MIAMI BEACH – A novel percutaneous system for isolating hepatic blood flow allowed clinicians to treat hepatic melanoma metastases with a high concentration of melphalan and then filter out the drug to minimize its entry into the systemic circulation in a study of 93 patients.
This method for percutaneous hepatic perfusion (PHP) produced a more than fourfold increase in the average duration of hepatic progression-free survival in PHP patients compared with control patients in the phase III, randomized controlled trial, Dr. Charles W. Nutting said at ISET 2011, an international symposium on endovascular therapy.
Based on these results, the company that developed the percutaneous catheter system, Delcath Systems, filed a new drug application with the Food and Drug Administration.
"High-dose melphalan, delivered via intra-arterial administration with subsequent hepatic hemofiltration, is effective against hepatic metastases from ocular and cutaneous melanoma and provides improved disease control when compared with standard treatment regimens," said Dr. Nutting, an interventional radiologist at Swedish Medical Center in Denver.
"The FDA told us what result they would want to see" to approve PHP – an average duration of hepatic progression-free survival of 7.7 months in PHP patients and an average 4.0-month survival in control patients, Dr. Nutting said in an interview.
"The results exceeded that," he noted, with an average hepatic progression-free survival of 245 days (8.2 months) in the patients randomized to initial PHP and an average of 49 days (1.6 months) in control patients who received best alternative care. The hazard ratio for the PHP patients compared with the controls for this primary end point was 0.301 (P =.0001.)
PHP is "now one of the primary treatments" for inoperable melanoma liver metastases in patients whose most significant disease is in the liver, he added.
The clear success of PHP also suggested that the method might also help patients with other types of liver tumors, including primary cancers and other malignancies that often metastasize to the liver, such as colon cancer, Dr. Nutting said.
The researchers who developed PHP envisioned it as a potentially easier-to-tolerate variation on isolated hepatic perfusion, a method first used more than a decade ago that involved an open surgical procedure to isolate the hepatic circulation (J. Am. Coll. Surg. 2000;191:519-30). It was so invasive, however, that each patient could tolerate only a single treatment, Dr. Nutting said.
The percutaneous approach, developed as a more tolerable alternative, was applied serially one to six times to each patient in the PHP arm of the current trial with a 4-week interval between treatments.
The procedure involves inserting a double-balloon catheter from the patient’s groin through the hepatic artery and into the inferior vena cava. The superior balloon is then inflated and brought down to occlude the upper hepatic veins, while the second balloon is inflated below the hepatic veins to isolate hepatic venous return. A continuous infusion of melphalan enters the patient via a second catheter into the hepatic artery. After the drug distributes through the liver, the first catheter sucks out the hepatic venous blood (which is blocked by the two balloons from entering the systemic venous flow) via a set of holes and shunts it to an externally placed filter at a rate of 500 mL/min. After the blood is cleansed of the drug, it is returned to the patient.
The total melphalan dose delivered is 3.0 mg/kg ideal body weight of the patient, with the total dose diluted in 500 mL of fluid. The system takes 30 minutes to pump the entire dose into the patient, after which the balloons isolating the hepatic venous system and the filtration mechanism remain in place for another 30 minutes to continue to cleanse the drug from the patient’s liver. The system cuts systemic exposure to the melphalan by 80% compared with the intrahepatic dose delivered, Dr. Nutting said.
The study enrolled 44 patients into the PHP arm and 49 into the control arm at 12 U.S. centers. All patients had metastatic melanoma that primarily affected the liver and was judged too extensive for surgical removal. Patients had a median of 20 hepatic metastases (range, 4-100). In 88% of patients the primary tumor was ocular melanoma, and 12% had cutaneous melanoma. Their average age was 55 years.
Despite the high melphalan dose used, the 40 PHP patients included in the safety analysis had "minimal toxicity that was well within acceptable limits for the doses of medication we gave," he said.
During the 116 total treatments these patients received, grade 3 or 4 neutropenia occurred after 61% of treatments, thrombocytopenia after 74%, and anemia after 47%. Grade 5 neutropenia occurred following two treatments, but these episodes were usually transient and manageable. A total of three patients in the PHP group died, two from neutropenia sepsis and one from hepatic failure.