Chemotherapy for resectable liver mets: Options and Issues Herbert Hurwitz Duke University Medical Center Durham, North Carolina, USA
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
Concept of All-3-Drugs - Update 2005 11 Phase III Trials, 5768 Patients Median OS (mo) 22 21 20 19 18 17 16 15 14 13 12 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 LV5FU2 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 FOLFOXIRI CAIRO 2007 Grothey & Sargent, JCO 2005
Chemotherapy Regimens in Resected Stage III CRC Useful FOLFOX XELOX 5FU Capecitabine Not Useful FOLFIRI IFL FOLFOX-BEV CO8, AVANT FOLFOX-Cetux N0147, PETACC
Stage III Adjuvant
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
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 (0.96-1.5) P- value 0.22
NSABP C-08 mff6 q2wk X 6 mo R Bev* q2wk X 1 yr *5mg/K N Wolmark ASCO 2009
NSABP C-08: DFS 0 20 40 60 80 100 % Ev 3yDFS mff6+b 291 77.4 mff6 312 75.5 HR 0.89 P 0.15 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Yrs
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
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 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 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 0.0 0 6 12 18 24 30 36 42 48 Time (months) 54 60 66 72 FOLFOX4 FOLFOX4 + Bev XELOX + Bev 955 960 952 890 921 900 823 868 865 779 791 784 740 728 722 708 695 688 609 586 580 451 436 415 282 280 268 121 123 110 32 33 28 0 1 0 0 0 0
Stage IV Peri-Op
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
EORTC 40983: PFS 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 B Nordlinger ASCO 2007
EORTC 40983: PFS in resected patients 100 90 HR= 0.73; CI: 0.55-0.97, p=0.025 80 70 60 Periop CT +9.2% At 3 years 50 40 30 20 10 Surgery only 42.4% 33.2% 0 0 1 2 3 4 5 6 (years) O N Number of patients at risk : 104 152 85 59 39 24 10 93 151 118 76 45 23 6 B Nordlinger ASCO 2007
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. 2400 mg/m 2 FOLFIRI N = 306 Every two weeks FA 2 hrs. IV 400 mg/m 2 (200 if Lform) Irinotecan 30-90 min. IV 180 mg/m 2 5-FU bolus 400 mg/m 2 5-FU CI 46 hrs. 2400 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
CPT-GMA-301: Disease-Free Survival 1.00 Treatment HR=0.89: 95%CI [0.66-1.19] Probability 0.75 0.50 0.25 0.00 Number at risk LV5FUs LV5FUs+IRI adjusted Logrank p=0.43 0 12 24 36 48 Months 153 95 65 44 25 153 114 70 41 22 LV5FUs LV5FUs+IRI 1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51% Ychou ASCO 2009
Pre-Op Chemotherapy
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
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
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
BOXER Study Design R Wong, I Chau et al. Ann Onc 2009
BOXER Response Rate N % CR 4 9 PR 31 69 SD 7 16 PD 3 7 ORR (95% CI) 35 78 (63-89) R Wong, I Chau et al. Ann Onc 2009
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
LiverMetsurvey Study design LiverMetsurvey Jan 1995 June 2010 8912 Patients 151 Centers in 39 Countries No Preop Chemotherapy 4468 Preop Chemotherapy 4444 49.9% Study population R Adam ASCO 2011
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 1-3 4-7 >7 Meta. at diagnosis 30mm Chemo preop 62.1% 61 ± 11 46.3% 30.7% 16.9% 3.2% 3.0% 66.6% 67.5% 23.8% 8.7% 59.5% No chemo preop 62.3% 64 ± 11 42.3% 32.1% 18.7% 3.5% 3.4% 60.7% 88.9% 8.9% 2.2% 56.6% P NS < 0.0001 0.005 < 0.0001 < 0.0001 0.01 R Adam ASCO 2011
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 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 R Adam ASCO 2011
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
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
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
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
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
LiverMetsurvey Disease free survival Patients with preoperative chemotherapy Multivariate Analysis Risk factors P RR CI 95% Metastatic primary LN 0.0008 1.32 [1.1-1.6] Abnormal CEA levels (>5) 0.005 1.25 [1.1-1.5] Metastases >3 0.0001 1.4 [1.2-1.7] Tumoral progression 0.05 1.3 [1.0-1.7] Type of chemotherapy NS - - Major hepatectomy 0.04 1.2 [1.0-1.4] More than 6 cycles 0.004 1.25 [1.1-1.5] R Adam ASCO 2011
LiverMetsurvey - Overall survival Patients with preoperative chemotherapy Multivariate Analysis Risk factors P RR CI 95% Metastatic primary LN 0.005 1.29 [1.1-1.5] Abnormal CEA levels (>5) < 0.0001 1.46 [1.2-1.7] Concomitant extrahep dz < 0.0001 1.66 [1.4-2.0] Metastases >3 0.006 1.29 [1.1-1.5] Tumoral progression 0.04 1.31 [1.0-1.7] Type of chemotherapy NS - - More than 1 line of Chemo. 0.0002 1.45 [1.2-1.8] R2 resection < 0.0001 1.65 [1.3-2.1] R Adam ASCO 2011
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
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
Patients have the answers: bench to bedside and back