colorectal liver metastasis management

1. Dr. MANISH KAUSHIK
MBBS, DNB (GENERAL SURGERY),
DrNB (T) –SURGICAL ONCOLOGY.
COLORECTAL LIVER
METASTASES MANAGEMENT

2.  Why intention to cure in stage IV disease?
 Role of PET CT scan?
 STRATEGY-
 SYNCHRONOUS VS METACHRONOUS
 LIVER F/b RECTUM OR RECTUM f/b LIVER OR RECTUM +
LIVER
 PERIOP CT
 WHAT IF cCR – disappearing metastases ?
 Staged liver resection – what if failure to achieve 2nd stage /
disease progression after 1st stage ?

3.  Globocan 2020
 Incidence rank : Colon (4th), Rectum (7th)
 About 20-25 % patients with colorectal cancer have liver mets at
diagnosis, ~ 50 % will develop later- mostly to the liver.
 Untreated - <8 months median survival
 Curative resection: 5 y OS (50-60 %), 10 Y OS (25 %). (Tzeng CW.
J Gastrointest Surg. 2013)
 Unfortunately – only 15-20 % are amenable to curative resection.

5. Synchrous : Metachronous
 Synchrous – diagnosed before or at the time of
diagnosis or surgery for primary ds.
 Metachronous – after the surrgery / treatment
of primary tumour.
 Some studies – metastases discovered upto 6
months after the treatment of primaty tumour-
synchronous

6. Diagnosis
 Synchronous – imaging for staging work-up
 Metachronous- usually asymptomatic
 CRC f/u- Sr. CEA, CECT CHEST + WA,
Colonoscopy
 NCCN - CEA- 3-6 MONTHLY FOR FIRST 3 YRS
THEN 6 MONTHLY IN 4-5 YRS.
 CECT ANNUALY FOR 5 YRS (ASCO- 3 YEARS)
 COLONOSCOPY- 1YR,3YR,5YR THEN EVERY 5
YRS.

7. Assessment
 Assessment is aimed at determining the resectability, the
operability, and the response to primary systemic therapy.
 Operability is assessed by general comorbidity status of the patient
and aggressiveness of the disease biology.
 Poor disease biology may be anticipated from a short disease-free
interval (from CRC to CRLM), rapid progression of CRLM, or
progression while on systemic therapy. Aggressive biology does not
preclude surgery with curative intent, but indicate inferior outcome
after surgery.
 Resectability is assessed by determining the hepatic tumor
burden, future liver remnant, and extent of extra-hepatic disease
(EHD).

8. WORK UP
 SR CEA
 CECT W/A + CHEST- Hypovascular visualised
as hypodense on the portovenous phase(sn
73,sp 96%)
 MRI – useful in steatotic liver or assessment
post CT.
 RAS MUTATION

9. JAMA May 14, 2014 Volume 311, Number 18
Among patients with potentially resectable hepatic metastases of colorectal adenocarcinoma,
the use of PET-CT compared with CT alone did not result in frequent change in surgical
management. These findings raise questions about the value of PET-CT scans in this setting.

10. The Oncologist 2012;17:1225–1239 EGOSLIM

11. Surgical management of CRLM
British Journal of Surgery 2010

12. The Oncosurgery Approach to Managing Liver Metastases from
Colorectal Cancer: A Multidisciplinary International Consensus
EGOSLIM (EXPERT GROUP ON ONCOSURGERY
MANAGEMENT OF LIVER METASTASES) GROUP 2012

13.  Liver resection surgery has evolved markedly
 Knowledge of anatomy / adavnces in surgical technique
 Better imaging modalities
 Exepertise
 Multimodality approach
 Modern chemotherapy
 Targeted approach
 Excellent results in terms of safety (acceptable mortality
and morbidity) and efficacy (5 YS OS ~ 50%)

14. Resectability
 Probability of achieving a negative margin and
same time ensuring a sufficient functional liver
remmant.

16. Technical aspects
 Ability to obtain R0 resection
 Adequate postop liver volume and function
 At least 20 % of TLV with normal function
 30% if any CT associated liver injury
 40% if any hepatic fibrosis or cirrhosis from any cause
 At least 2 functional contiguous segments with intact
portal and arterial inflow , venous outflow and biliary
drainage

17.  Limited extrahepatic disease that is resectable
 No portal lyphadenopathy or multiple
metastatic sites
 Limited progression if received preop CT
 No development of new hepatic lesions
 Medically fit to undergo a major surgery

18. VOLUMETRIC ASSESSMENT
OF LIVER REMNANT
 Extent of liver resection (i.e., the number of
segments resected) is strongly correlated with
risk of postoperative liver insufficiency.
 Although this is intuitive and easily assessed,
it is actually the volume of liver remaining (i.e.,
the FLR) that is more predictive of outcome
and thus critical to accurately measure.

19. Assessment
 Formal measurement of liver volumes is most
commonly accomplished by using computed
tomography (CT) or magnetic resonance imaging
(MRI).
 Cross-sectional images obtained from either of
these modalities are sequentially marked with the
planned resection line, following which the surface
area is derived and multiplied by the slice
thickness.

20.  Due to the variability in total liver size based on patient body habitus, the
FLR volume is typically expressed as a ratio of FLR to TLV. Although the
measurement of the FLR is fairly standard, there are several variations to
calculate the TLV.
 the tumor volume does not contribute to hepatic function and so provides a
falsely elevated value of the TLV and hence a falsely diminished anticipated
FLR ratio. Manually measuring the volume of each tumor and subtracting it
from the TLV to yield the total functioning liver volume can correct this but is
very labor intensive and prone to measurement error (Kubota et al, 1997).
The direct measurement technique of TLV is further limited by the fact that
the parenchyma beyond tumors may be abnormal due to biliary or vascular
obstruction.
 These limitations typically do not apply to the assessment of the FLR,
which usually does not contain tumors.

21.  An alternative method referred to as the total estimated liver
volume (TELV) was first proposed by Urata and colleagues.
 TELV = −794 + 1267 × BSA, has been extensively studied
and
 found to yield a precise estimate of TLV across institutions
with different CT scanners and three-dimensional
reconstruction techniques (Vauthey et al, 2002). When the
TELV is used as the denominator to calculate the FLR ratio
(i.e., FLR/TELV), the resultant ratio is referred to as the
standardized FLR (sFLR).

22.  TELV (i.e., sFLR) is a better measure of
postoperative hepatic insufficiency risk.
 Over the past several years, a number of more
sophisticated software packages have been
developed to simplify the process of volumetric
assessment.

23. CT Volumetry
• Presently, CT volumetry the most often used imaging method to determine
the sfatey of liver resection.
• Three dimensional CT software
• Residual liver volume (RLV) = Total Liver volume – resected liver volume is
calculated by subtracting the resected liver volume from the total liver
volume (TLV)
• Hepatectomy is considered safe if the RLV/TLV ratio is greater than 25%-30%.
• For living donor liver transplantation, the volume of the transplanted donor
liver should be greater than 30%-35% of the volume of the recipient liver.
• A margin of 40% is taken into account in patients with diseased liver.

24. CT Volumetry
• Remember, liver volume is not equal to liver function.
• CT volumetry is used for preoperative calculations of the volume
of resected livers, but does not demonstrate the effects of
diseased liver parenchyma on liver function.
• As CT only shows the anatomic form and the volume of the liver,
liver biopsy is required to assess donor liver function before
living donor liver transplantation.
• Moreover, the evaluation of liver function before liver surgery is
dependent on the combination of the results of CT volumetry
with those of other liver function test

25.  Anatomic distribution of disease and FLR are two most important
factors to be considered for successful outcome.
 Parenchyma sparing nonanatomical resections are associated with
lower morbidity (34 vs 25 %) and post op liver failure (2 vs 7%).
 Major liver resections have much highr risk of mortality (8.3 vs 1.4
%).
 Sparing of hepatic parenchyma also increases salvage options for
patients who recur in the liver after initial resection.

26. Strategies to Improve
Resectability
 only about 20–30% of CRLM patients are deemed resectable
 presence of multiple, bilobar tumors that would preclude primary surgery because of
the risk of POLF resulting from an inadequate FLR.
 Several liver volume remodeling strategies have been developed to improve
resectability in such cases.
 Portal venous embolization (PVE), usually performed percutaneously, is themost
commonly adopted technique.
 PVL-can produce a similar degree of liver hypertrophy but more invasive nature.
 ALPPS-Associating liver partition and portal vein ligation for staged hepatectomy -
inducing faster and greater liver hypertrophy by combining in situ splitting of the liver
with PVE.
 More complete vascular isolation is postulated to produce rapid and increased liver
hypertrophy. In a systematic review, the median rise in FLR was reported to be 65–
110.3%. However, it is associated with higher morbidity and mortality rates.

27. TSH
 Useful when large tumor volume or bilobar distribution of disease
and FLR is likely tobeinadequate.
 The first stage involves surgery to resect (± ablation) all lesions in
the FLR (usually left lobe). PVL (opposite lobe)during the first stage
of surgery or an post op PVE is performed to induce increase in
FLR.
 Reassessment is done by liver volumetry, 4 weeks after the
procedure.
 Dynamic measures of liver hypertrophy, such as the degree of
hypertrophy (DH), and the kinetic growth rate (KGR) are considered
important in the assessment. The acceptable criteria for a safe liver
resection include DH > 5%, and KGR > 2%/week, apart from a safe
FLR.
 All remaining CRLM are resected in the second stage of surgery.

28. Conversion CT
 Approximately 70–80% patients are unresectable
presentation
 As R0 resection is associated with a better survival, the goal
is to make unresectable CRLMs resectable.
 This can be achieved through systemic therapy (oxaliplatin-
or irinotecan-based chemotherapy with or without targeted
agents such as bevacizumab or cetuximab), along with liver
volume remodeling approaches.
 Conversion rates depend on the type and duration of
systemic therapy, anatomic extent of CRLMs, and definition
of resectability and reportedly vary from 6 to 38% .

29.  In an analysis of 10,940 patients undergoing
resection for CRLM from LiverMetSurvey
registry,
 initially unresectable CRLM patients
undergoing R0 resection after conversion
chemotherapy had a poorer survival than in
upfront resectable CRLM
 the outcome was much better than those who
were not resected

30. The Oncosurgery Approach to Managing Liver Metastases from
Colorectal Cancer: A Multidisciplinary International Consensus
EGOSLIM (EXPERT GROUP ON ONCOSURGERY
MANAGEMENT OF LIVER METASTASES) GROUP 2012

31. Disappearing Colorectal Liver
Metastases
 5–25% of patients are reported to have complete
radiological dissolution of CRLMs
 correlates poorly with complete pathological
response (cPR). 25 to 45% of patients reported to
have cRR show the presence of microscopic
disease at exploration
 non-resection of DCRLM is associated with
significantly higher incidence of local recurrence

32.  MRI is more accurate in evaluating CRLMs after
chemotherapy.
 Adequate mobilization, surgical exploration, and use of IOUS
can help in intraoperative detection of DCRLM.
 Pre-systemic therapy placement of a fiduciary is helpful in
patients at risk of developing DCRLM (small lesions).
 all presystemic therapy CRLM sites should be resected.
 However, if it involves complex resections, a period of
observation or resection of all macroscopic sites along with
adjuvant systemic or hepatic artery chemotherapy .

33.  there is a role for resection in CRLM with limited
EHD, provided an R0 resection is achieved.
 2308 CRLM patients with EHD, it was reported
that resection of CRLM with lung EHD resulted in
a 3- and a 5- year overall survival of 58% and
26%, respectively.
 For peritoneal EHD, 3- and 5-year survival rates
were 37% and 17%, while those for lymph node
EHD were 35% and 15%, respectively

35. Synchronous Colorectal Liver
Metastases
 Three strategies are described in this context.
 Primary-first or the classic approach. This involves
resection of the primary, followed by chemotherapy,
followed by hepatic resection.
 Liver-first or reverse approach involves initial
chemotherapy, followed by hepatic resection, followed by
resection of the primary.
 Simultaneous or combined approach offers the
benefit of a single surgery

36. Primary-first or the classic approach
 Advantages-
 (a) more reliable chemotherapy delivery,
 (b) disease progression during chemotherapy indicates adverse biology and
obviates unnecessary liver resection,
 (c) chemo-responsiveness may be assessed in vivo
 (d) as primary site is the source of most metastases, its removal lessens the risks
of further metastasis.
 Disadvantages-
 chemotherapy-associated liver injury,
 disappearing CRLM
 progression of CRLM
 Surgical complications may cause delay in institution of chemotherapy.

37. Liver-first or reverse approach
 concept that the liver disease is the
determinant in the outcome in CRLM.
 Cannot be used when primary is symptomatic
and needs urgent attention– ie –
obstruction,bleeding.

38. Simultaneous or combined approach
 Benefits of single surgery
 Prevent disease progression during waiting
period
 favored in low volume liver disease with the
primary presenting in a non-emergency
situation.
 Not suitable- large disease burden either
primary site or liver, poor PS.

39. Chemotherapy for CRLM
 Metastatic disease warrants systemic therapy as a
key therapy.
 Neoadjuvant CT (Upfront resectable)
 Conversion CT (Upfront unresectable)
 Adjuvant CT
 Even after an R0 resection, approximately 70% of
patients will have recurrence
 Hence adjuvant therapy as a means to reduce
recurrence

40. Neoadjuvant Chemotherapy in Upfront
Resectable CRLM
 Reduction of CRLM size leading to ease of surgery and less
hepatic tissue loss
 Chemoresponsiveness can be assessed before surgery
 Patients who progress during chemotherapy, unnecessary
surgery may be avoided
 Micrometastases may be treated early.
 Neoadjuvant chemotherapy has been reported as an
important predictor to outcome
 Disadvantages- such as delay in surgery, chemotherapy-
associated liver injury, and disappearing CRLM

41.  The EORTC 40983 trial (2008) , randomized
phase 3 trial comparing periop CT FOLFOX4
with surgery alone in 364 patients with
resectable CRLM, shown significant increment
in PFS in favor of periop CT but no significant
differences in long term overall survival
between the two treatment arms .
 Postop morbidity was higher in CT + Surgery

42. Chemotherapy-Related Liver
Injury
 Preoperative chemotherapy can produce liver-
specific toxicities.
 Chemotherapy-induced hepatotoxic effects
sustained by non-tumor-bearing liver
parenchyma are collectively known as CALI.

43.  Vauthey et al. enunciated the principles regarding perioperative
chemotherapy in CRLM:
 1) Pre-liver resection chemotherapy should not extend beyond 2–3
months, unless required for conversion to resectability.
 2) Benefit from repeat chemotherapy within 1 year of prior
administration is not established.
 3) Chemotherapy protocol should be based on the status of the liver
parenchyma. Irinotecan should be avoided in case of pre-
existing steatosis and oxaliplatin in case of splenomegaly.
 4) Bevacizumab may have a protective action against oxaliplatin-
induced SOS. Aspirin may have a similar action.

44. Targeted therapy
 EGFR inhibitors – cetuximab , panitumumab
 Anti angiogenesis- Bevacizumab
 Reduces the number and size of unresectable
lesions and allows rescue of 15-30 % of
patients, bringing them to surgery.

45. Adjuncts to resection
 Poor PS
 Small centrally located tumours that require
removal of significant normal hepatic
parenchyma.
 Palliative setting
 As conversion therapy

46.  Systemic therapy – CT +/- Targeted agents
 Ablative – RFA, MICROWAVE ,IEP
 SBRT
 Radioembolization (Y90 SIRT)
 Isolated hepatic artery perfusion
 TACE-DEBIRI (drug eluting beads-preloaded with
irinotecan)

47. Management of Recurrent CRLM
 As previously mentioned, 60-70 % of CRLM patients
undergoing hepatectomy develop recurrence.
 Treatment options in this scenario include repeat resection,
other locoregional therapies, and/or chemotherapy.
 Repeat resections are possible in approximately 10–15% of
recurrent CRLM patients , in one study (Lenhart DK et al.)
upto 27 %.
 similar R0 resection rates and morbidity-mortality profile to
primary resections.
 Repeat R0 is associated with upto 50 % 5 yr survival rates.

48.  Thank you.