SIR-Spheres microspheres are delivered slowly into the tumor vasculature via a microcatheter.
Illustration courtesy Sirtex Medical Inc.
The 5-year survival rate for patients with metastatic colorectal cancer (CRC) remains dismal.1
Liver metastases are a particularly common occurrence, developing in approximately half of all patients with colorectal cancer.2
While surgical resection is the current standard of care, only 10% to 15% of patients are eligible at diagnosis.3
Several lines of systemic chemotherapy and targeted agents are used in patients with unresectable disease, but these treatments are associated with significant toxicity, and patients eventually become refractory to them.
In an effort to improve outcomes for patients with metastatic CRC, liver-directed regional therapies that exploit the differential blood supply of the tumor and healthy tissue have been developed. Among them, selective internal radiation therapy (SIRT) has been proved safe and effective in a number of clinical settings. Here, we describe the clinical development of SIRT using SIR-Spheres microspheres, and the SIRFLOX trial, the results of which are eagerly anticipated.
SIRT: Liver-Directed Therapy
External beam radiation therapy (EBRT) has shown limited utility against primary tumors and metastases of the liver, as healthy liver tissue is highly sensitive to radiation. SIRT is a form of radiotherapy designed to specifically target the tumor with high doses of radiation, while sparing normal liver tissue.4,5
Also known as radioembolization, SIRT capitalizes on the fact that healthy liver tissue derives the majority of its blood supply via the portal vein, while the tumor, which requires oxygenated blood, uses the hepatic artery. Via SIRT, doses of internal radiation up to 40 times higher than conventional RT can be noninvasively targeted to the liver.6
The radioisotope yttrium-90 is most commonly used with SIRT. A high-energy, beta-emitting isotope, it ensures localized spread of radiation as it penetrates only around 2 mm into the tissue. It is also beneficial because of its medically useful halflife of 64 hours and its benign safety profile.7,8
FDA-Approved SIR-Spheres: Safety and Efficacy in Metastatic CRC
SIR-Spheres (Sirtex Medical Inc) microspheres are resin-based delivery devices for yttrium-90 administration, which are approved by the FDA for the treatment of colorectal liver metastases. They consist of biocompatible polymer microspheres with an average diameter of 32.5 μm—about the size of four red blood cells. They are injected into the hepatic artery via a femoral catheter and travel to and lodge in the tumor vasculature, where the yttrium-90 irradiates the tumor over its half-life of approximately 64 hours, inducing tumor cell death.8-10
SIRT can be performed in the outpatient setting as it has a good safety profile. Postembolization syndrome (severe nausea, vomiting, and abdominal pain that requires ongoing hospitalization) is common with certain liver-directed therapies, such as drug-eluting beads and transarterial chemoembolization, but is not a common occurence after SIRT and typically does not require hospitalization when it does occur.11-13
To reduce the risk of complications, careful patient selection and a meticulous pretreatment assessment are performed. Angiography is used to examine the arterial anatomy; extrahepatic vessels branching off of the hepatic artery are prophylactically occluded to prevent delivery of microspheres outside the liver. Technetium-99m–labeled macroaggregated albumin (99mTc-MAA), which closely mimics yttrium-90 distribution, is used to evaluate the degree of arterial shunting from the liver to the lungs and gastrointestinal (GI) tract. Shunting of >20% is a contraindication to therapy, as it can lead to radiation pneumonitis or GI ulceration.14
The implantation procedure is performed approximately 1 week after assessment is completed.
Dosimetry is based on whole liver infusion; the calculated activity (GBq) of the whole liver is multiplied by the ratio of the target site (the whole liver). Several methods of dosimetry are available, but the body surface area method is the most widely used and recommended.9,14
Anticipation of SIRFLOX Results
FDA approval of SIR-Spheres was granted in 2002 as a result of a trial of 74 patients with nonresectable liver metastases from primary CRC. SIR-Spheres were administered both as first-line therapy and in patients who had received prior chemotherapy. There was a significant improvement in response rate and time to progression.15
Since then, a number of prospective clinical trials have demonstrated the safety and efficacy of SIR-Spheres as first-line, second-line, and salvage therapy.16