Nonsurgical approach to the treatment of liver metastases

Non-surgical approach to the treatment of liver metastases Dr Evan Dyer Austin Health

Liver metastases § 15 -20% of patients at diagnosis § 25% develop metastases following resection of primary § Median survival untreated <12 months § Surgical resection - 25 -50% 5 year survival

Local/regional treatments and Systemic chemotherapy

Local/regional strategies

Local/regional strategies § § § § Radio frequency ablation Cryotherapy Microwave Ablation Laser ablation Hepatic intra-arterial chemotherapy Selective internal radiation therapy High intensity focused ultrasound Percutaneous ethanol/acetic acid injection

Local/regional treatments § Suitable for patients who are not candidates for curative resection § Less morbid alternative to surgical resection in high risk patients § Attempts to cure patients with metastatic disease isolated to the liver in some cases

Radiofrequency ablation § § Most widely used method High frequency current creates frictional heating Causes hyperthermic coagulative necrosis Can be performed percutaneously or via laparotomy and laparoscopy § Transcutaneous or intraoperative U/S to guide needle placement § Hepatic inflow occlusion facilitates RFA of large, hypervascular tumours

Radiofrequency ablation § Can be used for metastases close to vessels but not bile ducts § Low complication rate § Widely applied to patients with liver mets § No evidence of extrahepatic disease (except some neuroendocrine tumours)

Radiofrequency ablation § 50% patients progression free at 14 months (de Baere et al 2000, 100 cases) § Three year follow up of 117 patients (179 lesions), Solbiati et al 2001 – Local recurrence 33% (18 mo) – New lesions 66% – 46% three year survival – 50% disease free at 12 months

Radiofrequency ablation Disadvantages § Heat sink effect of large vessels near tumour § Complication 3 -7% – Bleeding – Abscess – Biliary 1% (cholecystitis/fistula)

Pre RFA C-

Pre RFA C+ Arterial

Pre RFA C+ Portal Venous

Post RFA C-

Post RFA C+ Arterial

Post RFA C+ Portal Venous

Pre RFA C+ Portal Venous

Post RFA C+ Portal Venous

Cryotherapy § Use of low temperature for tumour destruction § Suitable for tumours < 5 cm and multiple tumours § Zone of necrosis 3 -5 cm § May be useful with incomplete resection

Cryotherapy § § Performed at open surgery with U/S guide Freeze thaw cycles Follow up with CT Results – – 2 year survival to 62% (BJS Review) Median survival 24 -30 months § Ravikumar 1991 – – – 24 Patients 29% disease free at 2 years <10% recurrence at treatment site

Cryotherapy - disadvantages § § Non specific tissue damage ? True margin of tumour Requires laparotomy Complications – Bleeding – Thrombocytopaenia – Cold injury to normal tissues/hypothermia – Cryoshock

Microwave coagulation § Coagulates liver by agitation of water molecules causing frictional heating § Needle placed under ultrasound control § Survival rates similar to resection § Principally used in HCC § Small trials show disease free survival of 13 months and median survival 24 mo (Shibata et al 2000)

Laser ablation § § § Placement of laser fibres into tumour Causes lethal thermal injury to tumour cells Interaction between photons and chromophores (eg Hb, cytochrome pigments) § Unable to achieve large volumes of tumour necrosis

Laser ablation § Local control 40 – 75% § 30% 5 year survival

Hepatic intra-arterial chemotherapy § Tumours not suited to resection or local ablation § Adjuvant treatment post resection § Principles – High levels of rapidly metabolised drug – Macrometastases derive blood supply from hepatic artery – Percutaneous catheter or implantable pump

Hepatic intra-arterial chemotherapy § Technique – Placement of catheter to allow bilobar perfusion without chemotherapy to stomach/bowel – Angiogram pre-op – Laparotomy – Cannulation of gastroduodenal artery – Perfusion checked with Fluorescein/Woods lamp – Post op Tc-99 m scan

Hepatic intra-arterial chemotherapy § Studies show superior response rates but no survival advantage in colorectal cancer § Kemeny et al, Increased 2 year survival (86 v’s 72%) and freedom from disease (90 v’s 60%) § Explanation – Systemic disease – Toxicity leading to cessation of therapy – Surgical complications

Hepatic intra-arterial chemotherapy Complications § § § Arterial injury/thrombosis Incomplete or misperfusion Inflammation/ulceration stomach or duodenum § Biliary toxicity/sclerosis § Infection

Selective internal radiation therapy § § Labelled biocompatible microspheres 20 -40µm diameter Used in conjunction with chemotherapy Labelled 111 In-Octreotide used for neuroendocrine tumours

Selective internal radiation therapy § Results controlled trial 74 patients (Gray et al 2001) – Better response rate – Increased median time to progression – ? survival benefit

Selective internal radiation therapy § Drawbacks – Requires two angiograms – Nuclear medicine – Significant coordination between oncology/nuclear medicine/radiology

High intensity focused ultrasound § Use of ultrasound waves to produce heat § “Magnifying Glass” principle to focus in on lesion § Requires monitoring by MRI § Small tumours only

Percutaneous injection § Typically used for small hepatocellular tumours § Poor response with other histologies § Not an appropriate therapy for colorectal metastases

Systemic Chemotherapy § § § § 5 -Fluorouracil Leucovorin Capecitabine Irinotecan Oxaliplatin Combinations Other agents Future directions

Systemic chemotherapy § 30 -40% have locally advanced or metastatic disease at time of diagnosis § Treatment is palliative § Most effective single agents are 5 -FU, Irinotecan and oxaliplatin § Increases median and disease free survival

Systemic chemotherapy § 5 -FU – Used for 40 years – Impairs DNA and RNA synthesis – Rapidly metabolised – Most effective in combination

Systemic chemotherapy § 5 -FU and Leucovorin – Enhanced efficacy of 5 -FU – Interact with enzyme (thymidylate synthetase) resulting in prolonged inhibition by 5 -FU – Meta-analysis shows increased response rates, best with infusional 5 -FU – Weekly treatment has less toxicity than monthly regimens

Systemic chemotherapy § Capecitabine – Oral agent converted to 5 -FU once absorbed – Enhanced selectivity to tumour cells – Higher response rates but same time to progression and median survival – Less diarrhoea/stomatitis/neutropaenia – Approved for first line use by US FDA

Systemic chemotherapy § Irinotecan – Topoisomerase I inhibitor – Clinical benefit after 5 -FU failure – Increased one year survival compared to best supportive care – Diarrhoea is dose limiting side effect

Systemic chemotherapy § Irinotecan + 5 -FU + Leucovorin – 49% response rate v’s 31% for dual therapy – Increased time to progression and survival – Results seen in two trials

Systemic chemotherapy § Oxaliplatin – Causes inter- and intra- strand DNA cross links – Prevents replication/transcription – Second line treament – Sensory neuropathy and cold induced oesophageal dysaesthesia are dose limiting side effects – As single agent 20 – 25% response rate

Systemic chemotherapy § Oxaliplatin + 5 -FU + leucovorin – Preliminary results suggest superior efficacy other triple regimens – 1 st or 2 nd line therapy – No significant proven benefit as 2 nd line treatment – Unexpectedly high rates of toxicity (diarrhoea 20%, neutropaenia 39% and infection 13%. US Intergroup study) – Chronomodulation may improve response

Systemic chemotherapy § Trials underway (EORTC) comparing triple therapy pre +/- post surgery and surgery alone § Recruiting 330 patients 2000 -3 § Median follow up five years

Systemic chemotherapy § Other agents – Raltitrexed: Folate analogue, poorer profile than 5 -FU – Nitrosoureas, mitomycin C: Minimally active – Methotrexate, lomustine, vincristine – partial response

Systemic chemotherapy § Future directions – Targeted monoclonal therapies – Investigation of p 53, ras mutations, growth factors and their role in colorectal cancer – Vaccines – Signalling pathways

Summary § Long term prognosis remains poor § Short term prolongation of survival with palliative treatments § Interstitial ablative techniques show promise, are feasible and reasonably safe § Triple therapy most effective