Recent advances

1. Management of Patients with Primary
Colorectal Cancer and Synchronous
Liver Metastasis

2. Introduction:
 Approximately 40% of patients treated with colorectal cancer will develop liver
metastasis following treatment of primary cancer, these are termed as
Metachronous metastasis.
 Almost 15% percent of patients diagnosed with Colorectal malignancies will have
radiological evidence of Liver metastasis, these patients are said to have
Synchronous metastasis.

3. `
 Synchronous lesions are found to have poorer prognosis as compared to
Metachronous lesions, as they are known to have aggressive biological traits such
as
 Increased incidence of multiple, bilobar, large dimensional disease and hence end up
being irresectable
 Colorectal liver metastasis presenting within 1 yr of primary disease are likely to
behave biologically as synchronous lesions.
 Despite the differences, both synchronous and metachronous lesions are treated
surgically in a similar fashion.

4.  The classical strategy is sequential resection, i.e., primary tumor is resected first 
adjuvant chemotherapy  liver resection.
 In some cases reverse sequential approach is applied where liver lesion is resected
first followed by treatment of the primary
 In advanced Rectal cancers where the liver lesion is the primary cause of poor prognosis,
thereby avoiding unnecessary rectal surgery.
 This approach has shown to have survival benefits.
 These patients should be approached in a multidisciplinary manner with a team
including a surgical oncologist, medical oncologist and radiologist.

5. Selection for surgery
 Full characterization of extent and distribution of the disease is essential.
 All patients who are planned for radical treatment should undergo
 CT scan of the chest, abdomen and pelvis
 MRI dedicated for liver with contrast
 PET CT to identify extrahepatic metastasis
 In case of a rectal primary an MRI is performed.
 Untreated patients with SCLM have a five year survival of 3%
 Only surgical intervention gives possibility of long-term cure and survival ranging
between 37%-58%.

6.  Previously held criteria for inoperability such as more than 3 liver lesions, bilobar
disease and extrahepatic mets are no longer considered contra indications.
 Patients with controllable serosal disease, retroperitoneal nodal disease and even
for maximally debulking operations may even be eligible for treatment with
curative intent in 13-15% patients.
 In an era of Chemotherapy, all patients who’s primary disease can be controlled
adequately are amenable for liver resection provided there is sufficient residual
liver volume (25% of good quality liver and 40% if liver appears damaged), with
adequate inflow and outflow to support the patient in the post operative phase.

7.  The availability of Portal venous embolization, downsizing chemoRx,
Radiofrequency ablation and two stage hepatectomies have increased the
proportion of eligible patients.
 As majority of the patients will have significant medical comorbidities, which will
impact on the decision, timing and strategy of the operation, multidisciplinary
approach is essential.

8. Radiological evaluation:
MRI, PET CT
Borderline/irresectable
hepatic disease
Lower GI and Hepatobiliary
Multidisciplinary assessment
RAS testing followed by
suitable chemotherapy +/-
monoclonal agent (4-6
cycles)
Resectable hepatic lesion

9. Restaging Progression
Response Restaging
R0 resection
possible
Rectal
Margins at
risk
2nd line
chemotherapy or
palliation of
symptoms

10. Consider for
simultaneous
resection
Operation at 6 weeks
after use of
chemotherapy or
monoclonal agents
Simultaneous
resection

11. Oncological management:
 At diagnosis, patient may have a resectable disease or a borderline/irresectable
disease.
 For patients with de novo resectable disease, EORTC 40983 trial which
randomized, 364 patients with 12 cycles of perioperative FOLFOX (oxaliplatin +
fluorouracil) or surgery alone.
 This demonstrated a three year progression free survival of 8.1%, in favor of
chemotherapy.
 Overall survival though was not statistically significant.
 7% patients progressed during chemotherapy, these patients were shown to have
aggressive tumor behavior.

12. Chemotherapeutic agents
 For patients with borderline/irresectable disease receiving chemotherapy, the
speed and quality of response which is measured by dimensional, morphological
and functional changes which is correlated with probability of eventual resection
and both to PFS and OS.
 This implies that most appropriate chemotherapy should be selected which could
be either a doublet or triplet chemotherapy using a Flouropyridine backbone with
either or both of irinotecan and oxaliplatin.
 Triplet therapy is not only associated with better response but also increased
toxicity.

13. Monoclonal antibodies:
 Anti angiogenic antibody – Bevacizumab
 Anti EGFR antibodies – Cituximab or panitumumab
 These have significantly improved survival of stage IV irresectable cancers.
 Bevacizumab does not consistently improve response when used along with
cytotoxic drugs.
 Despite this controversy cytotoxic chemotherapy + Bevacizumab for patients with
RAS mutant stage IV disease is a reasonable option as it improves OS.

14.  With respect to anti EGFR therapy, extension of exon 2,3 & 4 of KRAS and NRAS
has aided further refining of the patient population who may benefit from these
agents.
 Retrospective analysis of Chemotherapy + cetuximab/panitumumab with
previously unexamined RAS mutations demonstrates that the addition of anti
EGFR therapy has significantly increased response rates for these patients.
 Hence for all patients RAS testing should be done prior to initiation of anti EGFR
therapy.

15. Operative planning:
 Preoperative assessment of pre-existing liver disease should be done.
 In addition, patient would have also received at least doublet therapy and likely ,
in addition, monoclonal Ab such as bevacizumab.
 Irinotecan can induce steatohepatitis, fibrosis or even cirrhosis.
 Oxaloplatin may lead to sinusoidal injury and intra-hepatic veno-occlusive disease.
 Hence preoperative, percutaneous biopsy of the future remnant liver should be
done

16.  An interval of 4-6 weeks should be considered before surgery following Chemo
and VEGF inhibitors.

17. Surgery:
 Liver resection is performed with a curative intent.
 Should be simultaneous whenever possible.
 If simultaneous resection is done then the primary tumor is resected first.
 If any complexity noted during surgery of the primary then the liver resection could be
deferred for a later date.
 During liver resection, things to be considered are, the use of intraoperative USG
to identify the lesion, extent and anatomical relations.
 If surgical field cannot encompass the lesion then use of RFA

18.  Steps to be considered are
 To avoid ischemia of chemo-exposed liver, inflow clamping is not done.
 Liver resection is carried out with bipolar coagulator initially followed by CUSA.
 To avoid imaging artefacts, metal clips are avoided over the resected surface.

19. Discussion:
 Standard treatment for SCLM is sequential resection.
 However there is a growing trend towards simultaneous resection.
 Applicable only in a selected group of patients
 Who are expected to have straight forwards colonic and hepatic resections.
 Where the patients performance status is of concern the simultaneous resection is inappropriate.
 Long term benefits of simultaneous resections is yet to be studied.
 The advantages though are,
 Avoiding repeat surgery
 Early onset of adjuvant therapy
 Decrease in hospital stay

20. Irresectable synchronous liver mets:
 Majority of patients presenting with colorectal mets will initially irresectable.
 Patients should undergo neoadjuvant chemo and should be restaged after
downstaging the tumor.
 12%-40% of the cases may become resectable.
 The use of monoclonal Abs increases this percentage.
 With this approach OS of 33% have been noticed, which is almost comparable with
patients with initial resectable lesions.
 There is no consensus regarding optimal management of primary tumor in patients
with irresectable disease.
 For the management of which nature & severity of primary disease should be taken
into consideration .
 Treatment is aimed at improvement of the QOL, control of symptoms and prolong the
OS.

21.  Patients with Rectal Cancers with better performance score should undergo
Chemoradiation when there is a high risk of obstruction or likelihood of
developing debilitating pelvic symptoms.
 Otherwise, following options are considered: defunctioning colostomy, primary
tumor resection, stenting, chemo, chemoradiation or laser recanalization to
achieve effective palliation.

22. Adjunctive Treatments
 Hepatic arterial infusion of chemo + Systemic chemo (OR) Intra-arterial infusion of
Yttrium 90 microspheres + systemic chemo are found to be effective in
Irresectable diseae.
 Stereotactic Body RT (SBRT) has been shown to have low toxicity and can prevent
progression in patients with limited hepatic disease and presently thought to have
implications in irresectable liver mets too.

23. Extra-hepatic metastasis:
 Until recently extrahepatic metastasis was considered to be absolute
contraindication to surgery.
 28-40% five year survival is reported in patients where extra-hepatic disease is
controlled by systemic or surgical treatment.

24. Follow Up:
 Though patient undergoes a liver resection with curative intent, most of them
develop recurrence in the liver within 2 years.
 Close surveillance of these patients as with earlier detection will be amenable to
surgery.

25.  Thank You…