Surgical management of hepatic metastases from colorectal cancer Joint Hospital Surgical Grand Round Dr HH Wong Department of Surgery PYNEH

Liver is the commonest site of distant metastasis of colorectal cancer Liver is the commonest site of distant metastasis of colorectal cancer Nearly half of the patients with colorectal cancer ultimately develop liver metastasis during the course of their diseases Nearly half of the patients with colorectal cancer ultimately develop liver metastasis during the course of their diseases Liver metastasis may be present in as many as 35% of patients with colorectal cancer at the time of operation Liver metastasis may be present in as many as 35% of patients with colorectal cancer at the time of operation

Prognosis of patients with untreated liver metastasis Prognosis of patients with untreated liver metastasis extent of hepatic involvement at the time of diagnosis extent of hepatic involvement at the time of diagnosis Histological grade of the primary tumour Histological grade of the primary tumour

0 % five-year survival for patients with untreated but potentially resectable liver metastases 0 % five-year survival for patients with untreated but potentially resectable liver metastases 28 % five-year survival for operated patients with resected liver metastases 28 % five-year survival for operated patients with resected liver metastases - Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancer. Arch Surg 1976; 111: )

patients with an untreated single liver metastasis had a median survival of 19 months, with no patients surviving 5 years patients with an untreated single liver metastasis had a median survival of 19 months, with no patients surviving 5 years while patients with a resected single liver metastasis had a median survival of 36 months with 25 % of patients surviving five years while patients with a resected single liver metastasis had a median survival of 36 months with 25 % of patients surviving five years Wanebo HJ, Semoglou C, Attiyeh F, Stearns MJ Jr. Surgical management of patients with primary operable colorectal cancer and synchronous liver metastases. Am J Surg 1978; 135: Wanebo HJ, Semoglou C, Attiyeh F, Stearns MJ Jr. Surgical management of patients with primary operable colorectal cancer and synchronous liver metastases. Am J Surg 1978; 135: 81-85

Surgical resection of distant metastases in colorectal cancer can produce long- term survival and cure in some selected patients. Surgical resection of distant metastases in colorectal cancer can produce long- term survival and cure in some selected patients. Five-year survival rates after resection of all detectable liver metastases range from 6 to 52 % Five-year survival rates after resection of all detectable liver metastases range from 6 to 52 %

Traditional selection criterion No more than 3 metastases No more than 3 metastases Unilobar disease Unilobar disease Tumours < 5cm Tumours < 5cm Metachronous detection of metastases Metachronous detection of metastases Resection margin > 1cm required Resection margin > 1cm required No extrahepatic disease No extrahepatic disease Not > 65 of age Not > 65 of age No portal nodal involvement No portal nodal involvement

Unilobar or bilobar disease Only 1/3 of patients with colorectal liver metastases have disease limited to one lobe Only 1/3 of patients with colorectal liver metastases have disease limited to one lobe segment-based resection allows excision of bilateral or multiple liver lesions that might previously have been deemed unresectable segment-based resection allows excision of bilateral or multiple liver lesions that might previously have been deemed unresectable

Unilobar or bilobar disease Up to 75 % of the liver can be removed if the liver function is normal Up to 75 % of the liver can be removed if the liver function is normal Vauthey JN. Liver imaging. A surgeon's perspective. Radiol Clin North Am 1998;36(2): Vauthey JN. Liver imaging. A surgeon's perspective. Radiol Clin North Am 1998;36(2):445-57

Long-term survival is rare in patient with resection of four or more lesions Long-term survival is rare in patient with resection of four or more lesions Ekberg H. determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986; 73: Ekberg H. determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986; 73: patients who underwent resection of more than four colorectal liver metastases revealed an overall 5 year survival rate of 23% patients who underwent resection of more than four colorectal liver metastases revealed an overall 5 year survival rate of 23% Weber SM et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 7: , 2000 Weber SM et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 7: , 2000 Number of metastases

no significant difference in the mortality, morbidity and five-year survival between patients whose lesions more than four and those less than four no significant difference in the mortality, morbidity and five-year survival between patients whose lesions more than four and those less than four Morris DL. Surgery for liver metastases: How many? ANZ J Surg 2002; 72: 2 Morris DL. Surgery for liver metastases: How many? ANZ J Surg 2002; 72: 2 Minagawa M et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: Longterm results. Ann Surg 231: , 2000 Minagawa M et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: Longterm results. Ann Surg 231: , 2000 Number of metastases

Resection margin Patients with incomplete removal of tumour have similar outcomes to non- operated patients Patients with incomplete removal of tumour have similar outcomes to non- operated patients Scheele J et al. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg, 77, Scheele J et al. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg, 77,

Resection margin Registry of Hepatic Metastases Registry of Hepatic Metastases Margin greater than 1cm was associated with a 45% 5-year survival Margin greater than 1cm was associated with a 45% 5-year survival Only 23% survived 5 years if the margin was less Only 23% survived 5 years if the margin was less

Resection margin Recent reports suggest a generous margin is not essential for achieving a curative outcome Recent reports suggest a generous margin is not essential for achieving a curative outcome Yamamoto J et al. Factors influencing survival of patients undergoing hepatectomy for colorectal metastases. Br J Surg, 86, Yamamoto J et al. Factors influencing survival of patients undergoing hepatectomy for colorectal metastases. Br J Surg, 86, Minagawa M et al. extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg, 231, Minagawa M et al. extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg, 231,

Resection margin 1mm tumour –free resection margin is enough to achieve comparable survival and disease-free survival 1mm tumour –free resection margin is enough to achieve comparable survival and disease-free survival Hamady Z et al. Current techniques and results of liver resection for colorectal liver metastasis. Br Med Bull 2004; 70: Hamady Z et al. Current techniques and results of liver resection for colorectal liver metastasis. Br Med Bull 2004; 70:

Other factors associate with poor prognosis Metastasis greater than 6cm Metastasis greater than 6cm Presence of extrahepatic metastases Presence of extrahepatic metastases Portal LN involvement Portal LN involvement None of these patients survives 5 years after hepatectomy None of these patients survives 5 years after hepatectomy Elevated pre-operative CEA level Elevated pre-operative CEA level

Preoperative assessment before operation Patient fitness Patient fitness Significant risk of transient liver failure following major resection Significant risk of transient liver failure following major resection Assessment of hepatic functional reserve has not reached clear conclusion Assessment of hepatic functional reserve has not reached clear conclusion Extrahepatic metastasis Extrahepatic metastasis Emerging role of PET scan Emerging role of PET scan

Intraoperative assessment Intraoperative ultrasound (IOUS) Intraoperative ultrasound (IOUS) Standard part of almost all liver resection procedures Standard part of almost all liver resection procedures Assess tumour burden and identify occult lesions Assess tumour burden and identify occult lesions Define relationship to vital intrahepatic structures Define relationship to vital intrahepatic structures Evaluate the patency of intrahepatic vessels and the presence of tumour thrombus Evaluate the patency of intrahepatic vessels and the presence of tumour thrombus

More sensitive (>90%) and more specific (>90%) in evaluating liver tumours than other imaging modalities More sensitive (>90%) and more specific (>90%) in evaluating liver tumours than other imaging modalities MachiJ et al. operative ultrasound in general surgery. Am J Surg, 172, MachiJ et al. operative ultrasound in general surgery. Am J Surg, 172, Up to 1/3 of cases the operative plan is altered based on IOUS findings Up to 1/3 of cases the operative plan is altered based on IOUS findings Patients with hyperechoic colorectal liver metastasis had better survival than patient with hypoechoic lesions Patients with hyperechoic colorectal liver metastasis had better survival than patient with hypoechoic lesions Gruenberger T et al. Echogenicity of liver metastases is an independent prognostic factor after potentially curative treatment. Arch Surg, 135, Gruenberger T et al. Echogenicity of liver metastases is an independent prognostic factor after potentially curative treatment. Arch Surg, 135,

Intraoperative blood loss Excessive blood loss is a major determinant of perioperative outcome Excessive blood loss is a major determinant of perioperative outcome Meticulous surgical technique Meticulous surgical technique Ultrasonic dissection Ultrasonic dissection Low central venous pressure (CVP) anaesthesia Low central venous pressure (CVP) anaesthesia Vascular inflow and outflow control Vascular inflow and outflow control Argon beam coagulation Argon beam coagulation

Anatomical or wedge resection? Anatomical resection Anatomical resection On or more complete segments are removed according to International Hepato-Pancreato- Biliary Association (IHPBA) terminology On or more complete segments are removed according to International Hepato-Pancreato- Biliary Association (IHPBA) terminology Preferred oncological procedure, allows better clearance Preferred oncological procedure, allows better clearance Less chance of intraoperative bleeding, fewer vessels lie in the interface between the segments Less chance of intraoperative bleeding, fewer vessels lie in the interface between the segments Removes more liver parenchyma thus greater chance of postoperative liver dysfunction Removes more liver parenchyma thus greater chance of postoperative liver dysfunction

Synchronous colorectal and liver resection Liver metastasis may be present in as many as 35% of patients with colorectal cancer at the time of operation Liver metastasis may be present in as many as 35% of patients with colorectal cancer at the time of operation Combined single-stage resection of colorectal cancer and liver metastases Combined single-stage resection of colorectal cancer and liver metastases Earlier initiation of adjuvant therapy Earlier initiation of adjuvant therapy Avoiding a second laparotomy Avoiding a second laparotomy

Synchronous colorectal and liver resection Safe and feasible with no increase in perioperative morbidity or mortality Safe and feasible with no increase in perioperative morbidity or mortality No difference in survival compared with staged resection No difference in survival compared with staged resection Lyass S et al. combined colon and hepatic resection for synchronous colorectal liver metastases. J Surg Oncol, 78, Lyass S et al. combined colon and hepatic resection for synchronous colorectal liver metastases. J Surg Oncol, 78, Jeack D et al. Strategie Chirurgicale dans le traitement des mestatases hepatiques synchornes des cancers colorectaux. Analyse d’une serie de 59 malades operes. Chirurgie, 124, Jeack D et al. Strategie Chirurgicale dans le traitement des mestatases hepatiques synchornes des cancers colorectaux. Analyse d’une serie de 59 malades operes. Chirurgie, 124,

Synchronous colorectal and liver resection R Martin et al. Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastasis. Journ Am Col Surg 2003; 197: R Martin et al. Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastasis. Journ Am Col Surg 2003; 197: patients were treated surgically for primary adenocarcinoma of the large bowel and synchronous hepatic metastasis 240 patients were treated surgically for primary adenocarcinoma of the large bowel and synchronous hepatic metastasis 134 patients underwent simultaneous resection 134 patients underwent simultaneous resection 106 patients underwent staged operations 106 patients underwent staged operations

Synchronous colorectal and liver resection Complications were less common in the simultaneous resection group Complications were less common in the simultaneous resection group 65 patients (49%) sustaining 142 complications for simultaneous resection group 65 patients (49%) sustaining 142 complications for simultaneous resection group 71 patients (67%) sustaining 197 complications for both hospitalizations in the staged resection group (p < 0.003) 71 patients (67%) sustaining 197 complications for both hospitalizations in the staged resection group (p < 0.003) Patients having simultaneous resection required fewer days in the hospital (median 10 days versus 18 days, P = 0.001) Patients having simultaneous resection required fewer days in the hospital (median 10 days versus 18 days, P = 0.001) Perioperative mortality was similar (simultaneous, N = 3; staged, N = 3). Perioperative mortality was similar (simultaneous, N = 3; staged, N = 3).

Laparoscopic liver resection Not widely accepted in view of technical difficulties Not widely accepted in view of technical difficulties Tumour cell seedings at port sites Tumour cell seedings at port sites Overall morbidity has been shown to be lower with laparoscopic resection Overall morbidity has been shown to be lower with laparoscopic resection Gigot J et al. laparoscopic liver resection for malignant liver tumours. Ann Surg, 236, Gigot J et al. laparoscopic liver resection for malignant liver tumours. Ann Surg, 236, 90- 7

Doubling of resection rates Doubling of resection rates Only 25 % of patients with colorectal liver metastases are candidates for liver resection Only 25 % of patients with colorectal liver metastases are candidates for liver resection Various methods to increase resectability Various methods to increase resectability

Neoadjuvant chemotherapy Downstaging of tumour to convert unresectable tumours into potentially resectable ones Downstaging of tumour to convert unresectable tumours into potentially resectable ones Permit resection of about 15% of metastases which have previously been considered unresectable Permit resection of about 15% of metastases which have previously been considered unresectable Adam R et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal liver metastases. Ann Surg Oncol, 8, Adam R et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal liver metastases. Ann Surg Oncol, 8, It rarely changes the tumour relationship to the vascular structures It rarely changes the tumour relationship to the vascular structures

Preoperative portal vein embolization Inducing ipsilateral atrophy and contralateral hypertrophy of the liver remnant in these patients Inducing ipsilateral atrophy and contralateral hypertrophy of the liver remnant in these patients Increase 50% the size of the non-embolized lobe in 4-6 weeks Increase 50% the size of the non-embolized lobe in 4-6 weeks Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg. 2001;88:165 – 175 Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg. 2001;88:165 – 175

Preoperative portal vein embolization Curative liver resection expected to be feasible in ~50% patient who were initially considered inoperable Curative liver resection expected to be feasible in ~50% patient who were initially considered inoperable 5 year suvival apporaching 37% 5 year suvival apporaching 37% Elias D et al. Preoeprative selective portal vein embolization before hepatectomy for liver metastases: long term results and impoact on survival. Surgery, 131, Elias D et al. Preoeprative selective portal vein embolization before hepatectomy for liver metastases: long term results and impoact on survival. Surgery, 131, 294-9

Two-stage resection Convert non-resectable liver metastases into potentially curable cases Convert non-resectable liver metastases into potentially curable cases Especially applied to multinodular bilobar metastase Especially applied to multinodular bilobar metastase First-stage resection remove the highest possible number of tumour lesions First-stage resection remove the highest possible number of tumour lesions

Two-stage resection Followed by liver regeneration period and chemotherapy Followed by liver regeneration period and chemotherapy 2 nd stage only perfomred if potentially curative and only if enough parenchymal hypertrophy has occurred to reduce the risk of postoperative liver failure. 2 nd stage only perfomred if potentially curative and only if enough parenchymal hypertrophy has occurred to reduce the risk of postoperative liver failure. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg. 2000;232:777 – 785. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg. 2000;232:777 – 785.

Only 25 % of patients with colorectal liver metastases are candidates for liver resection Only 25 % of patients with colorectal liver metastases are candidates for liver resection Other treatment modalities, such as local ablative therapy, systemic chemotherapy, hepatic artery infusion and isolated hepatic infusion may offer palliation and prolongation of disease-free and overall survival Other treatment modalities, such as local ablative therapy, systemic chemotherapy, hepatic artery infusion and isolated hepatic infusion may offer palliation and prolongation of disease-free and overall survival

Local ablative therapy Radiofrequency ablation Radiofrequency ablation Cryotherapy Cryotherapy Percutaneous ethanol injection Percutaneous ethanol injection Laser and photodynamic therapy Laser and photodynamic therapy

Radiofrequency ablation An electrode delivers a high-frequency alternating current to the tissue, causing hyperthermia and finally inducing coagulative necrosis An electrode delivers a high-frequency alternating current to the tissue, causing hyperthermia and finally inducing coagulative necrosis Single rigid probes inducing a cylindrical necrotic lesion Single rigid probes inducing a cylindrical necrotic lesion Multi-tined expandable electrodes induce a spherical lesion Multi-tined expandable electrodes induce a spherical lesion

Radiofrequency ablation Multiple insertions may be necessary when tumours are >3cm in diameter Multiple insertions may be necessary when tumours are >3cm in diameter Probe placed under ultrasound or CT guidance Probe placed under ultrasound or CT guidance RFA can be performed in combination with resection RFA can be performed in combination with resection

Radiofrequency ablation High complete response rates of 52%- 95% are achieved by RFA High complete response rates of 52%- 95% are achieved by RFA Curley SA et al. radiofrequency ablation of malignant liver tumours. Ann Surg Oncol 2003; 10: Curley SA et al. radiofrequency ablation of malignant liver tumours. Ann Surg Oncol 2003; 10: Ruers TJ et al. Long –term results of treating hepatic colorectal metastases with cryosurgery. Br J Surg 2001 Ruers TJ et al. Long –term results of treating hepatic colorectal metastases with cryosurgery. Br J Surg 2001

Radiofrequency ablation Prolongation of disease free and overall survival to repectively 50% and 94% at 1 year Prolongation of disease free and overall survival to repectively 50% and 94% at 1 year Median survival time of months Median survival time of months Solbiati L et al. Radiofrequency thermal ablation of hepatic metastases. Eur J Ultrasound 2001; 13: Solbiati L et al. Radiofrequency thermal ablation of hepatic metastases. Eur J Ultrasound 2001; 13:

Hepatic resection vs. RFA Aloia, Thomas A et al. Solitary Colorectal Liver Metastasis: Resection Determines Outcome. Arch Surg 141(5), 2006, p 460–467 Aloia, Thomas A et al. Solitary Colorectal Liver Metastasis: Resection Determines Outcome. Arch Surg 141(5), 2006, p 460– underwent HR and 30 underwent RFA 150 underwent HR and 30 underwent RFA Local recurrence (LR) rate was markedly lower after HR (5%) than after RFA (37%) (P<.001). Local recurrence (LR) rate was markedly lower after HR (5%) than after RFA (37%) (P<.001). Treatment by HR was associated with longer 5- year survival rates than RFA Treatment by HR was associated with longer 5- year survival rates than RFA LR-free (92% vs 60%, respectively; P<.001) LR-free (92% vs 60%, respectively; P<.001) disease-free (50% vs 0%, respectively; P =.001) disease-free (50% vs 0%, respectively; P =.001) overall (71% vs 27%, respectively; P<.001) survival rates overall (71% vs 27%, respectively; P<.001) survival rates

Hepatic resection vs. RFA Tumors 3 cm or larger (n = 79) Tumors 3 cm or larger (n = 79) LR occurred more frequently following RFA (31%) than after HR (3%) (P =.001) LR occurred more frequently following RFA (31%) than after HR (3%) (P =.001) 5-year LR-free survival rate of 66% after RFA vs 97% after HR (P<.001). 5-year LR-free survival rate of 66% after RFA vs 97% after HR (P<.001). Tumors < 3cm Tumors < 3cm longer 5-year overall survival rates after HR (72%) as compared with RFA (18%) (P =.006). longer 5-year overall survival rates after HR (72%) as compared with RFA (18%) (P =.006).

Conclusion Hepatic resection remains the only possible cure for colorectal liver metastases Hepatic resection remains the only possible cure for colorectal liver metastases Changing criteria for hepatic resection has doubled the resection rate Changing criteria for hepatic resection has doubled the resection rate Promising treatment modalities to increase resectablitiy Promising treatment modalities to increase resectablitiy RFA can achieve good results in patient with non-resectable disease, however, itself alone cannot replace hepatic resection in potentially curative cases RFA can achieve good results in patient with non-resectable disease, however, itself alone cannot replace hepatic resection in potentially curative cases

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