? (years) O N Number of patients at risk : Nordlinger et al. Lancet 2008

15 Resectable metastases New EPOC study Neoadjuvant FOLFOX +/- Cetuximab in LLD Primrose et al. Lancet Oncol 2014

16 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

17 Liver limited diesase: Patient selection Clearly resectable Chemotherapy adjuvant to surgery Borderline resectable Definitely NOT resectable Surgery adjuvant to chemotherapy

18 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

19 New EPOC is considered as a national embarrassment (Graeme Poston, personal communication) The PFS difference in New EPOC is a most likely a nonrelevant and biased artefact. (Köhne JCO 2015) New EPOC is a failed study without relevant consequences for the approved indication (for cetuximab) (European Medicine Agency)

20 Guidelines CRC unresectable (LLD) mut mut

21 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 /dl Bilirubin normal, LFT < 4x ULN

22 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

23 LLD Potentially resectable metastases Secondary liver resection rates and tumour response: 25 prospective studies Folprecht G.Köhne CH et al. Ann Oncol 2005; 16: Jones R et al. Eur J Cancer, 2014 Pre-defined resectability R 2 = 0.62 p = High response rate Quality of Response 13/07/2016 Earlier Response Depth of Response Patient selection Multidisciplinary team (MDT) Resectability defined Resectability not defined size of square denotes size of population studied Rates of secondary liver resection versus response to chemotherapy: Resectability clearly defined Resectability not clearly defined

24 ESMO acknowledges response parameters like early tumor shrinkage (ETS) or depth of response (DpR) for conversion therapy Fire-3 data OS Lethal tumor load Tumor load at Baseline ETS predicts sensitivity to treatment DpR predicts OS ETS Tumor nadir PFS Time since start of treatment FIRE-3 Study (AIO KRK-0306) Cetuximab + FOLFIRI (n=157) Bevacizumab + FOLFIRI (n=173) p Median DpR (95% CI) p< Median OS (95% CI) 33.1 ( ) 25.0 ( ) P=0.0056

25 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 Morbidity Sinusoidal distention 0 No CT =<5 cycles 6-9 cycles =>10 cycles Karoui Nordlinger et al, Ann.Surg Vauthey et al. JCO 2006

26 FOLFIRI vs. FOFOXIRI Regimen N RR Author FOLFIRI % Falcone FOLFOXIRI % JCO 2007 FOLFIRI+Bev % Falcone FOLFOXIRI+Bev % NEJM 2015 FOLFOXIRI more effective than FOLFIRI Unproven role of bevacizumab

27 Secondary endpoint: Resection of Metastases The GONO experience(cross trial comparison!) 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% R0 secondary surgery 8% 12% 15% 15% Liver-only subgroup N = 46 N = 59 Secondary surgery with radical intent 41% 39% R0 secondary surgery 12% 28% 36% 32% 0.823

28 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% 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) COIN (n=729) NORDIC (n=194) FOLFOX +/- Cetux 34% vs. 56% XELOX/FOLFOX +/- Cetux 57% vs. 64% FLOX +/- Cetxu 47 vs. 46% sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only

29 CRYSTAL: Resection rates by country Worked within MDTs No MDT working Country No. Pts Resections Data on file

30 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

31 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: %CI: Not R0 res.: %CI: HR 2.10 [ ] p<0.001 R0 resected: %CI: Not R0 res.: %CI: HR 2.25 [ ], p= y-OS: 45.8% few patients without relaps Update CELIM 12/2012, ASCO 2013

32 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) ~ NR Ychou Ann Surg Oncol 2013; Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010; Gruenberger Ann Oncol 2015

33 mcrc: Liver limited disease Clearly resectable Borderline resectable Chemotherapy adjuvant to surgery? Individual discussion Definitely NOT resectable Surgery adjuvant to chemotherapy

34 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

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36 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, % Non-Caucasian, % Achieve NED: FOLFOX, %* Prior Radiation, %* / Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

37 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, % curative intent % 13.6% 17.5% curative intent N Resected NED (R0) N Pat Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % Liver metastases only, % *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132

38 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) ( ) ( ) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy

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40 CLOCC study Patients with unresectable CRC liver metastases N=152 R A N D O M I Z A T I O N RF + Systemic treatment ± resection Systemic treatment ± resection if an option Designed as Phase III trial with primary endpoint OS downscaled to phase II trial due to decreasing accrual

41 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 Arm Resectio n CT 12% (years) Resection +RFA RFA only CT+RFA 47% 6% O N Number of patients at risk : Treatment CT RF+\-resection+CT

42 SIRFLOX: Study Design Design: Prospective open-label RCT Primary endpoint: Progression-Free Survival Eligible Patients Stratified by n = 263 enrolled Non-resectable liver-only or liverdominant mcrc No prior chemo for advanced disease WHO performance status 0 1 Presence of extrahepatic metastases Degree of liver involvement Intended use of bevacizumab Institution Randomized SIRT 1:1 n = 530 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

43 SIRFLOX is the first of three RCTs in a preplanned combined analysis of impact on Overall Survival Study Name Study Design Geographic Region (1) Recruitment Completed Patients Recruited OS Data Expected SIRFLOX RCT (2) ANZ, EME, US April FOXFIRE RCT (2) UK November Mid 2017 FOXFIRE Global RCT (2) ANZ, AP, EME, US January Total accrual 1, ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; UK: United Kingdom; US: United States 2. FOLFOX-based (+ biologic) vs. FOLFOX-based (+ biologic) + SIRT

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45 Patient Characteristics in the ITT Population Characteristic FOLFOX (+ bev) (n = 263) FOLFOX (+ bev) + SIRT (n = 267) Age, median (range) 63 (23 89) 63 (28 81) Sex Female Male 88 (34%) 174 (66%) 85 (32%) 182 (68%) WHO performance status (67%) 87 (33%) 176 (66%) 90 (34%) Extra-hepatic metastases 104 (40%) 108 (40%) Primary tumor not removed 121 (46%) 119 (45%) Synchronous metastases 233 (89%) 241 (90%)

46 Progression-Free Survival at Any Site 1.00 Proportion Not Progressing 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

47 PFS in the Liver: Competing Risk Analysis 0.7 Probability of Hepatic Progression n Events Median FOLFOX (+ bev) months FOLFOX (+ bev) + SIRT months HR: 0.69 (95% CI: ); p= Time from Randomization (months) Number at risk FOLFOX FOLFOX + SIRT

48 CELIM 2 Köhne JCO accepted for publication

49 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

50 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, % Non-Caucasian, % Achieve NED: FOLFOX, %* Prior Radiation, %* / Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

51 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, % Non-Caucasian, % FOLFOX, %* Prior Radiation, %* Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

52 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, % curative intent % 13.6% 17.5% curative intent N Resected NED (R0) N Pat Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % Liver metastases only, % *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132

53 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) ( ) ( ) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy

54 Impact of pathological response after chemotherapy on survival 1st line: 66% CPR: 29/738 (4%) FOLFOX: 6% Adam et al, JCO st line: 100% CPR total : 25/271 (9%) FOLFOX : 12% FOLFOX + Bev: 8.6% Blazer et al, JCO 2008

55 Evaluation of ORR Primary analysis FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p ITT population (N= 592) Assessable for response (N= 526) p = Fisher s exact test (one-sided) Heinemann V- et al J Clin Oncol 31, 2013 (suppl; abstr LBA3506)

56 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= ( ) Final RAS wt n= ( ) *ETS: early tumor shrinkage 20% at 6 weeks p = Fisher s exact test (two-sided)

57 Evaluation of Depth of Response (DpR*) FOLFIRI + Cetuximab FOLFIRI + Bevacizumab median DpR % SE % SE p KRAS exon 2 wt n= (±54.6%) (± 44.3%) Final RAS wt n= (±54.8%) % (± 42.3%) < 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

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59 Rate of resection in LLD and no formal MDT prior chemo NO16966 N R0 CTx + bevacizumab % CTx + placebo % 1.00 Patients with metastatic disease limited to the liv er at baseline (n =704) Hepatic metastasectomy and R0 resection (n=85) No R0 hepatic metastasectom y (n=619) OS at 24 months 95% 54% P < CRYSATL (KRAS wt) FOLFIRI+Cetuximab % Overall-survival estimate FOLFIRI % Months from commencin g treatment Okines et al. BJC 2009 Köhne etal. WCGIC 2011

60 - 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 = % 38% 36% 38% 39% 37% p = 0.99 p = 0.49 p = 0.48 Potential bleeding and wound healing complications

61 Questions to CALGB 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

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63 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) ~ NR OS non resected pts (mo) Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010

64 Study Regimens n ORR (95% CI), % R0 resections (95% CI), % Chemotherapy alone Surgical mortality, % Median OS (range), mo METHEP FOLFOX4/FOLFIRI (41-77) 23 ( ) ( ) [13] a FOLFIRI-HD (44-79) 25 ( ) ( ) Cetuximab-based regimens b FOLFOX (37-75) 23 ( ) ( ) FOLFOXIRI (54-88) 30 ( ) (21.9-NR) CELIM [9,14] Cetuximab + FOLFOX (54-80) 33 (25-52) ( ) c Cetuximab + FOLFIRI (42-70) 30 (18-44) ( ) c Ye et al. [15] mfolfox6/folfiri ( ) 7 ( ) ( ) c Cetuximab + mfolfox6/folfiri ( ) 26 ( ) ( ) c Bevacizumab-based regimens OLIVIA Bevacizumab + mfolfox (45-77) 31 (17-48) d ( ) Bevacizumab + FOLFOXIRI (65-91) 54 (37-69) d 0 NR (0-56.0)

65 Response rates = resection rates? CT CT + Erbitux Response (%) p< p= Why? R0 resection (%) p= p= 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:

66 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

67 Colorectales - Ca R0 Resection of Metastases Controversy: Adjuvant Therapy? USA Yes (Kemeny NEJM 1999) Europa No (Lorenz NEJM 200)

68 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