Evaluation and Evidence based management principles of Synchronous and Metachronous Colorectal Liver Metastases

1. Multidisciplinary
Approach to Colorectal
Liver Metastases
Dr Pradeep Dhanasekaran
MCh Surgical Oncology Postgraduate
Prof. M.P. Viswanathan and Prof. D. Suresh Kumar Unit
MMC, TNGMSSH, Chennai-02
11-06-2021

2. Outline
• Introduction
• Diagnosis and Evaluation
• Patient Selection
• Management of Resectable Liver Metastases
• Potentially resectable liver metastases
• Unresectable liver metastases with conversion therapy
• Liver Directed therapies
• Management of synchronous Liver metastases

3. Introduction
• More than 50% of patients with CRC develop liver metastases during the course of
disease with Synchronous metastases in 15% to 20% & Metachronous in 50% to 60%.
• Median Overall survival is almost 30 months with improved treatment strategies and
5 year overall survival more than 50% in medically fit patients who undergo surgical
resection (1).
• Around 30% develop recurrence, and 15% succumb to disease within 1 year of surgery.
• Proficient Multidisciplinary Team is important (Despite 84% of clinicians being certain
of their plan before discussion, Change was recommended in 36% of cases, of which
72% were major) (2).
(1) Kanas GP, Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012;
(2) Oxenberg J, Multidisciplinary cancer conferences for gastrointestinal malignancies result in measureable treatment changes: a prospective study of 149 consecutive patients.
Ann Surg Oncol 2015

4. CRLM definitions
EGOSLIM consensus group Terminology
• Synchronous liver metastases (detected at or before diagnosis of the primary tumour),
• Early metachronous metastases (detected within 12 months after diagnosis or surgery
of the primary) and
• Late metachronous metastases (detected more than 12 months after diagnosis or
surgery of the primary)
Adam R, de Gramont A, Figueras J, Kokudo N, Kunstlinger F, Loyer E, Poston G, Rougier P, RubbiaBrandt L, Sobrero A, Teh C, Tejpar S, Van Cutsem E, Vauthey JN, Påhlman L; of the
EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary
international consensus. Cancer Treat Rev 2015;

5. Evaluation of metachronous CRLM
• Patient’s general health (Performance status, Comorbidities and Liver volume and
function) and Extent of disease by Imaging
• Initial evaluation – Contrast CT abdomen and pelvis, chest
• Sensitivity of MRI is more than CT in detecting subcentimetric liver lesions and after
neoadjuvant chemotherapy (SS 91% vs 82%)
• With addition of hepatobiliary specific contrast, diagnostic accuracy of MRI reaches
upto 98.3% (3).
• PET/CT – Less sensitive but more specific in detecting CRLM and it helps in
identification of extrahepatic disease in 32%, leading to change in management in 24%
of cases (4).
(3) Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019
(4) Lake ES, The influence of FDG PET-CT on the detection of extrahepatic disease in patients being considered for resection of colorectal liver metastasis. Ann RCS Engl 2014

6. Evaluation
Modality Finding Value Limitations
USG (CEUS) SS 80-90% even in detecting lesions <1cm
Cannot be useful in surgical planning
Operator
dependent
Intraop US Identify new lesions in 16% and alter management in 9%, also
identify disappearing lesions after NACT
Availability
Cost
CECT Hypodense with heterogeneity
on portal phase, regular or
irregular margins
Detection rate 86%
SS 91%; PPV 96%
SS reduced for
lesions <1cm
MRI T1 hypointense, T2 hyperintense
with heterogenous rim
enhancement in arterial and
hypo enhancement in PV and
delayed
SS 94%; Gadobenate
dimeglumine, Gadoxetate
sodium improve
detection even lesions
<1cm, disappearing
lesions

8. Evaluation – Biopsy?
• Biopsy of suspected CRLM should be avoided (5).
• Needle track seedling happens in 10% to 19% which is associated with lower 4 year
survival on studies
• Given that low change of benign (about 2%) – strongly argue against preoperative
CRLM biopsy
(5) Jack Martin Colorectal liver metastases: Current management and future perspectives World J of Clinical Oncology Oct 24, 2020

9. FLR Evaluation
Technique Advantages Limitations
CT Volumetry Modern imaging software
with accurate calculation of
volumes
Not necessarily reflect the
function in cases where liver
parenchyma is suboptimal
ICG Clearance (6) Functional test
Gives global assessment of
liver function
Used intraoperatively
Uptake impaired in
hyperbilirubinemia
Cannot assess the function
of remnant liver
Tc99m Mebrofenin
Hepatobiliary scintigraphy
(7)
Segmental hepatic function
can be assessed
Useful in predicting post
hepatectomy liver failure
Uptake above 2.5%/min/m2
has 3% chance and below
2.5% has 56% chance of LF
Less evidence available
(6) De Gasperi A, Mazza E, Prosperi M. Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery? World J Hepatol 2016;
(7) de Graaf W, Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection. J Gastrointest Surg 2010;

11. Patient Selection
• Resectable – Definition: Liver metastases where R0 resection is achieved preserving
liver remnant of 25% consisting of two contiguous segments with adequate inflow,
outflow and biliary drainage (3).
• Not all patients are resectable, and not all benefit from surgery
(3) Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019
(8) Van custem, ESMO consensus guidelines for the management of patients with metastatic colorectal cancer, Annals of Oncology 2016
Technical Criteria (8) Oncologic Criteria
R0 resection feasible with adequate FLR
of 25% or remnant liver to body weight
ratio >0.5
Takes into account
1, Tumor biology (T, N, Grade)
2, Intrahepatic tumor burden (Number,
Size etc)
3, Mutation status (RAS, RAF)
4, Extrahepatic disease

12. Predictive Scores
• FONG Clinical Risk Score (9)
• Failed to demonstrate predictive accuracy in post neoadjuvant setting
(9) Yuman Fong MD, Clinical Score for Predicting Recurrence After Hepatic Resection for Metastatic Colorectal Cancer Analysis of 1001 Consecutive Cases, Annals of Surgery 1999

13. Predictive Scores
• ZHU Score (10) to predict who will benefit from NACT
• High risk (3 or more points) – benefit of NACT observed with 5 year OS 39% with NACT
vs 33% with upfront surgery
• Low risk (up to 2 points) – benefit of NACT not observed.
(10) Zhu D, Zhong Y, Wei Y, Ye L, Lin Q, et al. (2014) Effect of Neoadjuvant Chemotherapy in Patients with Resectable Colorectal Liver Metastases. PLoS ONE 9(1): e86543.
doi:10.1371/journal.pone.0086543
1. Primary tumor Stage T4
2. 4 or more liver lesions
3. Largest tumor size 5cm or more
4. Serum CEA 5ng/mL or more
5. Synchronous CRLM
Each assigned one point.

14. GAME Score Margonis et al
• Genetic and Morphological Evaluation Score (11)
• Low risk 0 -1; Intermediate risk 2-3; High risk 4 or more points
• 5 year OS (73.4% vs 50.6% Low vs Intermediate) and (50.6% vs 11% Intermediate vs
High risk) – Significant
(11) Margonis GA, Sasaki K, Gholami S, Kim Y, Andreatos N, Rezaee N, Deshwar A, Buettner S, Allen PJ, Kingham TP, Pawlik TM, He J, Cameron JL, Jarnagin
WR, Wolfgang CL, D'Angelica MI, Weiss MJ. Genetic And Morphological Evaluation (GAME) score for patients with colorectal liver metastases. Br J Surg. 2018
Aug;105(9)
1, KRAS mutated - 1
2, CEA 20ng/mL or more - 1
3, Nodal positivity - 1
4, Tumor Burden Score 3 – 8 - 1
5, Tumor Burden Score 9 or more - 2
6, Extrahepatic disease - 2
Total 7 points

15. Categorization of Patients
(8) Van custem, ESMO consensus guidelines for the management of patients with metastatic colorectal cancer, Annals of Oncology 2016

16. Resectable, Low Risk (FIT)
• Surgery – SoC
• R0 Resection is essential (5 yr OS 55% vs 26% with R1
resection)
• No need for perioperative chemotherapy
• No definitive Level I evidence available for adjuvant
chemotherapy in this setting
(12) Vera R, Multidisciplinary management of liver metastases in patients with colorectal cancer: a consensus of SEOM, AEC, SEOR, SERVEI, and SEMNIM, Clinical and
Translational Oncology (2020) 22:647–662

17. Resectable, High Risk
• Perioperative Chemotherapy is indicated
• Chemotherapy helps downstaging and R0 resection, eradicate micrometastases, assess
chemosensitivity and patient tolerability, identify patients who benefit from resection
• 5 year OS for Partial response 37% vs Stable disease 30% vs progressive disease 8%
even with R0 resection(13).
• FOLFOX4 or CAPEOX 3 months (6 cycles) before and after
• Chemo induced liver toxicity, Progressive disease, absence of survival benefit must be
kept in mind before giving chemotherapy in resectable liver metastases.
(13) Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B, Levi F, Bismuth H. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple
colorectal metastases? Ann Surg. 2004
(14) Nordlinger B, Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC
40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15.
Evidence Arms Results
EPOC Trial EORTC
40983 (14)
(Up to 4 mets, easily
resectable)
6 cycles of 2 weekly FOLFOX4
before and after surgery (PERI
OPERATIVE CHEMO) vs Surgery
alone
mOS: 61.3 m vs 54.3m
5 yr OS: 51.2% vs 47.8%
Not significant
Initially – PFS benefit seen (44.2%
vs 33.2%)

18. Regimens and Risks
• Alternatives – FOLFIRI and FOLFOXIRI
• Addition of Cetuximab – worse PFS (14.5 vs 20.5 months), RR (58.7% vs 53.4%) as per
New EPOC Trial (15)
• Addition of Bevacizumab – no survival benefit (PERIMAX Trial 16)
(15) Primrose J, Bridgewater J. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled
trial. Lancet Oncol 2014; 15: 601-611
(16) Stein A, et al. Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review
of the literature. BMC Cancer 2012; 12: 356
Risks:
1, Progression (Initially resectable 
Unresectable) in 7%
2, Oxaliplatin induced Sinusoidal obstruction
syndrome in 38%
3, Irinotecan induced steatohepatitis in 9.3%
4, Short interval of <4 weeks after chemo
5, >9 cycles of chemotherapy
6, Disappearing liver metastases due to chemo
induced compromised radiological detection

19. Chemotherapy related toxicity
Toxicity Findings Implication
Steatosis Fat accumulation  NAFLD 
Steato-hepatitis  Fibrosis and
Cirrhosis
5 FU causes reversible Steatosis
in 30% - 40%
Increased complications
post resection but not
impact on mortality
Steato-hepatitis “Yellow
Liver”
Irinotecan, High BMI,
preexisting steatosis
A/w postoperative
complications and 90 day
mortality 15% vs 2%
Sinusoidal Obstruction
Syndrome
“Blue liver”
78% of patients receiving
Oxaliplatin have sinusoidal
obstruction
Increased morbidity post
resection and not mortality

20. Disappearing Liver Metastases
• A Subset of CRLM totally vanish after NACT due to chemo induced
compromise in radiological detection
• Really cured?
• Incidence 7% to 37%
• Surgery identifies macroscopic residual disease in 17% to 67% and
microscopic residual disease in up to 80% of specimens (3)
• If not resected, local recurrence rate of 19% to 74%
• True pCR is 4%
• How to reduce DLMs? Avoid overtreatment with more cycles of
chemotherapy, assess with imaging after 3 cycles
(3) Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019

21. What Surgery?
• Minor Hepatectomy (up to 3 segments)
• Parenchymal sparing hepatectomy (PSH)
• Major Hepatectomy (4 or more segments) Morbidity of 20% and mortality of 5%
• Systematic review showed there is no difference between anatomical and non-
anatomical (parenchymal sparing) hepatectomy in terms of perioperative and long
term oncological outcomes R0 resection rate, Liver RFS and OS(17).
• Historical practice of 1 cm margin, but now a Propensity Score Case-Match study
showed that 1 mm cancer-free resection margin achieved 33% 5- year overall disease-
free survival, and that additional margin width did not add disease-free survival
advantage (18).
(17) Moris D, Ronnekleiv-Kelly S, Rahnemai-Azar AA, Felekouras E, Dillhoff M, Schmidt C, Pawlik TM. Parenchymal-Sparing Versus Anatomic Liver Resection for Colorectal Liver
Metastases: a Systematic Review. J Gastrointest Surg 2017
(18) Hamady ZZ, Lodge JP, Welsh FK, Toogood GJ, White A, John T, Rees M. One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score case-
match approach. Ann Surg 2014

23. Surgery
• Evidence from OSLO-COMET trial which compared with the open-surgery group, the
Laparoscopic Liver Resection group had less postoperative complications and a shorter
hospital stay, while 90-d mortality and percentage of involved resection margins were
similar (19).
• Role of Surgery In Extrahepatic disease
• Limited resectable EHD (not a CI)
• Resectable Lung metastases
• Not Peritoneal or para aortic nodal metastases
• Not with increased tumor burden
Contraindications to Liver Resection:
• R0 resection not feasible with FLR >25%
• Unresectable disease
• Unresectable extrahepatic disease
• 5 or more liver lesions
• Tumor progression
(19) Fretland ÅA, Dagenborg VJ, Bjørnelv GMW, Kazaryan AM, Kristiansen R, Fagerland MW, Hausken J, Tønnessen TI, Abildgaard A, Barkhatov L, Yaqub S, Røsok BI, Bjørnbeth BA,
Andersen MH, Flatmark K, Aas E, Edwin B. Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLOCOMET Randomized Controlled Trial. Ann Surg 2018

24. Adjuvant Therapy
• After resection of CRLM – Controversial
• No definite evidence available (3).
• Earlier studies (French FFCD and ENG trial) showed modest improvement in PFS and
OS with adjuvant 5 FU but not significant.
• Extrapolation from EORTC trial showed PFS benefit only in patients with high risk
• No Bevacizumab or Cetuximab
• However all Guidelines recommend Adjuvant Chemotherapy (FOLFOX or FOLFIRI)
• Recently Hepatic arterial Infusional Chemotherapy with 5 FU shows improved PFS but
not OS.
• Expertise and need for unique special catheter are limitations and whether it
continues the same benefit compared with modern doublet or triplet chemotherapy
(3) Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019

25. Resectable CRLM, Unfit (Poor PS, Comorbids, Not willing)
Vera R, Multidisciplinary management of liver metastases in patients with colorectal cancer: a consensus of SEOM, AEC, SEOR, SERVEI, and SEMNIM, Clinical and Translational
Oncology (2020) 22:647–662

26. Local Ablative Treatment
• Limitations: RAS mt, Size > 3cm, Nodules >5 in number, Proximity to vessels >3mm
• Local Cure Rates – RFA 90% , MWA 94%, SBRT 90% with 2 year OS 70%
Vera R, Multidisciplinary management of liver metastases in patients with colorectal cancer: a consensus of SEOM, AEC, SEOR, SERVEI, and SEMNIM, Clinical and Translational
Oncology (2020) 22:647–662

27. Potentially Resectable Liver Mets
Scenarios
1. Ro resection feasible, but
inadequate FLR
2. Ro not possible due to large tumor
burden but FLR adequate
3. Ro not possible and also
inadequate FLR
Vera R, Multidisciplinary management of liver metastases in patients with colorectal cancer: a consensus of SEOM, AEC, SEOR, SERVEI, and SEMNIM, Clinical and Translational
Oncology (2020) 22:647–662

28. Ro feasible, but inadequate FLR
• Goal to increase FLR
• Portal Vein Embolization – Gold standard (Makkuchi et al 1980s)
• Takes 3 – 5 weeks to achieve Contralateral lobe hypertrophy
• Mean increase in FLR of about 38% and adequate hypertrophy in 96% noted
• Despite this, 15%-20% cannot undergo surgery due to progression or extrahepatic
disease
• Major complication rates 0.4%, mortality rate 0.1%
(3) Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019

29. Ro not feasible due to large tumor burden
• Downstage the tumor with Neoadjuvant Chemotherapy
• A systematic review by Lam et al and others reporting a response rate
of 64%, with 22.5% of patients converted to curative liver resection
overall.
• The paradox of this chemotherapeutic success is the phenomenon of
the disappearing metastasis, which presents a problem for the surgical
team.
• Incidence 6% to 37%
• In 65% of DLMs, a lesion is found at laparotomy
• In remaining 35%, sx not done – 80% regrow at the same site of DLM

30. Ro not feasible and FLR inadequate
• Two Staged Hepatectomy – Adam et al
• In Advanced Bilobar liver mets
• 3 year OS with TSH 45% compared with one Stage 30%.
• 28% cannot undergo second stage due to progression

31. ALPPS
• Associating Liver Partition and Portal vein ligation for Staged hepatectomy – Dr Schlitt
• Total diversion of portal flow to FLR – induces inflammatory response and rapid
hypertrophy at a growth rate of 22 -35ml/day.
• Greater FLR hypertrophy
• Higher rate of completion of 2nd stage
• Superior resection rates
• Mortality 0%, morbidity 21%
• 3 year OS 50%
Sandström P, Røsok BI, Sparrelid E, Larsen PN, Larsson AL, Lindell G, Schultz NA, Bjørnbeth BA, Isaksson B, Rizell M, Björnsson B. ALPPS Improves Resectability Compared With
Conventional Twostage Hepatectomy in Patients With Advanced Colorectal Liver Metastasis: Results From a Scandinavian Multicenter Randomized Controlled Trial (LIGRO Trial).
Ann Surg 2018;

33. Unresectable Liver Metastases
• With Modern doublet or triplet chemotherapy, mOS improved to 20
months even in unresectable disease and chances of conversion into
resectable disease, It is deemed Unresectable only after 2 -4 months of
optimal treatment when maximum tumor shrinkage have occurred.
• Strategies
• Conversion Chemotherapy
• Liver directed therapy

34. Conversion Chemotherapy
• 15% to 30% of unresectable LMs can be made resectable by conversion chemotherapy
• Eg, Multiple Bilobar liver metastases, not able to achieve R0 with adequate FLR
• Factors – Tumor mutational status, patient factors, drug toxicity profiles
• Agents – FOLFOX/CAPEOX/FOLFIRI
• Conversion rates for FOLFOX / FOLFIRI – 9% to 33%; Response Rate 50%
• Triplet chemotherapy improved R0 resection rates, response rates but at the expense
of increased toxicity
• Addition of Cetuximab or Panitumumab has increased response rates and improved
conversion rates (23, 24)
• Addition of Bevacizumab to Doublet or Triplet Chemo has improved conversion rates
up to 40%
(23) Folprecht G. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase
2 trial. Lancet Oncol 2010; 11: 38-47
(24) Modest DP. FOLFOXIRI Plus Panitumumab As FirstLine Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO
KRK0109). J Clin Oncol 2019

35. Treatment Recommendations
Mutation Status Chemo regimen Inference Evidence
RAS Wild type Doublet Chemo FOLFOX/FOLFIRI
+ Cetuximab or Bevacizumab
Improved RR
Between Cetuxi and Bevaci
no significant difference in
DFS / OS
FIRE – 3
SWOG Trial
RAS Mutated Doublet / Triplet Chemo +
Bevacizumab
RR 81%
Ro rates 50-60%
OLIVIA Trial
BRAF mutated Triplet chemo + Bevacizumab mOS 19 months
mPFS 7.5 months
ORR 56%
TRIBE trial
Right colonic tumors
RAS WT
Chemo plus Bevacizumab EGFR mab had no benefit
in right sided tumors
CRYSTAL, FIRE 3 , PEAK
Left Colonic tumors Chemo with EGFRmab Superior OS, PFS and RR CRYSTAL, FIRE 3, PEAK,
PRIME and CALGB trials

36. Liver Directed Therapies

37. LDT
Local Chemotherapy
• Hepatic arterial Infusional Chemotherapy – Used in 2nd line setting
• DEBIRI – Transarterial delivery of Irinotecan coated beads
Radiation based therapy
• Selective Internal Radiotherapy using Yttrium 90 microspheres
• SBRT

38. Synchronous CRLM
• Less favourable biology
• 5 year post resection survival 39% compared with 48% in metachronous metastases.
• Liver Mets Survery International Registry showed that neoadjuvant therapy offered no
survival advantage in resectable synchronous CRLM, with a 5-year OS of 42% similar to
47% in the upfront surgery group.

39. Treatment decision
• Patient’s fitness, Tumor status (symptomatic primary due to obstruction)
• CRLM extent and magnitude of liver resection

40. Treatment Approach
• Conventional approach – Resection of colorectal primary followed by liver
metastatectomy with chemotherapy in between
• Chances of progression into unresectablility; only 30% complete whole treatment
• Liver first approach – After systemic chemotherapy f/b liver resection f/b primary CRC
resection
• Synchronous resection of CRC primary and Liver Metastases
• Metanalyses – no d/f in surgical outcome or survival advantage

50. Thank You