Yttrium-90 Within Glass Spheres for Mixed Hepatic Cancers

September 1, 2001

SAN FRANCISCO-Glass microspheres embedded with yttrium-90 (TheraSphere) infused into the liver appears to be a promising treatment strategy for mixed hepatic cancers, with possible application in other cancers, according to a poster presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1038).

SAN FRANCISCO—Glass microspheres embedded with yttrium-90 (TheraSphere) infused into the liver appears to be a promising treatment strategy for mixed hepatic cancers, with possible application in other cancers, according to a poster presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1038).

The insoluble glass microspheres are delivered through a catheter to the hepatic artery (via the femoral artery), and are trapped in the hepatic capillaries. The mean sphere diameter ranges from 20 to 30 µm, and each milligram contains between 22,000 and 73,000 microspheres.

The half-life of the beta radiation is 64.2 hours, said David A. Van Echo, MD, professor of medicine, University of Maryland School of Medicine, and director, New Drug Development Program, Greenebaum Cancer Center, Baltimore.

"The problem with radiation traditionally," Dr. Van Echo said, "has been damage to normal tissues. This may be a way to overcome that and deliver doses that sterilize tumors."

The extreme vascularity of tumors, along with the tortuosity and smaller size of their vessels, allows preferential delivery of the microspheres to the tumors rather than to normal tissues. "It is real simple—it is not high-tech," he said.

Two to 5 weeks prior to TheraSphere treatment, patients underwent a hepatic artery angiogram (HAA) to determine vascular anatomy and a technetium 99 MAA (macroaggregated albumin) scan via HAA to determine regional perfusion and to detect extrahepatic shunting. Six of 51 patients treated to date have been excluded due to shunting to the lungs or GI tract of greater than 5% to 10%.

Dr. Van Echo said that the MAA scan predicts the microsphere capture rate for the tumor and for normal tissue, because the albumin particles are the same size as the microspheres.

"There have been no changes in liver function tests, no increases in bilirubin—no signs of hepatic dysfunction whatsoever. So we know we are getting preferential distribution," he said.

Dr. Van Echo gave a preliminary report of delivery of the microsphere solution in 18 patients with unresectable intrahepatic carcinoma confined to the liver. Primary tumors were 11 colorectal, 3 neuroendocrine, 2 unknown, 1 bile duct, and 1 breast. Seven patients had prior liver procedures, and 10 had prior chemotherapy. All patients had performance status 0-2, with a median of 0, and normal blood work.

Treatment was delivered successfully (mean dose, 143 Gy; target dose, 140 Gy) in all but one patient, who required re-administration 35 days later to attain adequate radiation dosing. Where shunting to other organs was encountered (10 patients), coil embolization of visceral arteries was performed. Although the first five patients treated were kept overnight, subsequent patients, condition allowing, were able to go home the same day as treatment.

Dr. Van Echo reported that all three patients with neuroendocrine-like carcinoid tumors had a complete response. Furthermore, among 10 colorectal cancer patients who had failed chemotherapy, one fourth responded and half remained stable with normal functioning. "This is a group in which you would expect no responses," Dr. Van Echo commented.

Toxicities included vomiting in five patients (grade 3 in one patient), mild fever in four patients, and postembolization pain in four patients. Delayed onset (days 11 to 18) abdominal pain was reported in four patients; one had a documented radiation-induced gastric ulcer. Pain resolved in three of these patients 6 to 8 weeks later.

Rapid tumor lysis as a result of treatment may have caused a stroke in one patient, and hepatic laceration subsequent to extensive tumor necrosis occurred in another.

More than 50,000 patients annually in the United States would be potential candidates for this treatment. "In theory, if you have a highly vascular tumor, such as a neuroendocrine tumor, it should do better with this treatment, but I am not prepared to say that it will not work in relatively avascular tumors. Colon cancer is relatively avascular, and we are getting good response rates in these patients," Dr. Van Echo said.

Side effects are a concern. About 25% of patients, Dr. Van Echo stated, are experiencing GI toxicity, with abdominal pain starting 2 to 4 weeks after treatment and persisting for 6 to 8 weeks. The researchers are now using a split-dose regimen in which the right lobe of the liver is treated first and then the left lobe 2 to 4 weeks later. This has dramatically reduced GI toxicities, he said.

Dr. Van Echo added that results among subsequent patients treated (current total = 45) are consistent with those in this preliminary report. He suggested that TheraSphere might be a first-line treatment for primary hepatocellular cancer, for carcinoid tumors, or for colorectal cancers, and ultimately could be used as an adjunct to chemotherapy. "This represents a completely non-cross-resistant mechanism," he pointed out.

Use to date has been under an HDE (humanitarian device exemption) granted to MDS Nordion, which makes TheraSphere, and has been covered by Medicare and other insurance.