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Commentary on “The Role of Adjuvant Therapy After Liver Resection for Colorectal Metastases”
Commentary on “The Role of Adjuvant Therapy After Liver Resection for Colorectal Metastases” Romano Danesi Division of Pharmacology and Chemotherapy Department of Oncology University of Pisa, Italy
The liver is the most common site of recurrence in patients with colorectal cancer after resection of the primary tumor; the magnitude of the problem is evidenced by the fact that intrahepatic metastases develop after a median of 9-12 months in up to 50% of patients. Surgery, consisting of wedge resection and/or lobectomies to obtain tumorfree margins, is the treatment of choice for liver metastases from colorectal cancer, and curative resection results in a 5-year survival rate of 25%-30%.1 In order to decrease the rate of intrahepatic recurrence and improve survival in patients with radically resected liver metastases, the intra-arterial infusion of anticancer agents, mainly the fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FUDR), for adjuvant purposes has been evaluated in clinical trials. The rationale behind the administration of hepatic regional chemotherapy is based on well-established pharmacokinetic criteria by which this treatment modality is able to produce high levels of the cytotoxic drug in the target tissue together with low systemic drug exposure and toxicity, particularly when using chemotherapeutic agents with high metabolic clearance, such as FUDR. In this issue of Clinical Colorectal Cancer, Ruo et al2 provide a comprehensive review on this topic and present, in a balanced way, the results of several clinical trials on the adjuvant intravascular administration of anticancer agents in patients after resection of liver metastases. This paper addresses the 2 main issues of intrahepatic chemotherapy: 1) the choice of vascular route for drug infusion, and 2) the potential limitations of the use of regional therapy only, without the administration of systemic treatment. With respect to the first issue, the delivery of chemotherapeutic agents to the liver has been accomplished either by the portal vein or hepatic artery. Two anatomic considerations deserve attention. First, the blood supply to established metastases derives from the branches of the hepatic artery, while the portal vein represents the route of spread of tumor cells to the liver. From a theoretical point of view, it would be straightforward to deliver chemotherapeutic drugs by hepatic artery infusion for disease palliation to patients with unresectable liver metastases and to administer anticancer agents by the portal vein to those optimally
resected in order to prevent tumor regrowth from micrometastatic deposits not detected at the time of surgery. However, despite the limitations in comparing the results of studies not primarily designed to address the differences between the 2 intravascular routes of drug delivery, the clinical results demonstrated that the portal infusion approach yielded inferior results with respect to hepatic artery infusion as an adjuvant treatment after liver resection.3,4 This apparently contradictory finding might be dependent, at least in part, on reasons related to pharmacokinetics and drug distribution. As a matter of fact, the blood flow through the portal vein in normal adults exceeds 1 L/minute5 and is at least 3-4 times higher than that of the hepatic artery. A slow infusion through a portal vein catheter of 99mTc-macroaggregated albumin under conditions resembling those of cytotoxic drug administration resulted in low or absent perfusion of the left liver lobe, as well as in grossly nonhomogeneous perfusion in nearly all of the patients.6 A more homogeneous drug distribution may be obtained by the infusion of 99mTc-macroaggregated albumin through the hepatic artery.7 In addition to this, the low pressure in the portal vein district does not favor drug diffusion within hepatic tissue; therefore, cytotoxic drug concentrations might not be achieved at metastatic foci developing away from the blood vessels. The next issue for optimal treatment is related to the evidence that extrahepatic progression is a frequent cause of failure after hepatic arterial infusion of cytotoxic drugs, and the most common site of recurrence is the lung. Current regional treatment in the liver is performed by the use of fluoropyrimidines, particularly FUDR. The activity of FUDR toward prevention of disease recurrence at extrahepatic sites is unsatisfactory for 2 main reasons. First, there is very low systemic exposure due to high hepatic clearance of FUDR, and, second, there is potential resistance of malignant cells to fluoropyrimidines, since the tumor level of the target enzyme thymidylate synthase is high in patients with metastatic disease in the lung.8 Taken together, these 2 factors may result in negligible effect of FUDR treatment on extrahepatic sites of relapse and reduction of the benefits of liver-directed therapy. The combined approach of systemic chemotherapy with 5-FU (325 mg/m2) plus leucovorin (200 mg/m2) administered daily for 5 days as an intravenous bolus to prevent extrahepatic recurrence, alternated with hepatic artery infu-
sion of FUDR (0.25 mg/kg/day) for 14 days plus dexamethasone (20 mg) and heparin (50,000 U) to prevent the growth of undetected micrometastases at the time of surgery,9 appears an effective way to treat advanced colorectal cancer patients subjected to radical resection of liver metastases. This strategy has the advantages of the administration of chemotherapeutic agents with high hepatic clearance (FUDR) in combination with dexamethasone to mitigate chemical hepatitis and biliary sclerosis, together with the systemic application of active agents for the treatment of colorectal cancer. However, overall progression-free survival was not increased as much as hepatic progression-free survival in the combinedtherapy group, indicating that survival was negatively affected by extrahepatic disease progression not controlled by the systemic administration of 5-FU/leucovorin. This suggests that more effective agents should be used by systemic route in conjunction with those given by hepatic arterial infusion.9 A possible solution is the use of novel active agents for the treatment of colorectal cancer, including irinotecan and oxaliplatin, whose activity is not affected to a significant extent by the enhanced activity of thymidylate synthase within the tumor, at variance with fluoropyrimidines.10 Hepatic arterial infusion with FUDR and steroids, in combination with systemic administration of irinotecan or oxaliplatin, is a rational approach to the problem, and the results of clinical studies with this combination are awaited with interest.11 The intrahepatic administration of drugs with low hepatic clearance, eg, oxaliplatin, may not offer an advantage over FUDR in the adjuvant setting because a significant systemic exposure occurs, as the pharmacokinetic profiles of this agent administered by hepatic artery or intravenous infusion are similar. However, the rate of delivery of the drug into the systemic circulation after intrahepatic administration is not equivalent, under a therapeutic point of view, to the same agent given systemically. Therefore, it is safer to administer the treatment by systemic route if the effort is the prevention of disease relapse at extrahepatic sites, while it is advisable not to rely upon the amount of drug that distributes into the systemic circulation after intrahepatic administration. A 2arm randomized clinical trial comparing hepatic artery infusion with FUDR and dexamethasone plus systemic adjuvant therapy versus systemic adjuvant therapy alone is thus warranted. However, the choice of the “best” systemic treatment is a difficult task
Clinical Colorectal Cancer November 2001
• 167
due to the continuous developments of novel combinations and schedules, including irinotecan, 5-FU, and oxaliplatin, with improved activity and toxicity profiles.12 Finally, the hepatic intravascular delivery of anticancer agents by a catheter is associated with perioperative and postoperative morbidity (thrombosis, infection) and causes more adverse effects than systemic chemotherapy, including potentially severe liver toxicity. In addition, the experience needed for optimal surgical procedure, the economic cost, the surgical burden, and catheter care are factors to be taken into consideration. The outlook for prevention of liver recurrence relies on the investigation of novel, less toxic and more active drugs for intrahepatic infusion, including cytokines, antiangiogenic agents, and inhibitors of biologic activation of the ras oncogene (ie, farnesyl transferase inhibitors). Furthermore, an area of important research is the development of orally active anticancer agents, ie, thirdgeneration fluoropyrimidines with improved absorption through the intestinal wall and extensive liver uptake to mimic vascular perfusion. The obvious advantage of chronic oral treatment is the continuous exposure of target tissue to active agents without the need for vascular access, and this therapy may be successfully combined
with systemic treatment. The development of such agents is now underway, ie, the third-generation fluoropyrimidines S-1 and capecitabine as well as platinum compounds conjugated with carriers to improve intestinal absorption and liver uptake. There is significant room for improvement of novel therapies with the use of noninvasive techniques, including positron emission tomography, for pharmacokinetic assessment of hepatic distribution in vivo. Thus, it may be possible that orally active agents will represent an attractive alternative to intravascular drug infusion in the future. In conclusion, the present data underscore the importance of regional treatment plus systemic chemotherapy for the management of patients after liver resection but encourage the investigation of novel avenues to provide a potential cure for selected patients.
01. Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998; 228:756-762. 02. Ruo L, DeMatteo R, Blumgart L. The role of adjuvant therapy in liver resection for colorectal cancer metastases. Clin Colorectal Cancer 2001; 1:154-166. 03. McMurrick PJ, Nelson H. Liver-directed therapies
168 • Clinical Colorectal Cancer November 2001
for gastrointestinal malignancies. Curr Opin Oncol 1997; 9:367-372. 04. Ambiru S, Miyazaki M, Ito H, et al. Adjuvant regional chemotherapy after hepatic resection for colorectal metastases. Br J Surg 1999; 86:1025-1031. 05. Iwao T, Toyonaga A, Shigemori H, et al. EchoDoppler measurements of portal vein and superior mesenteric artery blood flow in humans: interand intra-observer short-term reproducibility. J Gastroenterol Hepatol 1996; 11:40-46. 06. Aeberhard P, Bissat A, Koella C, et al. Non-homogeneous intrahepatic drug distribution in intraportal infusional chemotherapy demonstrated by Tc-99mMAA perfusion SPECT. Eur J Surg Oncol 1989; 15: 119-123. 07. Copur MS, Capadano M, Lynch J, et al. Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access. J Clin Oncol 2001; 19:2404-2412. 08. Gorlick R, Metzger R, Danenberg KD, et al. Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 1998; 16:1465-1469. 09. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039-2048. 10. Danesi R, De Braud F, Fogli S, et al. Pharmacogenetic determinants of anti-cancer drug activity and toxicity. Trends Pharmacol Sci 2001; 22:420-426. 11. Zahalsky A, Kemeny N, Sullivan D, et al. A phase I study of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (DEX) in combination with systemic (SYS) irinotecan (CPT-11) after resection of hepatic metastases from colorectal cancer. Proc Am Soc Clin Oncol 2000; 19:293a (Abstract #1146). 12. Fishman A, Wadler S. Advances in the treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2001; 1:20-35.
The liver is the most common site of recurrence in patients with colorectal cancer after resection of the primary tumor; the magnitude of the problem is evidenced by the fact that intrahepatic metastases develop after a median of 9-12 months in up to 50% of patients. Surgery, consisting of wedge resection and/or lobectomies to obtain tumorfree margins, is the treatment of choice for liver metastases from colorectal cancer, and curative resection results in a 5-year survival rate of 25%-30%.1 In order to decrease the rate of intrahepatic recurrence and improve survival in patients with radically resected liver metastases, the intra-arterial infusion of anticancer agents, mainly the fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FUDR), for adjuvant purposes has been evaluated in clinical trials. The rationale behind the administration of hepatic regional chemotherapy is based on well-established pharmacokinetic criteria by which this treatment modality is able to produce high levels of the cytotoxic drug in the target tissue together with low systemic drug exposure and toxicity, particularly when using chemotherapeutic agents with high metabolic clearance, such as FUDR. In this issue of Clinical Colorectal Cancer, Ruo et al2 provide a comprehensive review on this topic and present, in a balanced way, the results of several clinical trials on the adjuvant intravascular administration of anticancer agents in patients after resection of liver metastases. This paper addresses the 2 main issues of intrahepatic chemotherapy: 1) the choice of vascular route for drug infusion, and 2) the potential limitations of the use of regional therapy only, without the administration of systemic treatment. With respect to the first issue, the delivery of chemotherapeutic agents to the liver has been accomplished either by the portal vein or hepatic artery. Two anatomic considerations deserve attention. First, the blood supply to established metastases derives from the branches of the hepatic artery, while the portal vein represents the route of spread of tumor cells to the liver. From a theoretical point of view, it would be straightforward to deliver chemotherapeutic drugs by hepatic artery infusion for disease palliation to patients with unresectable liver metastases and to administer anticancer agents by the portal vein to those optimally
resected in order to prevent tumor regrowth from micrometastatic deposits not detected at the time of surgery. However, despite the limitations in comparing the results of studies not primarily designed to address the differences between the 2 intravascular routes of drug delivery, the clinical results demonstrated that the portal infusion approach yielded inferior results with respect to hepatic artery infusion as an adjuvant treatment after liver resection.3,4 This apparently contradictory finding might be dependent, at least in part, on reasons related to pharmacokinetics and drug distribution. As a matter of fact, the blood flow through the portal vein in normal adults exceeds 1 L/minute5 and is at least 3-4 times higher than that of the hepatic artery. A slow infusion through a portal vein catheter of 99mTc-macroaggregated albumin under conditions resembling those of cytotoxic drug administration resulted in low or absent perfusion of the left liver lobe, as well as in grossly nonhomogeneous perfusion in nearly all of the patients.6 A more homogeneous drug distribution may be obtained by the infusion of 99mTc-macroaggregated albumin through the hepatic artery.7 In addition to this, the low pressure in the portal vein district does not favor drug diffusion within hepatic tissue; therefore, cytotoxic drug concentrations might not be achieved at metastatic foci developing away from the blood vessels. The next issue for optimal treatment is related to the evidence that extrahepatic progression is a frequent cause of failure after hepatic arterial infusion of cytotoxic drugs, and the most common site of recurrence is the lung. Current regional treatment in the liver is performed by the use of fluoropyrimidines, particularly FUDR. The activity of FUDR toward prevention of disease recurrence at extrahepatic sites is unsatisfactory for 2 main reasons. First, there is very low systemic exposure due to high hepatic clearance of FUDR, and, second, there is potential resistance of malignant cells to fluoropyrimidines, since the tumor level of the target enzyme thymidylate synthase is high in patients with metastatic disease in the lung.8 Taken together, these 2 factors may result in negligible effect of FUDR treatment on extrahepatic sites of relapse and reduction of the benefits of liver-directed therapy. The combined approach of systemic chemotherapy with 5-FU (325 mg/m2) plus leucovorin (200 mg/m2) administered daily for 5 days as an intravenous bolus to prevent extrahepatic recurrence, alternated with hepatic artery infu-
sion of FUDR (0.25 mg/kg/day) for 14 days plus dexamethasone (20 mg) and heparin (50,000 U) to prevent the growth of undetected micrometastases at the time of surgery,9 appears an effective way to treat advanced colorectal cancer patients subjected to radical resection of liver metastases. This strategy has the advantages of the administration of chemotherapeutic agents with high hepatic clearance (FUDR) in combination with dexamethasone to mitigate chemical hepatitis and biliary sclerosis, together with the systemic application of active agents for the treatment of colorectal cancer. However, overall progression-free survival was not increased as much as hepatic progression-free survival in the combinedtherapy group, indicating that survival was negatively affected by extrahepatic disease progression not controlled by the systemic administration of 5-FU/leucovorin. This suggests that more effective agents should be used by systemic route in conjunction with those given by hepatic arterial infusion.9 A possible solution is the use of novel active agents for the treatment of colorectal cancer, including irinotecan and oxaliplatin, whose activity is not affected to a significant extent by the enhanced activity of thymidylate synthase within the tumor, at variance with fluoropyrimidines.10 Hepatic arterial infusion with FUDR and steroids, in combination with systemic administration of irinotecan or oxaliplatin, is a rational approach to the problem, and the results of clinical studies with this combination are awaited with interest.11 The intrahepatic administration of drugs with low hepatic clearance, eg, oxaliplatin, may not offer an advantage over FUDR in the adjuvant setting because a significant systemic exposure occurs, as the pharmacokinetic profiles of this agent administered by hepatic artery or intravenous infusion are similar. However, the rate of delivery of the drug into the systemic circulation after intrahepatic administration is not equivalent, under a therapeutic point of view, to the same agent given systemically. Therefore, it is safer to administer the treatment by systemic route if the effort is the prevention of disease relapse at extrahepatic sites, while it is advisable not to rely upon the amount of drug that distributes into the systemic circulation after intrahepatic administration. A 2arm randomized clinical trial comparing hepatic artery infusion with FUDR and dexamethasone plus systemic adjuvant therapy versus systemic adjuvant therapy alone is thus warranted. However, the choice of the “best” systemic treatment is a difficult task
Clinical Colorectal Cancer November 2001
• 167
due to the continuous developments of novel combinations and schedules, including irinotecan, 5-FU, and oxaliplatin, with improved activity and toxicity profiles.12 Finally, the hepatic intravascular delivery of anticancer agents by a catheter is associated with perioperative and postoperative morbidity (thrombosis, infection) and causes more adverse effects than systemic chemotherapy, including potentially severe liver toxicity. In addition, the experience needed for optimal surgical procedure, the economic cost, the surgical burden, and catheter care are factors to be taken into consideration. The outlook for prevention of liver recurrence relies on the investigation of novel, less toxic and more active drugs for intrahepatic infusion, including cytokines, antiangiogenic agents, and inhibitors of biologic activation of the ras oncogene (ie, farnesyl transferase inhibitors). Furthermore, an area of important research is the development of orally active anticancer agents, ie, thirdgeneration fluoropyrimidines with improved absorption through the intestinal wall and extensive liver uptake to mimic vascular perfusion. The obvious advantage of chronic oral treatment is the continuous exposure of target tissue to active agents without the need for vascular access, and this therapy may be successfully combined
with systemic treatment. The development of such agents is now underway, ie, the third-generation fluoropyrimidines S-1 and capecitabine as well as platinum compounds conjugated with carriers to improve intestinal absorption and liver uptake. There is significant room for improvement of novel therapies with the use of noninvasive techniques, including positron emission tomography, for pharmacokinetic assessment of hepatic distribution in vivo. Thus, it may be possible that orally active agents will represent an attractive alternative to intravascular drug infusion in the future. In conclusion, the present data underscore the importance of regional treatment plus systemic chemotherapy for the management of patients after liver resection but encourage the investigation of novel avenues to provide a potential cure for selected patients.
01. Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998; 228:756-762. 02. Ruo L, DeMatteo R, Blumgart L. The role of adjuvant therapy in liver resection for colorectal cancer metastases. Clin Colorectal Cancer 2001; 1:154-166. 03. McMurrick PJ, Nelson H. Liver-directed therapies
168 • Clinical Colorectal Cancer November 2001
for gastrointestinal malignancies. Curr Opin Oncol 1997; 9:367-372. 04. Ambiru S, Miyazaki M, Ito H, et al. Adjuvant regional chemotherapy after hepatic resection for colorectal metastases. Br J Surg 1999; 86:1025-1031. 05. Iwao T, Toyonaga A, Shigemori H, et al. EchoDoppler measurements of portal vein and superior mesenteric artery blood flow in humans: interand intra-observer short-term reproducibility. J Gastroenterol Hepatol 1996; 11:40-46. 06. Aeberhard P, Bissat A, Koella C, et al. Non-homogeneous intrahepatic drug distribution in intraportal infusional chemotherapy demonstrated by Tc-99mMAA perfusion SPECT. Eur J Surg Oncol 1989; 15: 119-123. 07. Copur MS, Capadano M, Lynch J, et al. Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access. J Clin Oncol 2001; 19:2404-2412. 08. Gorlick R, Metzger R, Danenberg KD, et al. Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 1998; 16:1465-1469. 09. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039-2048. 10. Danesi R, De Braud F, Fogli S, et al. Pharmacogenetic determinants of anti-cancer drug activity and toxicity. Trends Pharmacol Sci 2001; 22:420-426. 11. Zahalsky A, Kemeny N, Sullivan D, et al. A phase I study of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (DEX) in combination with systemic (SYS) irinotecan (CPT-11) after resection of hepatic metastases from colorectal cancer. Proc Am Soc Clin Oncol 2000; 19:293a (Abstract #1146). 12. Fishman A, Wadler S. Advances in the treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2001; 1:20-35.