Hepatic Artery Infusion: Still an Option?

Time and science have been kind to patients with colorectal cancer metastatic to the liver. The combination of a decrease in surgical mortality, increased operative tools, increase in the number of active chemotherapeutic drugs— both general and targeted—accompanied by an acceptance of multimodality therapies have improved patient outcomes. A few tools have maintained a quiet hum in the treatment cacophony. The focus of the paper by Ammori et al. is one of those tools: the continuous hepatic artery infusion (CHAI) pump. Emerging in the 1980s as an effective method of delivering floxuridine to the liver via the hepatic artery, its success was consistent but simultaneously limited to a few centers and physicians (medical oncologists and surgeons) who had adequate and specific skill in using this treatment modality. There were many challenges to the use of continuous infusion hepatic artery delivery of floxuridine. They included the complexities of managing the idiopathic liver transaminitis with appropriate dose reductions, surgically placing the pump and working through the vagaries of the hepatic arterial anatomy, dealing with the mechanical challenges of accessing the chambers for filling, and removing the drug and replacing with heparinized saline, and a continued surveillance for late biliary sclerosis. Clearly, using the technology in the ‘‘adjuvant setting,’’ i.e., following hepatic resection for colorectal metastases, was most problematic. The saving grace in this setting was that the patient did not require an additional surgery for the pump placement; however, concerns of functional liver reserve and recovery created an enhanced anxiety. Despite all the challenges, the committed group of oncologists (medical and surgical) consistently demonstrated in pilot and phase 2 studies, a series of outcomes that exceeded those generated with only the systemic chemotherapy available during the same time period. When the limited choice for chemotherapy morphed from 5-fluoruracil and leucovorin—excellent agents with known toxicity and carefully studied therapeutic regimens— to oxaliplatin, irinotecan, capecitabine, and subsequently the targeted agents led initially by bevacizumab and cetuximab, that’s when things changed. An enthusiasm for the new agents with potential for sequential use and improved response rates emerged. The CHAI with the reasonably toxic floxuridine fell from favor and nearly all medical oncologists began to transition their clinical practice to the new systemic agents. A few strongholds of CHAI remained active but the incorporation of pump based chemotherapy rapidly lost ground. The clinical trials that had been developed during the height of interest in pump therapy suffered poor accrual and failed to definitively answer the question of superiority or even equivalence (noninferiority). During this same timeframe came the battle cry for more aggressive surgical approaches following successful ‘‘neoadjuvant’’ conversion chemotherapy. The selection of neoadjuvant treatments were focused on efficacy measured as response and safety as measured by the morbidity and mortality of the subsequent operations. Those practitioners with experience in CHAI accepted and worked around the hepatocyte damage as measured in the hepatic transaminitis and the measurable and presumed intraand extrahepatic biliary injury that resulted from the chemotherapy-infused blood bathing the biliary structures. Thoughtful attempts to reduce the injury with dexamethasone were admirable but not adequate to consistently reduce hepatic injury. The ‘‘soft’’ hepatic damage of oxaliplatin (sinusoidal injury), fluoropyrimidine and irinotecan (steatosis), and bevacizumab pales compared with a liver arterially infused 2 weeks on and 2 weeks off with floxuridine. It is almost ironic to consider the current restrictions on timing of hepatic surgery after systemic chemotherapy compared with the post-CHAI liver. So where does this leave us when faced with colorectal cancer metastatic to the liver? Metastatic disease that is resectable at presentation may or may not be treated with Society of Surgical Oncology 2013