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The topics of this lecture: The latest changes in surgery of liver metastatic colorectal cancer. Preoperative evaluation of the patient with hepatic metastases Treatment of liver metastatic colorectal cancer –Surgical, chemotherapy and biological.
General Information • Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. • CRC is the second-most common cause of cancer death in western countries.
In approximately 50% of patients with CRC liver metastatic, the metastatic disease is confined to the liver. • The liver is the most frequent site of metastasis in CRC, both at the time of diagnosis (20–25% of cases) or after an apparently radical surgery on the primary tumor (40% of cases).
Overall survival in advanced colorectal cancer 1928-1998 100 1943 First hepatectomy for colorectal liver metastasis 1957 Introduction of 5-fluorouracil % surviving 50 Wider acceptance of role of liver surgery 1928 1988 1998 3% 0% 0 <1% 0 1 2 3 4 5 Years after diagnosis of colorectal metastases Rougier P et al. Brit J Surg 1995
The Benefits and Side effects of Surgery • Recent reports- 5 years overall survival >28%. • Low mortality-1.5% (high volume), and 9.6% (low volume) but higher morbidity- 15-30% : hemorrhage, abscess, bile leaks, hepatic failure.
Hepatic resection for colorectal metastases, limited to the liver, has become the standard of care. • Surgery currently remains the only potentially curative therapy.
“Defining Resectability” • Criteria for surgery • Imaging.
Old approach criteria for surgery(1989, Steele et al): • Less then four lesions in the same lobe. • Maximum lesion dimensions<5cm. • Non metachornous. • Absence of extra-hepatic spread. • More then 1 cm margin of healthy liver tissue • Adequate liver remnant. • Radical resection(R0).
Current approach for liver surgery • New approach criteria for surgery(2006,Vauthey et al): • Complete Radical resection(less then 1cm margin). • Preservation of two adjacent liver segments. • adequate vascular inflow and outflow and biliary drainage can be preserved • Future liver remnant(total volume>20%). • Aggressive approach • More then one hepatectomy • Resecting metastases in other sites as well(lungs, adrenal etc…)
Contra-indications: • Radiographic evidence of involvement of the common hepatic artery, common hepatic or common bile duct, or main portal vein • Extensive liver involvement (>70 percent, more than six segments, or involvement of all three hepatic veins) • Inadequate predicted post resection functional hepatic reserve
Liver Remnant Volume Normal Underlying Liver 20% of TLV High Dose Chemotherapy 30% of TLV Chronic Liver Disease 40% of TLV Abdalla, Arch Surg2002 Vauthey, Ann Surg2004 Kubota, Hepatology1997 Azoulay, Ann Surg2000 Azoulay, Ann Surg2000 Adam, Ann Surg2004
Preoperative portal vein embolization • Minimized the postoperative mortality- preserving a liver remnant that is >20% of the total liver volume. • pre-operative portal vein embolization (PVE) to initiate compensatory hypertrophy of the future remnant liver. • Atrophy of embolized lobe. • Hypertrophy of non embolized lobe- Increasing Remnant liver. • More potential surgical candidates
Imaging – CT • CT is the staging modality most widely used in CRC • Widespread availability and relatively low cost in comparison with MRI or PET/CT. • In a study with surgically proven liver lesions, a sensitivityof 69% to 73% and a specificity of 86% to 91% was shown.* • Limitations: steatosis, lesions smaller than 1 cm, Hemangiomas . *Kamel et el.Jcomput 2003, Kinkel et el. Radiology 2002, Bhattacharjya et al .Br J Surg. 2004.
Imaging – FDG-PET/CT • Evaluation of patients with known or suspected recurrent colorectal cancer. • Most sensitive method for detecting extra-hepatic disease in patients with CLM . • Alters surgical management in 23% to 29% of patients. • Measures the responsiveness of the tumor to preoperative treatment. • For hepatic lesions compared with CT, it has a Sensitivity - 91–100 % and Specificity- 75-100% (Patel S et el. Ann Surg 2011). • Limitations: Correlation of pathological response and metabolic response , detecting lesions smaller than 1 cm, expansive.
Imaging – MRI • Sensitivity 81.1% and specificity of 97.2%. • mangafodipirtrisodium imaging has a sensitivity of 100%, a specificity of 92%. • Better sensitivity with patients that have steatosis, lesions smaller than 1cm. • Best preoperative imaging technique for CLM detection, but not used routinely. • Used to differentiate metastatic findings from benign findings such as- cysts, adenomas, and hemangiomas. • Limitations: length of the scan time, patient compliance and higher costs.
Imaging – US • Widespread availability. • Sensitivity is in the range of 36 to 61% in small liver lesions. • Limitations: lesions> 2cm, experience of the operator, impaired accuracy with: obese patients, liver steatosis. • Used for surveillance and liver lesion biopsy.
Imaging- Intraoperative US • Intraoperative US- most sensitive technique for detecting liver lesions (sensitivity 93 to 94%). • Discovers 25 – 30 % new lesions. • May change planning of the operation.
Imaging- Summary • CT scan is an essential tool in the optimal imaging of the majority of CLM. • MRI : for patients with liver damage owing to prolonged treatment or co-morbidities. • For lesions smaller than 1cm, the sensitivity estimates for MRI were higher than those for CT. (Niekelet al 2010). • PET/CT is extremely useful to exclude extrahepatic disease. • Intraoperative evaluation by IOUS, mandatory in all patients undergoing surgical resection of CLM.
Overall survival in advanced colorectal cancer in 2008: The impact of multi-disciplinary management 100 2008 chemotherapy Median survival >24 months 5 year survival 9 % 2008 overall (Surgery + Chemo) Median survival ~36 months 5 year survival 20 % % surviving 50 1928 1988 1998 20% 9% 3% <1% 0 0 1 2 3 4 5 Years after diagnosis of colorectal metastases Poston GJ. EJSO 2005; 31: 325-30
The Arsenal Of Treatment • Systemic chemotherapy • Intra-hepato-arterial chemotherapy • Biologic treatment • New surgery techniques • Radiofrequency ablation/Cryosurgery.
Systemic chemotherapy (CT) • FOLFOX: oxaliplatin, 5-FU, leucovorin. • FOLFORI: irinotecan, 5-FU, leucovorin. • XELOX/CapeOx: capecitabine(xeolda), oxaliplatin • CT as a “conversion therapy” ,preoperative chemo: • Bismuth et al (1996): conversion rate- 16%, 5yr survival- 40%. • Adam et al(2001)- conversion rate- 13.5%, 5yr survival- 38%. • Alfaro et al(2002)- conversion rate- 23%. • Limitations: liver toxicity and postoperative complications.
Biologic treatment • Anti VEGF -Bevacizumab • Anti-EGFR Agents • Cetuximab • Panitumumab
Bevacizumab (Avastin) • humanized monoclonal antibody. • angiogenesis inhibition by inhibiting vascular endothelial growth factor A (VEGF-A). • Main side effects- hypertension and heightened risk of bleeding. • Bevacizumab moderately improved resectability rates (8.4 versus 6.1 percent with chemotherapy alone) when added to XELOX or FOLFOX.
Anti-EGFR Agents • EGFR plays a crucial role in multiple cellular processes, such as cell proliferation, migration, survival and adhesion. • KRAS mutational status as a key determinant of sensitivity to anti-EGFR treatment in mCRC. • Cetuximab(Erbitux) • A chimeric IgG1 antibody • Folprecht et al (2010) - retrospective review, resectability rates increased from 32% to 60% after chemotherapy with cetuximab. • Van Cutsem et al (2011)- KRASwild-type patients, radical surgery was achieved in 5.1% of patients treated with cetuximab compared with 2.1% of patients treated with chemotherapy alone , in liver-only metastases the percentages raise to 13.2 and 5.6%, • Panitumumab(Vectibix) • A fully human IgG2 antibody • PRIME trail (Douillard et el 2010) – panitumumab+FOLFOX4 did not improve secondary resection rate over FOLFOX4 alone.
Adjuvant • The role of adjuvant chemotherapy is not clearly defined. • Portier et al (2006) –post-opreative 5-FU/leucovorinvs surgery alone – 5 year survival: 34% vs 27%. • UpToDate: best postoperative strategy is uncertain we suggest completion of a full six month course of oxaliplatin plus 5FU/capecitabine. • NCCN: FOLFOX/CapeOx.
Radiofrequency ablation (RFA) • Needle probe under image guidance generating heat and thus destroying the interstitial. • Temperatures >60° results in cell necrosis
Others • Cryosurgery • Yittrium 90
Summary: Hepatic resection for colorectal metastases that are limited to the liver is a standard of care. Preoperative Evaluation of the Patients is vital. Each patient needs a different care. The future is promising.