Influence of Preoperative Chemotherapy on the Risk of Major Hepatectomy for Colorectal Liver Metastases

To the Editor:

Modern systemic chemotherapy agents for liver metastases from colorectal carcinoma, such as oxaliplatin and irinotecan, have been widely used in the preoperative setting for their ability to increase the cure rate in resectable tumors and to rescue some unresectable metastases to surgery, becoming standard of care in these settings.¹ Along with the benefits of such chemotherapies, several authors have reported an increased incidence of vascular changes, steatohepatitis, and the challenge of postoperative management of the patients with hepatic damage from use of these agents.^2,3 The interesting article by Karoui et al published in the January 2006 issue of Annals of Surgery represents a further evidence of the possible hepatotoxicity issues that modern systemic neoadjuvant chemotherapy imposes.⁴

An alternative to systemic chemotherapy for the treatment of isolated colorectal liver metastases is represented by hepatic artery infusion (HAI) chemotherapy, since the initial report by Sullivan et al in 1964.⁵ Even though HAI therapy for hepatic metastases from colorectal cancer can produce high response rates and it may also be valuable to induce resectability even as second-line setting,¹ recent advances in the systemic therapy for colorectal cancer seem to have made HAI an old-fashioned therapy.

Karoui et al⁴ state that HAI chemotherapy is associated with significant pathologic abnormalities of liver parenchyma that may explain the high rate of postoperative complications observed in patients who underwent liver resection after HAI chemotherapy.

However, data concerning preoperative HAI chemotherapy are scarce. Reports of hepatic resection following preoperative HAI chemotherapy with floxuridine (FUDR) are limited to small case series.^6–9

Several factors have restricted the wide application of HAI therapy. Intra-arterial hepatic chemotherapy with FUDR, the most used agent, is associated with a well-defined group of toxicities, including chemical hepatitis, biliary sclerosis, and gastritis,¹⁰ and increased postoperative complications have been described in patients undergoing liver resection after HAI chemotherapy.⁶ Furthermore, the need for a surgical procedure to implant the catheter into the gastroduodenal artery, the wide range of anatomic variations of hepatic vasculature, and the catheter-related complications have represented other significant limiting factors to the extensive application of HAI therapy in patients with metastatic liver disease.¹⁰

A number of strategies have been adopted in an attempt to overcome treatment-limiting toxicity of HAI with FUDR. The Memorial Sloan-Kettering group has been able to markedly diminish hepatic toxicity through the use of dexamethasone, as well as lowering of the FUDR dose and close monitoring of patients.¹⁰ The description of increased postoperative complication rate following preoperative HAI chemotherapy is limited to a heterogeneous series of 14 patients with primary and metastatic tumors preoperatively treated with different systemic chemotherapy regimens and HAI with FUDR.⁶ In our experience, hepatic resection following preoperative HAI with FUDR is not correlated with increased postoperative morbidity, even in elderly patients.¹¹

Catheter-port systems percutaneously implanted with a transaxillary approach can overcome both the necessity of a major surgical procedure and the presence of aberrant arterial vessels.¹² In a previous study from our institution, complications of 204 patients who underwent percutaneous transaxillary implantation of a catheter for intra-arterial hepatic chemotherapy were evaluated.¹³ HAI therapy could be completed in 91.2% of the patients, and the complication rate was similar to those reported in wide series of surgical implanted devices.⁶ The reduced invasiveness and the reversibility of a percutaneous implant may facilitate an increase in the number of patients treated by HAI therapy and the realization of extensive clinical trials about neoadjuvant HAI chemotherapy.

The recent study of Kemeny et al suggests that HAI with FUDR may be also a valid addition to modern systemic chemotherapy regimens to render resectable previously unresectable liver metastases despite disease progression or prior systemic regimens.¹⁴ The further development of the combination of HAI with modern systemic chemotherapy may address the concern of extrahepatic tumor progression while achieving maximal therapeutic effect in the liver.

We think that, in centers with adequate experience, there are several reasons to consider HAI chemotherapy as a valid downstaging technique for colorectal liver metastases.

First, HAI therapy with FUDR yields tumor response rates similar to modern systemic chemotherapy agents. Second, patients receiving HAI chemotherapy experience fewer side effects than systemic chemotherapy, such as myelosuppression, sensory peripheral neuropathy, and steatohepatitis, which may affect the outcome of subsequent liver resection. Third, percutaneous radiologic implantation of intra-arterial hepatic catheter may overcome the disadvantages of surgical implantation. Fourth, the application of some prophylactic measures and the close monitoring of patients may minimize the potential toxicity associated previously with HAI of FUDR.

Unless new data are available, HAI chemotherapy with FUDR may still be considered a valid strategy for downstaging of unresectable liver metastases from colorectal cancer. However, further studies are necessary to evaluate the impact of preoperative HAI chemotherapy with FUDR on the outcome of liver resection.

Carlo Pulitanò, MD*
Luca Aldrighetti, MD, PhD*
Marcella Arru, MD*
Giordano Vitali, MD†
Monica Ronzoni, MD†
Marco Catena, MD, PhD*
Renato Finazzi, MD*
Eugenio Villa, MD†
Gianfranco Ferla, MD*
Departments of *Surgery–Liver Unit and †Oncology
Scientific Institute H San Raffaele
Vita-Salute San Raffaele University
School of Medicine
Milan, Italy
pulitano.carlo@hsr.it