July 14, 2008

Small Beads, Big Hope — Radioembolization With Microspheres Targets Liver Cancer
By Dan Harvey
Radiology Today
Vol. 9 No. 14 P. 26

The American Cancer Society estimates that 21,370 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the United States this year. Additionally, about 18,410 people (12,570 men and 5,840 women) will die from these cancers—and the problem could substantially worsen. U.S liver cancer diagnoses have increased and are expected to continue rising due to the growing number of people infected with hepatitis B and C.

This deadly disease manifests mostly as metastatic or primary liver cancer, the most frequent of which is hepatocellular carcinoma (HCC), which starts in the liver and is the fifth most common cancer in the world. Patients diagnosed with it often die within a year.

But new hope for treating those with liver cancer presents itself in a small package: microspheres. These minute particles, which measure about 30 microns, or one third the diameter of a hair strand, are used in a novel radioembolization procedure that can improve survival and enhance quality of life.

“Microspheres are glass beads bonded with Yttrium 90 [Y-90], an isotope that emits beta radiation,” explains T. Clark Gamblin, MD, an assistant professor of surgery at the University of Pittsburgh School of Medicine, where the devices are being put to clinical use. “Several years ago, microspheres gained [FDA] approval for the treatment of metastatic colorectal cancer.”

The microspheres have demonstrated promise in treatment of unresectable HCC. More than 1 million people throughout the world are diagnosed with HCC each year, and 90% of them have tumors that cannot be removed by surgery.

Selective Targeting
Microsphere treatment is based on the concept of selective internal radiation therapy (SIRT), a technique that minimizes the risk of nontarget radiation by delivering radiation doses directly to the tumor site, utilizing a tumor’s own hypervascularity. During this minimally invasive procedure, millions of radioactive microspheres are placed in the liver via a catheter infusion. Once inside, they selectively target tumors with internal radiation doses, and SIRT (basically a brachytherapy process) can target and destroy liver tumors inaccessible by other techniques.

The treatment, which is administered by interventional radiologists, effectively addresses major limitations of external beam radiotherapy applied to primary and metastatic liver tumor treatment. Radiation doses that are necessary to destroy solid tumors are more than a liver can withstand, and external radiation therapies can’t focus tightly on a tumor, which impacts surrounding healthy tissue and causes significant side effects.

“Microspheres are very effective tools,” says May Abdel Wahab, MD, an associate professor of radiation oncology at the University of Miami School of Medicine, which is one of the few U.S. facilities that offers this treatment. “While options such as external beam radiation therapy are limited in terms of tumor size and radiation dose, this method has such a low penetration. That’s very significant, as it isn’t something you generally see in radiation oncology. So microspheres enable us to do something we couldn’t do before.”

She adds that this treatment provides an option besides surgery or radiofrequency ablation, and it is well tolerated by patients.

Currently, two Y-90 labeled microsphere products are available in the United States: SIR-Spheres from Sirtex Medical Ltd. and TheraSphere from MDS Nordion Inc. “They’re very similar in terms of composition and function,” says Gamblin, who uses both products. “Both are biocompatible glass beads that are implanted into the liver by embolization through the hepatic artery.”

The procedure is comprised of two major components: embolization and brachytherapy. It begins with a small incision in a patient’s upper thigh, which allows the interventional radiologist to place a catheter into the femoral artery. Then, utilizing fluoroscopic guidance, the radiologist maneuvers the catheter toward the hepatic artery, one of two blood vessels that supply blood to the liver. “Because at least 90% of the blood flow to the tumor is supplied by the hepatic artery, the device provides a unique opportunity for us to focus treatment toward liver cancer,” says Gamblin.

The catheter is then guided into the hepatic artery branch feeding the liver tumor. “That’s when the microspheres are injected through the catheter and into the tumor blood supply,” explains Wahab, who uses the TheraSphere product. “The blood carries the microspheres to the tumor area of greatest vascularity where they become trapped.”

Once trapped, the microspheres emit their beta radiation. This destroys the tumor by reducing its blood supply, which is the embolic effect, as well as by damaging the cancer cells’ DNA. “I think it’s an ingenious idea to use the blood supply to the tumor as a weapon against the tumor itself,” Wahab says.

The targeted radiation is contained within the patient’s body and delivered over a two-week period as the radioactivity decays.

Vital Preparation   
Wahab notes that careful preparation is needed before microsphere treatment. “Because the technique is driven by the vasculature, the microspheres can potentially travel anywhere throughout the body,” she points out. “To prevent this from happening, we perform a couple of procedures before treatment.” These include an angiogram to determine if any vessels leading to other body areas need to be coiled. “For example, we sometimes need to coil some vessels leading to the stomach. If the microspheres entered the stomach, a patient could develop gastric ulcers,” she says.

Also, to prevent any damage to the lung, the physicians perform a nuclear technetium-99m macroaggregated albumin (MAA) study. Physicians use it to assess the proper placement of venous and arterial access systems. This avoids risk of leakage and ensures that therapeutic agents are delivered as intended.

Gamblin says that at the University of Pittsburgh, pretreatment preparations include CT scans, as well as angiograms. “We gauge the administered amount of radiation based on these two studies,” he says. “The CT scan examines the volume of the portion of the liver to receive treatment. We use angiograms to examine the arterial anatomy to make sure the microspheres only go to the liver and not the intestine, lung, or other places. You have to be very careful when doing this procedure.”

As far as follow-up protocols, Gamblin says that for patients with colorectal cancer, University of Pittsburgh clinicians perform a carcinoembryonic antigen blood test. This particular antigen is a tumor marker, and elevated levels are associated with several cancers. “We do that on a monthly basis, and we perform a PET/CT scan every three months,” he says.

For patients with HCC, the physicians follow up with CT scans and an alpha-fetoprotein blood test, which is a normal serum protein synthesized by the liver and useful for diagnosing HCC.

Treatment Time            
Wahab reports that, beyond the preparation, the actual treatment doesn’t take long. “Preparation is what takes up time. The actual microsphere delivery only takes about 20 minutes to a half hour,” she explains.

Treatment can be performed on an outpatient basis, usually within a facility’s radiology suite, with the patient remaining conscious during the procedure. Most often, treatment is administered in two sessions, one involving the liver’s right lobe and the second involving the left lobe. “But it can vary, depending on the clinical situation,” says Wahab. “In many situations, we can do a one-time treatment and that’s it. But if a patient has disease in both lobes, then they would require the staged treatment.”

When two sessions are necessary, treatment is administered about 30 days apart. “The majority of our patients are treated only once on each side of the liver,” says Gamblin.

Indications and Contraindications                 
To undergo treatment, patients need to be at least 18 years old and have a minimum life expectancy of three months. The best-served patients are those who have unresectable hepatic primary or metastatic cancer, where surgery or tumor ablation are no longer practical treatment options. “It’s also viable for patients who fall beyond transplant criteria,” adds Gamblin.

“Also, treatment can be combined with other therapies or as an alternative therapy. It provides us with one more tool in our armamentarium,” says Wahab.

She also points out that it’s possible to downstage tumors with TheraSphere treatment, which could make some patients potential candidates for surgery or transplantation.

“At Pittsburgh, we currently use SIR-Spheres for treatment of metastatic colorectal cancer, and we use the TheraSpheres for treatment of HCC,” informs Gamblin.

However, microsphere treatment isn’t feasible for patients who have undergone external radiation therapy, suffer from clinical liver failure, have more than 20% lung shunting, or have widely distributed or extrahepatic disease. Other contraindications include angiograms or MAA studies that reveal substantial reflux of hepatic arterial blood to the stomach, pancreas, or bowel or tumors that can benefit by surgical resection.

While it is not considered a cure, this treatment can shrink cancer when combined with chemotherapy. Overall, studies show that it has about a three-year survival rate, and the quality of life for patients previously deemed untreatable is improved.

Upcoming Clinical Trial
Microspheres are FDA approved for HCC treatment, as well as for the treatment of unresectable HCC under the provisions of a “humanitarian device exemption,” which restricts medical use. Sirtex Medical recently received an investigational device exemption from the FDA to conduct a clinical trial that will evaluate the effect of treatment with SIR-Spheres on the survival of patients with unresectable HCC.

Gamblin and Ravi Murthy, MD, an interventional radiologist at the University of Texas M. D. Anderson Cancer Center, will serve as the study’s coordinating investigators. “Sirtex wanted to conduct this trial to gain a new indication for its SIR-Spheres product for unresectable HCC, which is a huge global problem,” says Gamblin. “This open-labeled, single-armed trial will examine the feasibility and safety of using SIR-Spheres for unresectable HCC.”

In previous, nonrandomized studies, SIR-Spheres were reportedly effective and well tolerated in patients with unresectable HCC. Also, the company indicates that SIRT using SIR-Sphere microspheres has been used extensively in other parts of the world for HCC treatment. “But this is the first trial of this kind involving this particular microsphere and treatment of unresectable HCC,” adds Gamblin.

The study will include 40 participants aged 18 or older with documented HCC confined to the liver. The study’s primary objective will be to evaluate the impact of SIR-Spheres on those patients’ survival rates. It is also designed to assess treatment safety, time-to-disease progression, health-related quality of life, and tumor response to treatment.

Meanwhile, Gamblin is enthusiastic about microsphere uses and potentials. “It is an exciting technology, and I think it is going to evolve as insurance companies become more aware of it,” he says. “So far, we have seen some dramatic responses to treatment, and it has enhanced patients’ quality of life.”

— Dan Harvey is a freelance writer based in Wilmington, Del., and a frequent contributor to Radiology Today.