Chemotherapy for resectable liver mets: Options and Issues. Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA

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1 Chemotherapy for resectable liver mets: Options and Issues Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA

2 Chemotherapy regimens in 1 st line mcrc Standard FOLFOX-Bev FOLFIRI-Bev XELOX-Bev FOLFIRI-Cetux FOLFOX-Pmab IFL-Bev 5FU-Bev/Cape-Bev Non-Standard? FOLFOX-Cetux FOLFIRI-Pmab FOLFOXIRI FOLFOXIRI-Bev FOLFOXIRI- Pmab

3 Concept of All-3-Drugs - Update Phase III Trials, 5768 Patients Median OS (mo) P =.0001 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU Patients with 3 drugs (%) OS (mos) = (%3drugs x 0.1), R^2 = 0.85 FOLFOXIRI CAIRO 2007 Grothey & Sargent, JCO 2005

4 Chemotherapy Regimens in Resected Stage III CRC Useful FOLFOX XELOX 5FU Capecitabine Not Useful FOLFIRI IFL FOLFOX-BEV CO8, AVANT FOLFOX-Cetux N0147, PETACC

5 Stage III Adjuvant

6 N0147: Final Design K-ras WT Arm A mfolfox6 Stage 3 Colon Cancer (N = 3768) Centralized K-ras analysis Arm D mfolfox6 + Cetuximab K-ras Mut Arm G Adjuvant therapy per primary oncologist Alberts ASCO 2010

7 N0147: DFS (N=1847, Ras wt) Arm FOLFOX N=902 FOLFOX O + Cmab N=945 3 Year Rates (95% CI) 75.8% (72.1%-79.6%) 72.3% (68.5%-76.4%) HR (95% CI) 1.2 ( ) P- value 0.22

8 NSABP C-08 mff6 q2wk X 6 mo R Bev* q2wk X 1 yr *5mg/K N Wolmark ASCO 2009

9 NSABP C-08: DFS % Ev 3yDFS mff6+b mff HR 0.89 P Yrs

10 AVANT Study Design FOLFOX4 Observation Follow-up Surgery for high-risk stage II or stage III colon cancer (N=3451) FOLFOX4 + bevacizumab Bev 5 mg/kg q2w Bevacizumab monotherapy Bev 7.5 mg/kg q3w Follow-up XELOX + bevacizumab Bevacizumab monotherapy Follow-up Bev 7.5 mg/kg q3w Bev 7.5 mg/kg q3w 24 weeks 24 weeks

11 DFS (ITT Stage III) Data cut-off date: 30 June 2010 (3-year minimum follow-up) Event-free rate FOLFOX4 1.0 FOLFOX4 + Bev 0.9 XELOX + Bev HR (95% CI) FOLFOX (N=955) FOLFOX4 + Bev (N=960) 1.17 (0.98, 1.39) XELOX + Bev (N=952) 1.07 (0.90, 1.28) Number at risk Time (months) FOLFOX4 FOLFOX4 + Bev XELOX + Bev

12 Stage IV Peri-Op

13 EORTC 40983: Peri-op FOLFOX Study design R a n d o m iz e FOLFOX4 6 cycles (3 months) Surgery Surgery FOLFOX4 6 cycles (3 months) N=364 patients B Nordlinger ASCO 2007

14 EORTC 40983: PFS 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 : B Nordlinger ASCO 2007

15 EORTC 40983: PFS in resected patients HR= 0.73; CI: , p= Periop CT +9.2% At 3 years Surgery only 42.4% 33.2% (years) O N Number of patients at risk : B Nordlinger ASCO 2007

16 CPT-GMA-301: Post-op FOLFIRI Study design R LV5FUs FA 2 hrs. IV 400 mg/m 2 (200 if Lform) 5-FU bolus 400 mg/m 2 5-FU CI 46 hrs mg/m 2 FOLFIRI N = 306 Every two weeks FA 2 hrs. IV 400 mg/m 2 (200 if Lform) Irinotecan min. IV 180 mg/m 2 5-FU bolus 400 mg/m 2 5-FU CI 46 hrs mg/m 2 Chemotherapy will be administered for a total of 12 cycles (6 months) except in case of unacceptable toxicity, progression or consent withdrawal. Ychou ASCO 2009

17 CPT-GMA-301: Disease-Free Survival 1.00 Treatment HR=0.89: 95%CI [ ] Probability Number at risk LV5FUs LV5FUs+IRI adjusted Logrank p= Months LV5FUs LV5FUs+IRI 1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51% Ychou ASCO 2009

18 Pre-Op Chemotherapy

19 Pre-Op Chemotherapy and Met Resection Issues Resectability issues Lesion size, #, location Surgeon Patient Radiologist, Medical Oncologist R0 vs R1 vs R2 Denovo vs Converted resectable Chemo issues PreOp, PostOp, Both Variable regimens and dose intensity/compliance Uncommon events and variable endpoints --> wide confidence intervals Cross study comparisons are at best challenging

20 Biopsy: EGFR screening CELIM Patients with non-resectable colorectal liver metastases (technically non-resectable / 5 liver metastases) without extrahepatic disease closed early, patients were randomized to cetuximab arms Randomization FOLFOX6 + cetuximab FOLFIRI + cetuximab EGFR IHC non-detected FOLFOX6 Therapy: 8 cycles (~ 4 months) Evaluation of resectability Technically non-resectable Technically resectable 4 additional therapy cycles Resection Primary endpoint: Response Therapy continuation for 6 cycles (~ 3 months) Folprecht et al, Lancet Oncology 2010

21 CELIM: Response and resection rates All FOLFOX6 + FOLFIRI + K-ras K-ras pts cetuximab cetuximab wild-type mutant n=106 n=53 n=53 n=67 n=27 CR/PR 62% 68% 57% 70% 41% 95% CI 52-72% 54-80% 42-70% 58-81% 22-61% R0 resections 34% 38% 30% 33% 30% 95% CI 25-44% 25-52% 18-44% 22-45% 14-50% Folprecht et al, Lancet Oncology 2010

22 BOXER Study Design R Wong, I Chau et al. Ann Onc 2009

23 BOXER Response Rate N % CR 4 9 PR SD 7 16 PD 3 7 ORR (95% CI) (63-89) R Wong, I Chau et al. Ann Onc 2009

24 Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases R. Adam, E. Barroso, C. Laurent, G. Nuzzo, C. Hubert, G. Mentha, J. Ijzermans, L. Capussotti, S. Lopez-Ben, D. Mirza, G. Kaiser, E. Housseau, T. Gruenberger, G. J. Poston, O. Skipenko, The LiverMetSurvey Centers

25 LiverMetsurvey Study design LiverMetsurvey Jan 1995 June Patients 151 Centers in 39 Countries No Preop Chemotherapy 4468 Preop Chemotherapy % Study population R Adam ASCO 2011

26 LiverMetsurvey Patients and Tumour Characteristics (1) Characteristics Male Age (yrs,mean±sd) Tumor localization Left including sigmoid Rectum Right Transverse Multiple localizations Metast. primary lymph nodes No meta. at diagnosis >7 Meta. at diagnosis 30mm Chemo preop 62.1% 61 ± % 30.7% 16.9% 3.2% 3.0% 66.6% 67.5% 23.8% 8.7% 59.5% No chemo preop 62.3% 64 ± % 32.1% 18.7% 3.5% 3.4% 60.7% 88.9% 8.9% 2.2% 56.6% P NS < < < R Adam ASCO 2011

27 LiverMetsurvey Patients and Tumour Characteristics (2) Characteristics Synchronous Initial resectability Bilateral localization Abnl prehep CEA level (>5) Concomitant extrahep dz Major hepatectomy R2 resection Combined techniques Post-op chemotherapy Center volume (mean±sd) (Max done in a year) Chemo preop 68.7% 62.8% 49.0% 58.1% 12.8% 63.6% 12.9% 28.2% 57.9% 57.8 ± 38.4 No chemo preop 38.4% 95.0% 23.8% 67.0% 8.6% 46.2% 6.7% 14.1% 47.4% 45.1 ± 33.1 P < < < < < < < < < < R Adam ASCO 2011

28 LiverMetsurvey Overall Survival : Global Population 65% 58% 47% Without Preop. chemo With Preop. chemo 39% No of exposed pts Preop. chemo R Adam ASCO 2011

29 LiverMetsurvey: Overall Survival Initially resectable patients 65% 62% 47% Without Preop. chemo With Preop. chemo 44% No of exposed pts Preop. chemo R Adam ASCO 2011

30 LiverMetsurvey: Overall Survival Initially non resectable patients 54% 50% 33% Without Preop. chemo With Preop. chemo 33% No of exposed pts Preop. chemo R Adam ASCO 2011

31 LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 61% 57% 41% Irino-based 34% Oxali-based Oxali-Irino-based No of exposed pts Preop. Chemo. type RAdamASCO2011

32 LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 59% 57% 50% Bevacizumab 39% Cetuximab/Panitumumab Without Preop. Targeted therapy No of exposed pts Preop. Targeted therapy R Adam ASCO 2011

33 LiverMetsurvey Disease free survival Patients with preoperative chemotherapy Multivariate Analysis Risk factors P RR CI 95% Metastatic primary LN [ ] Abnormal CEA levels (>5) [ ] Metastases > [ ] Tumoral progression [ ] Type of chemotherapy NS - - Major hepatectomy [ ] More than 6 cycles [ ] R Adam ASCO 2011

34 LiverMetsurvey - Overall survival Patients with preoperative chemotherapy Multivariate Analysis Risk factors P RR CI 95% Metastatic primary LN [ ] Abnormal CEA levels (>5) < [ ] Concomitant extrahep dz < [ ] Metastases > [ ] Tumoral progression [ ] Type of chemotherapy NS - - More than 1 line of Chemo [ ] R2 resection < [ ] R Adam ASCO 2011

35 LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 62% 54% 44% Not initially resectable Initially resectable 33% No of exposed pts Initially resectable R Adam ASCO 2011

36 Conclusions Resection of liver mets with curative intent Is good for patient but very complicated trial endpoint Cross study comparisons and subset analyses are fraught with difficulties No clear guidance on pre-op vs post op vs both For resectable patients, pre-op chemo No advantage No harm (if duration limited) No clearly better resection regimen FOLFOX vs FOLFIRI Cetuximab vs Bevacizumab No role for biologic post op For now, tailor to the patient Novel approaches needed: pre-op and post op

37 Patients have the answers: bench to bedside and back