Cure in metastatic colorectal cancer

Programme details

Speaker

Discussion

Introduction

• Liver metastasis is commonest form of metastasis in CRC
• 35-55% of patients with colorectal cancer will develop hepatic metastasis
• Only 30% will have metastases confined to the liver – potential candidates for resection
• Untreated hepatic metastasis – dismal survival
• Median survival 6 – 12 months
• Median survival with chemotherapy: 12 – 24 months (deemed resectable retrospectively)

Types of liver metastasis

• Synchronous
  • Diagnosed at the same time as the CRC or 3-6 months after resection
  • 20-30% of patients with CRC
• Metachronous

Aiming at cure​

• Surgical resection offers cure with 40% 5-year survival
• Only few resectable
• Tumour biology most important prognostic factor
• Pushing forward the frontiers of resection
• Personalized approach

Need of biopsy confirmation

• Need depends of clinical picture
• Needle tract seeding – very low incidence
• Confirmatory imaging, rising markers, histopathology from primary– no need

Rationale of resection

• 5-year survival following resection - 50-60%
• Operative mortalitiy <1% (high volume centers)
• 65% will have a recurrence at 5 years
• Liver resection is the only treatment associated with long term survival

Work up and staging

• Surveillance
• Triple phase CECT
  • Hypovascular and hypodense in venous phase
• MRI
  • Characterization of subtle and indeterminate lesions; steatotic liver; disappearing metastasis
• PET – identification of extrahepatic disease
  • Recent RCT in metachronous lesions did not show significant difference in resectability or survival

Goals of preoperative imaging​

• Identify the number and distribution of hepatic lesions
• Proximity to major vascular (e.g., hepatic arteries, portal veins and inferior vena cava) as well as biliary structures
• Idnetify extrahepatic disease
• Calculate future liver remnant

Extrahepatic Disease​

• Good survival in highly selected cases
• Sites amenable: lung and ovarian metastases, locoregional recurrences of the primary tumor, portal lymph node, limited peritoneal disease
• 5-yr survival for patients with concomitant EHD were 26% compared with 49% for those without (P < 0.001)
• 95% ultimately recurred; median time to recurrence was 9 months

Prognostic indicators

• Stage, nodal status of the primary CRC
• Differentiation of the primary CRC
• Disease-free interval from primary CRC to development of hepatic metastases
• Number and distribution of the hepatic metastases
• Preoperative CEA
• Presence ofextrahepatic disease
• Positive resection margin

Clinical Risk Score​

Preoperarive factors - 1 Point assigned for each

• Node-positive primary
• Disease-free interval from primary to metastases less than 12 months
• More than one hepatic metastases
• Largest hepatic metastases greater than 5 cm
• CEA level greater than 200 ng/ml

Resectability

• Ability to achieve R0 resection (including resectable extra hepatic disease)
• Sufficient future liver remnant
• Patient’s tolerance to major surgery
• Resection for ≥ 4 metastases is no longer a contraindication
  • 5-year survival rate of 23-51%
  • High recurrence rates

Future Liver Remnant​

• Normal liver: 20-30% of total liver volume​

• Steatosis or steatohepatitis: 30-40%
• Cirrhosis: 40-50%

Strategies to increase FLR

• Parenchyma sparing and segmental resections
• Portal vein embolization
• Two stage resections
• Combination of liver directed therapies
  • Surgery, ablation, SBRT
• ALPPS

Portal Vein Embolization (PVE)

• 20% of patients requiring hepatectomy have adequate FLR
• Insufficient remnant liver volume is the main cause
• PVE by increasing FLR helps in improving surgical candidacy
• Healthy liver regenerates at rates of 12-21 cm³/d at 2 weeks, 11cm³/d at 4 weeks, and 6 cm³/d at 32 days after PVE
• Cirrhotic livers, in contrast, regenerate at a rate of 9 cm³/d at 2 weeks

Resection strategies

• Simultaneous
• Sequential bowel first
• Sequential liver first

Review of scientific evidence

• Non randomized studies
• Important selection bias
• Sequential in patients with greater liver disease
• No clear evidence

Sequential liver first

• Asymptomatic primary
• Unresectable or borderline resectable liver lesion
• Doubtful resectable extrahepatic disease
• Liver lesions at risk of becoming unresectable if they progress after resection of primary
• Complex surgery of the CRC and liver lesion

Sequential colon first

• Complicated primary

Simultaneous surgery

• Good general condition patient who can withstand both procedure​

• High probability of R0 in both fields
• Sufficient liver remnant
• No extrahepatic disease
• Uncomplicated primary
• Do not associate complex surgeries in the two fields

Extensive bilobar metastases / Unresectable metastasis

• Inadequate FLR
• MRI more sensitive than CT for sub-centimetre lesions, reassessment after NACT and in fatty liver
• Conversion therapy - potentially curative resection
• Combination of liver directed therapies
  • Surgery, ablation, radiation
  • Staged surgery

Surgical Margins

• Positive margins are associated with higher risk of recurrence and decreased overall survival
• Classically 1 cm margin is sought
• Negative margins irrespective of width is associated with favourable long term survival
• R1 resection had a median survival of 24 months compared with 46 months for patients who underwent an R0 resection

Conversion chemotherapy

• Initially unresectable disease
• 10-60% of such patients have a sufficient objective response to permit R0 resection
• HAI chemotherapy has shown promising results
• Resected patients have outcomes similar to those of patients who were initially resectable disease
• Five-year survival rates average 30 to 35 percent

Effect of chemotherapy​

• Shrinking margin
  • Margin that is produced by shrinkage of metastasis is likely tumor free
• Disappearing lesion

  • Complete response rate; 4 – 9%​

  • Residual microscopic disease in 80%​

  • Hinders identification and resection​

  • Optimal to remove all the liver that ever contained tumor​

• Goal is not to treat to 'maximal' effect, but rather for a defined time course (neoadjuvant) or until the disease is resectable (conversion therapy)

Liver Toxicity

• Oxaliplatin: hepatic sinusoidal obstruction
• Irinotecan: steatosis / steatohepatitis
• Higher perioperative infectious complications and 90-day mortality has been reported
• >12 weeks of chemotherapy, or resection ≤ 4 weeks after stopping chemotherapy - more complications, higher reoperation rates and longer hospital stay

Combined Local Therapy

• Complimentary approach
• Extensive disease: larger lesions can be resected, while smaller ones can be ablated
• Combining hepatic resection with ablative techniques is well-tolerated with perioperative complications (< 10%) and mortality comparable to resection alone

Repeat hepatectomy

• About two thirds of cases recur
• ∼5% of these are candidates for a second liver resection
• Operative mortality and postoperative morbidity similar tothat of first hepatectomy
• 5-year survival of 44%

Peritoneal metastasis

• In selected patients with peritoneal metastasis, complete cytoreductive surgery and HIPEC may provide prolonged survival when carried out in experienced high-volume centres
• Depends on the extent of peritoneal dissemination and is scored using the peritoneal cancer index (PCI), which is the main prognostic factor
• Particularly effective in patients with low-volume peritoneal disease (a PCI <12 is often suggested) and no evidence of systemic disease