Disclosures 1. None 2. Will only focus on resection as the liver - PDF document

Colon Cancer Liver Metastases: Resection is the Goal Shishir K. Maithel, MD, FACS Assistant Professor of Surgery Division of Surgical Oncology Winship Cancer Institute Emory University Disclosures 1. None 2. Will only focus on resection as the ‘liver directed therapy of choice’ a) Hepatic arterial infusion therapy b) Ablation c) Trans-arterial Chemoembolization (TACE) d) Yttrium-90 Radioembolization e) SBRT 1

RESECTABLE DISEASE Outline • Rationale for Surgery – Risk stratification – Patient selection • Preoperative Chemotherapy – Rationale – Morbidity – Duration of therapy – Disappearing lesions – EORTC trial • Clinical Strategy – Metachronous – Synchronous 2

RATIONALE FOR SURGERY Rationale for surgery Natural history of unresected hepatic metastases • Wagner, et al (Mayo 1983) Extent of liver mets 3 yr survival 5 yr survival Solitary (n=39) 21% 3% Multiple, one lobe (n=31) 6% 0% Widespread (n=182) 6% 2% • Wood, et al (Glasgow 1976) Extent of liver mets 1 yr survival 3 yr survival Solitary (n=15) 60% 13% Multiple, one lobe (n=11) 27% 10% Widespread (n=87) 6% 0% 3

5 yr Survival: 0% Colucci et al. JCO 2005 Hepatic Resection for Colorectal Metastases Study N Mortality% 5-yr Surv Hughes, 1986 607 NS 33 Scheele, 1991 219 6 39 Rosen, 1992 280 4 25 Scheele, 1995 469 4 39 Nordlinger, 1995 1568 2 28 Jamison, 1997 280 4 27 Fong, 1999 1001 3 37 Abdalla, 2004 190 NS 58 Adam, 2006 2122 1.2 42 4

Factors to Consider • Number of tumors • Size of tumors • Unilobar versus bilobar disease • Stage of primary cancer • Nodal status • Response to chemotherapy • Presence of extra-hepatic disease • Disease-free interval Risk Stratification: Clinical Risk Score Colorectal Cancer Liver Metastases Multivariate analysis, n=1001 • Node (+) colorectal primary • Disease-free interval < 1 year • More than 1 hepatic tumor • Largest hepatic tumor > 5 cm • CEA > 200 ng/mL 1 point for each criterion Clinical risk score = sum (0-5) Fong et al. Ann Surg 1999 5

Clinical Risk Score (CRS) Clinical risk score predicts survival after resection, n=1001 Survival Score 1-yr 3-yr 5-yr Median(mos) 0 93% 72% 60% 74 1 91% 66% 44% 51 2 89% 60% 40% 47 3 86% 42% 20% 33 4 70% 38% 25% 20 5 71% 27% 14% 22 Fong et al. Ann Surg 1999 10 yr Survival Stratified by CRS 1.0 0.8 proportion surviving 0.6 CRS 0 Low CRS 0.4 1 n = 359 2 0.2 3 4 High CRS 5 n = 161 0.0 0 60 120 180 240 months Tomlinson et al. J Clin Onc 2007 6

10-year survival (n=612) What precludes long term survival? <2yr 2-5yr 5-10yr >10yr Survival Survival Survival Survival Synchronous Dz (%) 13% 11% 5% 7% 50% Node positive primary % 63% 56% 52% Preop CEA > 200 16% 11% 8% 7% DFI < 12mos 51% 46% 36% 36% # of hepatic mets >1 59% 51% 32% 39% Size of hepatic met>5cm 53% 41% 41% 35% Margin Positive 20% 10% 9% 0% Resection: ≥ Lobectomy 63% 63% 62% 68% ≥ 4 metastases 23% 16% 11% 5% Tomlinson et al. J Clin Onc 2007 Partial Hepatectomy is Potentially Curative 1.0 1985 – 94 n = 612 with 10 yr FU .8 Proportion surviving .6 <2yr Median Survival 44mos .4 2-5yr 5-10 yr .2 >10 yr ≈ CURE n=102 0 0 5 10 15 Years Tomlinson et al. JCO 2007 7

Shift in Perspective Surgery is not an adjunct to Chemotherapy Chemotherapy is an adjunct to Surgery CHEMOTHERAPY 8

Preoperative Chemotherapy • Rationale – Eradicate microscopic disease prior to resection – Allows determination of effectiveness of chosen regimen – Time delay to surgery allows declaration of occult disease (biologic selection) • Identify patients who progress – Patients will not tolerate chemo after surgery • Considerations – Toxicity (patient and hepatic) – Duration of therapy – Disappearing lesions Adam R et al. Ann Surg 2010 9

No Difference in Survival Preop Chemo No Preop Chemo Postop Chemo did NOT influence OS or DFS in patients with tumors < 5 cm in size Adam R et al. Ann Surg 2010 Identical Recurrence Pattern Adam R et al. Ann Surg 2010 10

Adam R et al. Ann Surg 2004 Blazer DG, Vauthey JN et al. JCO 2008 11

Gallagher DJ, Kemeny N et al. Ann Surg Onc 2009 Carpizo DR, D’Angelica M et al. Ann Surg Onc 2009 12

Carpizo DR, D’Angelica M et al. Ann Surg Onc 2009 CHEMOTHERAPY TOXICITY 13

Oxaliplatin Toxicity Sinusoidal Obstruction Portal Hypertension Splenomegaly Thrombocytopenia Overman MJ et al. JCO 2010 Rubbia-Brandt L et al. Ann of Oncology 2004 14

No Preop Chemo Preop Oxaliplatin Postop Complication 18.3% 26.5% Major Complication 9.5% 15.1% Vauthey JN et al. JCO 2006 No Steatohepatitis Steatohepatitis 90-Day Mortality 1.6% 14.7% Death from postop 0.8% 5.8% liver failure Vauthey JN et al. JCO 2006 15

Neoadjuvant Chemotherapy • Study design – 67 patients • Major liver resection for colorectal metastases ( ≥ 3 segments) • 45 (67%) had neoadjuvant chemotherapy • 22 (33%) no preoperative therapy – Chemotherapeutic agents • FOLFOX FOLFIRI Karoui M et al. Ann Surg 2006; 243(1): 1-7 Neoadjuvant Chemotherapy • Results – No difference in preoperative characteristics Karoui M et al. Ann Surg 2006; 243(1): 1-7 16

Neoadjuvant Chemotherapy • Results – No difference in intra- operative characteristics Karoui M et al. Ann Surg 2006; 243(1): 1-7 Neoadjuvant Chemotherapy • Results – Increased morbidity in chemotherapy group Karoui M et al. Ann Surg 2006; 243(1): 1-7 17

Neoadjuvant Chemotherapy Duration Minimal change in tumor response in the 4 – 6 month interval White, Kemeny et al. J. Surg Onc 2008 Neoadjuvant Chemotherapy Duration Minimal change in tumor response in the 4 – 6 month interval White, Kemeny et al. J. Surg Onc 2008 18

Complete Response (CR) after Chemotherapy: Does it mean cure? • 586 patients treated • 38 patients with CR of at least 1 lesion • 66 sites disappeared on imaging • Surgery 4 weeks after imaging Benoist S et al. JCO 24(24) 2006 Radiologic Response Does NOT Equal Pathologic Response 66 Sites with CR 20 sites seen at surgery 46 sites no lesion found 15 sites resected 31 sites left in place 12 (80%) viable tumor cells In situ recurrence in 23 (74%) 55/66 (83%) not cured Benoist S et al. JCO 24(24) 2006 19

R A N D Chemo  Surg  Chemo O (n=182) mCRC with Liver M only Metastases Endpoint I (up to 4 lesions) 3-yr PFS Z (N=364) A Surgery T (n=182) I O N Chemotherapy = FOLFOX4 X 6 cycles before and after surgery Nordlinger et al. Lancet 2008 Progression Free Survival Chemo + Surgery Surgery alone Nordlinger et al. Lancet 2008 20

Details of the EORTC Trial • Not a trial of preoperative vs postoperative chemotherapy • Only 7% progressed on preoperative chemotherapy • 36 patients not given postoperative chemotherapy – 6 patients: toxic effects from preop chemo – 8 patients: perioperative complications Nordlinger et al. Lancet 2008 Details of the EORTC Trial Preop Chemo Surgery Postop 25% 16% Complications Preop Chemo Surgery 3-yr PFS 35.4% 28.1% • 7.3% improvement in 3-yr PFS – 6% difference in unresectability rate (4% vs 10%) – 1 patient not resected due to liver damage from chemotherapy – Survival curves remain parallel after time point of resection • No difference in OS at 8-year follow up Nordlinger et al. Lancet 2008 21

CLINICAL STRATEGY METACHRONOUS Resectable Disease Low CRS ( ≤ 2) High CRS (> 2) Preoperative Resection Chemotherapy (limited duration of 2 months) Postoperative Chemotherapy Resection Postoperative Chemotherapy 22

CLINICAL STRATEGY SYNCHRONOUS Asymptomatic Primary Lesion Poultsides et al. JCO 2009 23

Simultaneous Resection • Study design – 240 patients with synchronous metastases – Retrospective review • Sep 1984 – Nov 2001 • Results – Group I: 134 patients with simultaneous resection • Small and fewer liver metastases • Less extensive liver resection – Group II: 106 patients with staged resection Blumgart L et al. JACS 2003 Simultaneous Resection • Results – Postoperative outcomes • Fewer complications in Group I – 49% versus 67% • Decreased hospital stay (10 versus 18 days) • No difference in perioperative mortality (< 3%) • Conclusions – Simultaneous resection is safe and efficient in selected patients Blumgart L et al. JACS 2003 24

Resectable Disease Asymptomatic Symptomatic Resection Preoperative (Primary ± Liver) Chemotherapy (limited duration of 2 months) Chemotherapy (limited duration of 2 months) Resection (Simultaneous or Staged) Liver Resection Postoperative Postoperative Chemotherapy Chemotherapy Conclusions • Patient selection is key • Complete resection is the goal • Perioperative chemotherapy is individualized 25

Colon Cancer Liver Metastases: Resection is the Goal Shishir K. Maithel, MD FACS Assistant Professor of Surgery Division of Surgical Oncology Winship Cancer Institute Emory University August 10, 2014 26