You
are here: Home: CCU 3 | 2003: Lawrence D Wagman, MD, FACS
Edited comments by Dr Wagman
Rationale for NSABP-C-09: Hepatic artery infusion of floxuridine
Clinical studies have been conducted in the last 15 years evaluating hepatic artery infusion of floxuridine, either as an adjuvant or as a treatment for nonresectable colorectal cancer that has metastasized to the liver. Compared to the systemic agents that were available earlier, it’s a more potent therapy. In nonresectable disease, there are higher response rates using hepatic arterial infusions of floxuridine.
A recent Phase III single-institution randomized trial by Nancy Kemeny at Memorial Sloan-Kettering added systemic 5-FU/leucovorin to floxuridine hepatic artery infusions that were administered after complete resection of hepatic metastases. There was a statistically significant improvement in the disease-free survival for the patients treated with both intrahepatic and systemic therapy. That trial generated renewed interest in floxuridine hepatic artery infusions.
NSABP-C-09: Phase III randomized trial comparing oxaliplatin/capecitabine with or without hepatic artery infusion of floxuridine
The NSABP-C-09 trial currently in development will assess the value of adding a hepatic artery infusion of floxuridine to systemic capecitabine and oxaliplatin following resection, ablation, or both, of liver metastases. Patients with colorectal cancer who have no more than six hepatic metastases and no extrahepatic disease will be randomized to either pump placement or no pump placement. The treatment arms are nearly parallel, except for the addition of the hepatic artery infusion.
The trial allows either cryoablation or radiofrequency ablation of the hepatic metastases. Standardization of the ablation is critical and will be accomplished primarily by intraoperative identification of the lesions on ultrasound, which is equivalent and sometimes slightly better than intraoperative palpation of the liver by the surgeon. An ultrasound of the lesions will be taken at the time of needle (radiofrequency ablation) or probe (cryoablation) placement to document the placement and then after the completion of the ablation. We will review the first three cases for all the sites participating in the trial.
Input from the medical oncologists on the protocol-development team assisted in making the decision to use postoperative oxaliplatin and capecitabine. Reports of toxicities with irinotecan led us to be more interested in oxaliplatin as one of the two primary agents in the protocol. Oxaliplatin has now taken a very important position in our trials.
Capecitabine is particularly interesting because it’s an oral agent. It relieves the complexity of delivery but is still administered over an extended period of time. Because capecitabine is absorbed in the gut, it goes to the liver via the portal circulation. In that sense, we’re achieving both a portal infusion and an arterial infusion. Although we’ve never proven that or evaluated drug levels, it’s a very interesting concept. Another attractive feature of capecitabine is its preferential up-take by cancer cells. In Phase II trials, oxaliplatin and capecitabine together have activity that exceeds 5-FU/leucovorin.
Quality-of-life issues associated with hepatic artery infusion of floxuridine
NSABP-C-09 will also have a quality-of-life analysis to help us decide which of the therapies is better in terms of the patient’s psychological and physical response to having a pump. We’ve completed a pilot quality-of-life study at the City of Hope in patients with pumps. Patients are very aware of the presence of the pump, and there’s more pain when they are rolling over in bed. Psychologically, though, some of the patients describe an increased sense of protection because they have an additional therapy, whereas other patients sense they are getting more therapy, which puts more pressure on them.
The side effects from hepatic artery infusion definitely affect how patients feel. Patients who develop a rise in their liver function test levels and an elevated bilirubin level may start to notice the obvious manifestations — jaundice and more fatigue. The symptoms may be minimal; therefore, it is important for oncologists to do the blood work on schedule. After two weeks of an infusion, patients can feel 100 percent, but they may actually be developing abnormalities in their liver function that require either a dosage reduction or holding the drug.
Management of patients with colorectal cancer with liver-only metastases
Our first choice for these types of patients — who are willing to enroll and meet the eligibility criteria — is the North Central Cancer Treatment Group Phase II trial evaluating the treatment arm of the proposed NSABP-C-09 trial. Those patients will have their liver metastases resected or ablated. Then, they will receive a hepatic artery infusion of floxuridine and systemic oxaliplatin and capecitabine. If patients don’t want to enroll in that trial, we offer them similar therapy off protocol.
We also offer these patients participation in a trial we have been conducting at the City of Hope for a number of years. Instead of a hepatic artery infusion, we use a portal vein infusion of floxuridine. We use portal vein infusions only in patients with completely resected disease.
Portal vein infusions
We’re probably the only ones who have studied portal vein infusions in the adjuvant setting. It was studied in patients with nonresectable disease and found to be ineffective. Portal vein infusions have no value in that setting because a metastasis that is one-half to one centimeter has primarily hepatic artery perfusion. On the other hand, the blood supply to very small metastases is a mixture from the hepatic artery and the portal vein.
Although we have never done a prospective randomized trial comparing infusions in the hepatic artery to infusions in the portal vein, our experience indicates that the outcomes with portal vein infusions are very similar to those with hepatic artery infusions. Additionally, the toxicity with the portal vein infusion is much lower. Chemical hepatitis is essentially nonexistent with portal vein infusions. There is no biliary sclerosis or long-term complications such as stenosis of the bile ducts that is associated with hepatic artery infusions. The mechanical complications and infection rates with both methods of administration are the same.
Select publications
|
