Management of Patients with Primary Colorectal Cancer and Synchronous Liver Metastasis

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.

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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.

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.

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%.

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.

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.

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

Restaging Progression

Response Restaging

R0 resection possible

Rectal Margins at

risk

2nd line chemotherapy or

palliation of symptoms

Consider for simultaneous

resection

Operation at 6 weeks after use of

chemotherapy or monoclonal agents

Simultaneous resection

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.

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.

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.

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.

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

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

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

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.

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

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.

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.

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.

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.

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.

Thank You…