Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis. Several randomized trials of HAI therapy in patients with unresectable liver metastases from CRC have demonstrated higher response rates and longer TTHP than those seen with systemic fluoropyrimidine-based chemotherapy. Analysis of survival benefits is limited by methodological flaws, technical problems, and high toxicity in early studies; however, a recent CALGB multicenter study demonstrated an overall survival benefit for HAI of FUDR and dexamethasone versus systemic 5-FU and LV.
A great deal of progress has been made in the regional treatment of CRC liver metastases since the introduction of HAI chemotherapy over 40 years ago. Improvement in surgical techniques and the development of implantable pumps have decreased technical complications and improved patient tolerability of treatment. Whether this benefit will hold up in comparison with more active systemic regimens using irinotecan or oxaliplatin is unknown.
The use of HAI of FUDR and systemic 5-FU/LV following resection of hepatic metastases clearly decreases local recurrence and can improve 2-year survival, and further study of HAI in this setting is warranted. Both hepatic and extrahepatic relapses remain a problem and, therefore, initial studies combining HAI with newer systemic agents, such as irinotecan and oxaliplatin, are under way. These should provide a framework to guide us as to which combination regimens are the most effective and well-tolerated. Ultimately, this should lead to randomized trials of HAI therapy plus systemic chemotherapy versus our most active systemic chemotherapy alone in order to determine the best approach to treating hepatic CRC metastases.
The real question is whether these studies apply to HAI versus new multi-drug therapies, which are much more effective.
Anotehr question is whether systemic therapy Is necessary in addition to intraarterial therapy. It is also not known whetehr drugs such as cisplatin mitomycin work better than FUDR – this has not been tested. Experts remain in conflict but NCCN does recommend HAI.
Chari et al, Chemotherapy and Regional Therapy of Hepatic Colorectal Metastases: Expert Consensus Ann Surg Oncol.2006; 13: 1293-1295
Other expert opinions:
Chemotherapy and Regional Therapy of Hepatic Colorectal Metastases: Expert Consensus Statement
David L. Bartlett, Jordan Berlin, Gregory Y. Lauwers, Wells A. Messersmith, Nicholas J. Petrelli, and Alan P. Venook
Annals of Surgical Oncology Oct 1 2006: 1284-1292.
Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement
Chusilp Charnsangavej, Bryan Clary, Yuman Fong, Axel Grothey, Timothy M. Pawlik, and Michael A. Choti
Annals of Surgical Oncology Oct 1 2006: 1261-1268.
Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement by Charnsangavej et al.
William C. Chapman, Paulo M. Hoff, and Steven M. Strasberg
Annals of Surgical Oncology Oct 1 2006: 1269-1270.
Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement By Abdalla et al.
Reid B. Adams, Daniel G. Haller, and Mark S. Roh
Annals of Surgical Oncology Oct 1 2006: 1281-1283.
Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement
Eddie K. Abdalla, René Adam, Anton J. Bilchik, Daniel Jaeck, Jean-Nicolas Vauthey, and David Mahvi
Annals of Surgical Oncology Oct 1 2006: 1271-1280
Unresectable Hepatic Colorectal Metastases: Need for New Surgical Strategies
Jean-Nicolas Vauthey and Eddie K. Abdalla
Annals of Surgical Oncology Jan 1 2006: 5-6.
Alice C. Wei, Paul D. Greig, David Grant, Bryce Taylor, Bernard Langer, and Steven Gallinger Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience Annals of Surgical Oncology May 1 2006: 668-676.
NCCN.ORG, Colon Cancer