Isolated Hepatic Perfusion for Colorectal Liver Metastases
Isolated Hepatic Perfusion for Colorectal Liver Metastases
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: In a series of 154 patients taken to surgery for isolated hepatic perfusion to treat unresectable liver metastases, the hepatic response rate was 50% and the median progression-free and overall survival was 7.4 and 24.8 months, respectively. Of a large number of potential prognostic factors, three were significantly associated with survival; absence of ability to perfuse through the hepatic artery, the development of postoperative complications, and > 10 liver metastases. Progression-free survival was enhanced in the subset of patients who received adjuvant chemotherapy.
Source: van Iersel LBJ, et al. Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients. Ann Oncol. 2008;19:1127-1134.
Approximately one third of patients with advanced colon cancer have metastatic disease confined to the liver.1 The past decade has seen an expanded role for surgery in this setting, particularly if the number, location and size of the metastatic deposits allow complete resection.2 If not, radiofrequency ablation (RFA) and isolated hepatic perfusion (IHP) are alternative approaches that can provide aggressive local treatment while reducing systemic toxicity. Phase II studies involving IHP in colorectal cancer have shown hepatic response rates up to 74% with a median time to hepatic progression up to 14.5 months, a median overall survival of 27 months and a 5 year survival of 9%.3 van Iersel and colleagues from Leiden report on their experience with patients with liver metastases who underwent IHP with 200 mg melphalan to identify prognostic factors for local and systemic failure.
Over a ten year period, 154 colorectal cancer patients with measurable, non-resectable metastatic disease confined to the liver underwent laparotomy for isolation of hepatic circulation for chemotherapy infusion. This complex procedure was conducted by use of extracorporeal bypass. Melphalan, 200 mg was administered either as a bolus or a 20 minute infusion in the isolated hepatic circuit. Post operatively, patients were observed in the intensive care unit for a minimum of one day and received antibiotics and granulocyte colony stimulating factor until their white blood count had risen to >1.0 x 109/L. Objective tumor response measurements were obtained by follow-up CT scans, initially at 3 month intervals.
There were six deaths within 30 days of the procedure due to progressive liver failure, and another at 90 days because of hepatic abscess. Overall, 41 (39%) experienced grade 3 or 4 hepatotoxicity, which was transient in most, but not in those who developed veno-occlusive disease (n = 9) or portal hypertension (n = 2).
Comparative CT scans revealed an hepatic response rate of 50% by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.4 Progression-free and overall survival were 7.4 and 24.8 months, respectively. Univariate analysis revealed that positive prognostic factors for hepatic response to IHP were female sex and the use of adjuvant systemic chemotherapy. Multivariate analysis confirmed the benefit of adjuvant chemotherapy (odds ratio for complete or partial remission, 5.91; 95% confidence interval [CI] 1.54-22.6; P = 0.009) whereas the effect of female sex was only marginally significant (odds ratio for complete or partial remission, 2.65; 95% CI 0,98-7.15; P = 0.05). Regarding overall survival, the absence of ability to perfuse through the hepatic artery (P = 0.003), severe postoperative complications (P = 0.048) and >10 liver metastases (P = 0.006) were independent adverse factors, whereas not using adjuvant chemotherapy adversely influenced progression-free survival P = 0.039.
Commentary
Thus, IHP is an effective approach for patients with liver confined, but unresectable metastatic colorectal cancer. Current indications are influenced by community experience with the technique, in relation to other local approaches including surgery and RFA. Furthermore the introduction of new systemic approaches may offer comparable success in terms of overall survival. Yet, a 9% 5-year survival rate in patients with metastatic disease to the liver is encouraging, and this number might increase by more successfully excluding patients with extrahepatic diseases. In the current cohort, for example, 22% of the patients taken to surgery for IHP were found at laparotomy to have extrahepatic disease and were not infused, and 30 of the 89 infused patients later developed disease at extrahepatic sites, most notably lung, lymph nodes and brain. The routine use of FDG-PET scanning prior to the IHP procedure may identify those with extrahepatic disease and direct a more systemic approach.
Another significant finding from this work is the demonstrated importance of additional systemic (ie, adjuvant) therapy, the use of which turned out to be among the strongest of independent prognostic factors for hepatic-response and disease free progression.
Where this procedure fits among the options available for the management of hepatic confined metastatic colorectal cancer is determined by local expertise. In this regard, it is notable that a percutaneous approach is now reported,5,6 providing the obvious advantage of sparing an operative procedure. However, the technique is still quite complex and furthermore it eliminates the advantage inherent in surgical exploration, as witnessed in the current study in which 34 of the 154 patients (22%) were discovered at laparotomy to have extrahepatic metastases, and thus not treated with hepatic infusion. Although there have been encouraging advances in the management of patients with unresectable, but liver confined metastatic disease, several questions persist, such as when should procedures such as IHP or RFA be performed in relation to systemic therapy, and for those situations when IHP and RFA are both available, what factors should be considered in making the choice. It would be nice to think that a randomized clinical trial comparing the two approaches would be undertaken, but this seems unlikely.
References
1. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol. 1986;150(3):195-203.
2. Yamamoto J, Shimada K, Kosuge T, Yamasaki S, Sakamoto M, Fukuda H. Factors influencing survival of patients undergoing hepatectomy for colorectal metastases. Br J Surg. 1999;86(3):332-7.
3. Bartlett DL, Libutti SK, Figg WD, Fraker DL, Alexander HR. Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery. 2001;129(2):176-87.
4. Husband JE, Schwartz LH, Spencer J, et al. Evaluation of the response to treatment of solid tumours - a consensus statement of the International Cancer Imaging Society. Br J Cancer. 2004;90(12):2256-60.
5. Pingpank JF, Libutti SK, Chang R, et al. Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies. J Clin Oncol. 2005;23(15):3465-74.
6. van Etten B, Brunstein F, van IMG, et al. Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study. Ann Surg Oncol. 2004;11(6):598-605.
In a series of 154 patients taken to surgery for isolated hepatic perfusion to treat unresectable liver metastases, the hepatic response rate was 50% and the median progression-free and overall survival was 7.4 and 24.8 months, respectively.Subscribe Now for Access
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