Is it possible to cure patients with liver metastases? Taghizadeh Ali MD Oncologist, MUMS

Survival Rates of by Stage of Adenocarcinoma of the Colon

Liver Resection New Perspective

Colorectal cancer liver metastases Disease is limited to the liver: Unresectable liver metastases: Chemotherapy Low number of patients are cured Neoadjuvant or induction chemotherapy followed by resection if response: conversion therapy If resectable: 20-30% of cure rate Chemotherapy + RFA? (other local treatments??) Resectable liver metastases: Resection with neoadjuvant and/or adjuvant chemotherapy 25-40% of patients are cured

Future Liver Remnant Volume (FLR)

Resection of metastases: an optimal treatment goal

Survival after liver resection: 10,940 patients Resectable vs initially non-resectable

Survival in patients undergoing surgery Overall survival probability in relation to response to preoperative chemotherapy in 4,851 patients undergoing a first resection of colorectal liver metastases

Unresectable CRC metastases Aim of chemotherapy is to render unresectable metastases resectable Choose best regimen to convert unresectable metastases: Achieve high response rate Clinically manageable with minimal toxicity The long term survival of patients who undergo complete resection after conversion of initially unresectable liver metastases approaches the survival of patients with initially resectable metastases Need for multidisciplinary discussions (expert surgeons, GI oncologists, radiologists, etc) before and after chemotherapy

Which regimen should be used as conversion treatment? OPTIONS: FOLFIRI and FOLFOX are likely to be equally effective Triple drug combinations such as FOLFOXIRI superior to FOLFIRI (RR 60% vs 34%, R0 resection 36% vs 12%) Not confirmed in Greek Study (Souglakis et al, Brit J Cancer 2006) Many phase 2 studies with promising data FOLFIRI or FOLFOX plus cetuximab (KRAS wild type) FOLFIRI or FOLFOX plus bevacizumab FOLFOXIRI + biological

FOLFOXIRI + biologic Phase III TRIBE study: FOLFIRI/bev vs FOLFOXIRI/bev as first-line therapy for mcrc 1 N = 508 PFS: 9.7 vs 12.2 mo (HR: 0.73 [0.60-0.88] p = 0.0012) RR: 53 vs 65% (p = 0.006) FOLFIRINOX + cetuximab 2 Preliminary evaluation: high activity

Colorectal cancer liver metastases Disease is limited to the liver: Unresectable liver metastases Resectable liver metastases Resection: 5 years survival 25-40% Neoadjuvant and/or adjuvant chemotherapy Pre- and postoperative FOLFOX (3 + 3 months) Postoperative IV 5-FU/LV Postoperative intrahepatic ± IV chemotherapy Postoperative FOLFIRI Postoperative FOLFOX (6 months) No published data on lung metastases: identical attitude (extrapolation of the data)

OncoSurgical strategies in liver metastases: from palliative to curative

Conclusions Patients with metastatic CRC can be cured, if resection is possible Chemotherapy can downsize unresectable metastases and may allow resection of unresectable liver metastases: conversion concept. Cure can also be obtained in these patients. Correlation between response rate and resection rate Response to chemotherapy leads to better outcome Most active regimen should be proposed in unresectable CRC metastases Resectable metastases: should be resected combination of 2 cytotoxics (FOLFOX) perioperative or postoperative MULTIDISCIPLINARY EXPERT TEAM

BRAF Mutations in CRC BRAF is the primary effector of KRAS signaling BRAF mutations: Only in KRAS wt Portends poor prognosis

WHAT DIAGNOSTIC TESTS? KRAS BRAF UGT1A1 polymorphism VEGF-A EGF-R P53 PI3K

Neoadjuvant Chemotherapy

Multimodality Management of CRC Liver Metastases Neoadjuvant chemotherapy Resectable liver metastases Facilitate surgery Obtain predictive and prognostic information Early systemic therapy for poor-prognosis pts Conversion chemotherapy Unresectable liver metastases Allow R0 resection via downsizing Postoperative (adjuvant) chemotherapy Hepatic arterial infusion (HAI) Systemic treatment

FIRE-3

Similar Survival After Primary or Secondary Resection of Liver Metastases

Treatment-Associated Liver Toxicity 5-FU: steatosis Irinotecan: steatohepatitis Oxaliplatin: sinusoidal/vascular injury Bevacizumab Potential wound healing complications Need to wait 6-8 wks before surgical resection Cetuximab: no acute or chronic effects to date Incidence of postoperative complications increases with prolonged use

Conversion Therapy: Practical Issues FOLFOXIRI attractive but at expense of increased toxicity Limit duration of preoperative therapy to 3-4 mos Treat to resectability and not to best response Minimizes hepatotoxicity Role of biologics is evolving Data with cetuximab appears to be most mature in wild-type KRAS CRC Bevacizumab is an appropriate option in setting of mutant KRAS If bevacizumab is used, discontinue 6-8 wks before planned surgery

Advanced Disease: Standard Biological Targets in mcrc Angiogenesis Cancers need new vasculature to grow beyond a certain size [1] Erratic/irregular blood vessel growth with leaky, poorly formed vasculature [2] Key molecular target VEGF promotes tumor angiogenesis [3] Epidermal growth factor receptor (EGFR) Hetero- or homodimerization leads to activation of multiple downstream pathways including Ras/RAF/MEK/ERK and PI3K/AKT [4] Results in proliferation, survival, angiogenesis, and metastasis [4]

Radioembolization

SRS or Radiation Therapy

SRS