stage IVA colorectal liver metastasis

1. PAINTING THE GREY ZONES
COLORECTAL LIVER
METASTASIS
Dr Sujan Shrestha
MCh, first year
GI, TUTH

2. Grey zone
An area of uncertainty or indeterminacy
No defined YES / NO

3. Grey zone
An area of uncertainty or indeterminacy
No defined YES / NO
EXAMPLE:
1. MANAGEMENT OF STAGE FOUR STOMACH CANCER
2. MANAGEMENT OF STAGE FOUR COLORECTAL CANCER
3. BOWEL PREPARATION OR NO PREPARATION IN COLORECTAL SURGERY
4. MANAGEMENT OF DISAPPERING RECTAL CANCERS POST NA
AND MORE………..

4. COLORECTAL LIVER METASTASIS
COLORECTAL LIVER METASTASIS

5. IN THIS CASE ITS LIVER

6. Why intervention is necessary ?
• Median survival without treatment
is <8 months after disease
presentation, and with a 5-year
survival rate of 11% or less
• In cases who are operated with
free margin (>1 mm), 5-year
survival rates could be up to
40%
Liver met survey . org
5 yrs 10 yrs

7. BURDEN OF DISEASE

8. BURDEN OF DISEASE
GLOBOCAN 2018

9. BURDEN OF STAGE IV COLORECTAL METASTASIS
• 20% of patients with CRC will have
metastases at the time of diagnosis.
• More than 50% of patients with CRC
develop metastatic disease during the
course of their disease.
Leporrier J, et, al. Br J
Surg. 2006;93:46574.
Synchronous
metachronous

10. Large no of patient
15th June 2012-15th June 2017 (5 years)
CONCLUSION: FEW STUDIES ON COLORECTAL AND NO STUDIES FOUND ON SURGERY FOR STAGE 4
COLORECTAL CANCER.

11. Where are we?
Journal of Clinical and Diagnostic Research. 2018 Oct
No colorectal metastasis cases
Study period 1 yr and six months

12. FEW DATA ON COLORECTAL CANCER TREATMENT
NO AVAILABLE DATA ON SURGICAL MANAGEMENT OF CRLM
CONCLUSION

13. Where is
Europe
Between 1996 and 2011
Ten European centers

14. Where is japan
Average of 17 cases per year per institution

15. What is reason for limited cases in liver surgery?
• Liver surgery (social dogma no to go for surgery)
• Patient draining to neighbor country
• Limited HPB surgeons
• Limited centers
• Belief of liver metastasis as point of no return
 Doctors (including surgeons) refer these cases for palliation
 Oncologist do not refer for possible evaluation and operation
• Staying on conservative(NO)side of grey zones
Patient factors

16. Grey zone
NOWE ARE ON THE NO SIDE

17. How to shine this grey area?
1. MDT approach
2. Patient and tumor evaluation
3. Patient approach as per defined algorithm

18. MDT approach
• A change was
recommended in 36% of
cases, 72% of which were
major.
Oxenberg J, et, al. Ann Surg Oncol
2015
GI AND HPB SURGEON
ONCO-PATHOLOGIST
NURSE
RADIOLOGISTONCOLOGIST

19. PATIENT AND TUMOUR EVALUATION
Radiological assessment
OR
• Guidelines recommend CT scan of thorax, abdomen and pelvis for
initial workup.
• 94% vs 91% Sensitivity MRI vs CT
• So, CT scan is best initial tool.
• Sub-centimetre lesions
• Reassessment after neoadjuvant chemotherapy (when the
sensitivity of CT dropped to 77%)
• Gadoxetic contrast further increased the diagnostic confidence of MRI
to 98.3%
• So, MRI is best second tool for post NACT or for small metastasis

20. PATIENT AND
TUMOUR
EVALUATION
PET CT
• PET-CT to assess for extra-
hepatic disease (EHD).
• Significantly reduced the number
of futile operations and
prevented an unnecessary
surgery in every 6 patients.
Moulton CA, et, al. JAMA
2014

21. STAGE 4A IS OUR DIAGNOSIS
CRLM

22. Evaluation of future liver remnant
ICG
CT VOLUMETRY
• Lack of qualitative liver volume
ICG
• Its uptake impaired by
hyperbilirubinemia
• Fails to address regional variations
within the liver (Global vs Local)
9mTc-mebrofenin
hepatobiliary scintigraphy
• Provides regional
qualitative and
quantitative liver volume.
FLR
• Normal liver (24%)
• Disease liver (40%)
• Post neoadjuvant
 < 6 cycles (30%)
 >6 cycles (40%)

23. Assessing fitness of patient
Does not want surgery?

24. Collection of available information
• Fit or Unfit patient.(operable or not)
• Stage of the tumor (stage 4 A) (grey zone)
• Ruling out EHD
• Liver metastasis location, size and number. (resectable or not)
• Remnant liver assessment.
Algorithm
We all are doing this?
We all need to do this?
Referring cases for palliation
Cases do not reach to us

25. FOR FIT PATIENT

26. AlgorithmThree possible scenarios
1 2 3
Focus here

27. • metastatic liver disease in which a R0 resection can
be performed, leaving at least 20–25% of total liver
volume with adequate inflow, outflow and biliary
drainage.
• Primary tumor at stage T4,
• >4 liver metastases,
• Largest liver metastasis >5 cm in diameter, and
• Serum CEA level >5 ng/ml
High risk = more than two factors (ZHU SCORE)
Zhu D.
PLoS ONE.
2014
Patients with Fong Score 3-5 are considered “high risk”
Fong Y, et,
al. Ann Surg.
1999
The GAME score
• KRAS-mutated tumours (1 point)
• Carcinoembryonic antigen level 20ng/ml or more (1
point)
• Primary tumour lymph node metastasis (1 point)
• Tumour Burden Score between 3 and 8 (1 point) or
• TBS of 9 and over (2 points)
High-risk group (GAME score at least 4
points)
Margonis GA, et,

28. • SURGERY
• ADJUVANT CHEMOTHERAPY
FIT PATIENT

29. SURGERY
• PARENCHYMAL SPARING HEPATECTOMY
• MINOR HEPATECTOMY (<4 LIVER SEGMENTS)
• MAJOR HEPATECTOMY (>3 LIVER SEGMENTS)
• PARENCHYMAL SPARING HEPATECTOMY
• Open or laparoscopic
Fretland ÅA, et, al. Laparoscopic Versus Open Resection
for Colorectal Liver Metastases: The OSLO- COMET
Randomized Controlled Trial. Ann Surg 2018
• Resection (≥ 1 mm) is enough, extra margin
width does not add DFS/OS advantage.
Pawlik TM,. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann
Surg 2005

30. SURGERY
• PARENCHYMAL SPARING HEPATECTOMY
• MINOR HEPATECTOMY (<4 LIVER SEGMENTS)
• MAJOR HEPATECTOMY (>3 LIVER SEGMENTS)

31. Adjuvant chemotherapy
It is recommended
Two commonly used regimen
• FOLFOX
12 CYCLES
 5FU
 LEUCOVORIN
 OXALIPLATIN
• CAPOX (XELOX)
8 CYCLES
 CAPICITABINE
 OXALIPLATIN
DAY 1 AND DAY 2
FOLLOWED BY NEXT CYCLE AFTER DAY 14
Nordlinger B, et, al. (EORTC 40983): long-term results
Its chemoprotective agent
DAY 1
DAY1 - DAY14
FOLLOWED BY NEXT CYCLE AFTER DAY 21

32. NEOADJUVANT THERAPY
FIT PATIENT

33. NEOADJUVANT THERAPY
• Assessment of the natural history of disease.
• Potentially shrinks the tumour and reduces the extent of liver
resection
• Treats micro-metastases thereby lowering recurrence rate,
• Guides further therapeutic plan based on disease response to
treatment
Advantages :
Disadvantages:
• Progression of disease
• Previously resectable disease may be unresectable

34. • RANDOMISATION DONE IN 364 PATIENTS
• FRENCH STUDY
3-year progression- free survival (PFS) modestly –
42.4% compared with 33.2% in surgery-only patients, an
absolute 9.2% increase – BUT at the cost of higher
peri-operative morbidity (25% vs 16%).
• NETHERLANDS
• RESULT AWAITED
CONCLUSION: NACT is advisable for resectable cases with high risk factor

35. Regimens
12 cycles
6 cycles before operation
6 cycles after operation
• CAPOX
• FOLFOX
Alternative
• FOLFIRI
• FOLFOXIRI
NO TO ADDITION OF
• CETUXIMAB (NEW EPOC TRIAL)
• BEVACIZUMAB (PERIMAX TRIAL)
Restaging MRI or CT
3 to 4 wks after last dose
Response evaluation
Radiologic response
minor (volume reduction <33%), medium (33-66%) and major (>66%)
Metabolic response
• Progressive metabolic disease- increase in FDG tumor SUV
of greater than 25%
• Stable metabolic disease -increase in tumor SUV of less
than 25% or a decrease of less than 25%
• Partial metabolic response as a reduction greater than 25%
in tumor SUV
• Complete metabolic response as the complete resolution of
uptake within the tumor volume.
RECIST CRITERIA

36. Neoadjuvant
Re evaluation
Stable or partial response progression
Second line chemo
Third line chemo
Surgery
Plus ACT
FOLFIRI If previous FOLFOX
(vise versa)
Regorafenib and Trifluridine/tipiracil
Response
FIT PATIENT
Disappearing LM

37. Disappearing LM
CRLMs can totally vanish on imaging after neoadjuvant treatment; they were referred as
disappearing LMs (DLMs).
Incidence of DLMs after NCT is 7 to 37%
Kuhlmann K, et, al. Management of disappearing colorectal liver metastases. Eur J Surg
Oncol 2016
DLMs area should be operated
• Complete disappearance of all initial CRLMs is rare, with an incidence of 0%-6%.
• In laparotomy, macroscopic residual disease could be detected at 11%-67% DLM areas.
• DLMs were resected, microscopic residual disease was found in up to 80% of specimens.
• Leaving DLMs in-situ resulted in a local recurrence rate of 19% to 74%
Benoist S, et, al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006
Kuhlmann K, et, al. Management of disappearing colorectal liver metastases. Eur J Surg
Oncol 2016

38. R0 resection is compromised
as a result of a large tumor
burden, but FLR are adequate
R0 resection is feasible, but FLR is
inadequate in volume or quality
R0 resection is compromised as a result of a large tumor
burden, but FLR also inadequate
FIT PATIENT

39. R0 resection is compromised
as a result of a large tumor
burden, but FLR are adequate
• Neoadjuvant chemotherapy
• NACT
Plus
TARE(Trans arterial radioembolization (TARE) with micro-spheres impregnated with yttrium-90 (Y90))
Garlipp B, Gibbs P, Hazel G,
et, al. SIRFLOX trial. J Clin
Oncol. 2017
SURGERY PLUS ACT
CONTINUE
TREATMENT
FIT PATIENT
Second line chemo/third line

40. R0 resection is feasible, but FLR is
inadequate in volume or quality
PORTAL VEIN EMBOLISATION
PORTAL VEIN LIGATION
TACE (plus minus role)
TARE
APEAL( associating portal embolization and artery ligation)
Adequate FLR
SURGERY PLUS ACT
SALVAGE ALPPS
ACT
Adequate FLR
SURGERY PLUS ACT
CT
CT
FIT PATIENT

41. R0 resection is compromised as a result of a large tumor
burden, but FLR also inadequate
• Two staged hepatectomy
• ALPPS
Followed by ACT
NCT
FIT PATIENT

42. First Stage:
• Hepatectomy aims to treat all metastases of the less invaded hepatic lobe by resection or local
ablation.
• Contralateral portal vein branch percutaneous embolization or surgical ligation.
TWO STAGE HEPATECTOMY
Second Stage:
• Formal hepatectomy or resection of the involved liver.
Disease progression or recurrence
Poor performance status after the first hepatectomy are the two most frequent reasons for
not performing the second resection. This takes places in 28.1% of the
cases
Regimbeau JM, Cosse C, Kaiser G, et, al.
A LiverMetSurvey analysis. HPB (Oxford).
2017
DISADVANTAGE

43. ALPPS
Associating liver partition and portal vein ligation for stage hepatectomy
First Stage:
Ligation of the contralateral portal vein and liver parenchyma transection
Second Stage:
Completion hepatectomy.
9 studies included 657 patients with
unresectable CLM (ALPPS, n = 186 vs
TSH, n = 471).
• There was no difference in final
postoperative FLR between ALPPS
versus TSH (mean difference: 31.72,
95% CI: -27.33 to 90.77, p = 0.29).
• The kinetic growth rate was faster
with the ALPPS versus TSH (mean
difference 19.07 ml/day, 95% CI 8.12-
30.02, p = 0.0006).
• TSH had a lower overall and major
morbidity versus ALPPS (overall
morbidity: RR: 1.39, 95% CI: 1.07-1.8,
p = 0.01; I 2: 58%, p = 0.01; major
morbidity: RR: 1.57, 95% CI: 1.18-2.08,
p = 0.002; I 2: 0%, p = 0.44).
• Overall survival was comparable
following ALPPS versus TSH.
CONCLUSION:
While ALPPS may be a suitable approach for patients, the
higher morbidity and mortality should be considered
when determining the operative approach for patients with
extensive CLM.

44. NCT As conversion therapy
• An objective radiological response was achieved in
64% (range 43%-79%) patients
• 22.6% underwent macroscopically curative liver
resection (most studies reported a range of 12.5%-
45%)
• R0 resection rate was 87%.
Lam VW, et, al. A systematic review of clinical
response and survival outcomes of downsizing
systemic chemotherapy and rescue liver surgery in
patients with initially unresectable colorectal liver
metastases. Ann Surg Oncol 2012
FIT PATIENT

45. LOCOREGIONAL THERAPY IN LIVER METASTASIS
SUITABLE FOR METS NEAR TO BILIARY AND VASCULAR STRUCTURE

46. Intra-arterial therapies
• Trans-arterial chemoembolization (TACE)
• Drug-eluting bead (DEB)-TACE
• Selective internal radiation therapy (SIRT)

47. Optimal surgical sequencing for resectable synchronous disease
• Fit patient
• Burden of liver metastasis (resectable, partially resectable or unresectable)
• Symptomatic or Asymptomatic primary
Three approaches
1.Conventional (primary – chemo - mets – chemo)
2.Reverse approach (chemo – mets – chemo – primary – chemo )
3.Combined liver and primary operation.

48. Conventional treatment
Advantages:
• Avoids potential complications of the primary tumour.
Disadvantages:
• Carries significant risk of CRLM progression (less than 30%
patients will complete the whole treatment and will go for liver
resection )
Andres A, et, al. A survival analysis of the liver-first reversed management of advanced
simultaneous colorectal liver metastases: a LiverMetSurvey-based study. Ann Surg 2012

49. Reverse approach
Suitable candidates
1. Asymptomatic colon primary coexists with extensive CRLM
2. Primary tumour is a locally advanced rectal cancer (which needs
neoadjuvant chemoradiation)
Advantages
• More patients (around three quarters) could complete the whole
paradigm
Lam VW, et, al. A systematic review of a liver-first approach in patients with colorectal cancer and
synchronous colorectal liver metastases. HPB (Oxford) 2014

50. Combined liver and primary operation
Suitable patient
• Easy-to-resect primary tumours and limited hepatic disease.
5300 patients included from 30 studies.
The average length of hospital stay was six days shorter with simultaneous approach
[MD = -6.27 (95% CI: -8.20, -4.34), p < 0.001]. Long term survival was similar for the two
approaches [HR = 0.97 (95%CI: 0.88, 1.08), p = 0.601].
CONCLUSION:
In selected patients, simultaneous resection of liver metastases with colorectal resection is
associated with shorter hospital stay compared to delayed resections, without adversely
affecting perioperative morbidity or long-term survival.

51. Role of liver transplantation
Traditionally CRLM was regarded as a contraindication to liver
transplantation (LT)
In a prospective pilot study, liver transplantation
for nonresectable CLMs was performed (n = 21).
Main inclusion criteria were liver-only CLMs,
excised primary tumors, and at least 6 weeks of
chemotherapy.
• Kaplan-Meier estimates of the OS rate at 1, 3, and 5
years were 95%, 68%, and 60%, respectively.
• 35% patients remained recurrence-free at 1 year;
most of the recurrences were small slow-growing
lung metastases.
CONCLUSIONS:
OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient
group.
SECA study
Secondary cancer
Transl Gastroenterol Hepatol 2018;3:74

52. Not covered in this presentation
•Approach to local and metastatic recurrence
•Approach to metachronous lesion