Making Strides With Microspheres: Trial Aims to Extend SIR-Spheres Usage in CRC Liver Metastases

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.

SIRT: Liver-Directed Therapy

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.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

FDA-Approved SIR-Spheres: Safety and Efficacy in Metastatic CRC

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.^7,8SIR-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.

Anticipation of SIRFLOX Results

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.^9,14FDA 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

According to Michael Pishvaian, MD, PhD, assistant professor in the Department of Hematology/ Oncology at the Lombardi Comprehensive Cancer Center in Washington, DC, “Traditionally, [SIRSpheres] have been used primarily for refractory patients who have no other therapeutic options, but there’s a growing body of data indicating that using them earlier in the course of therapy may improve therapeutic outcomes, and that combining them with chemotherapy concurrently is safe.” Several studies are investigating the utility of SIRSpheres treatment in combination with standard chemotherapy earlier in the course of disease.

One such study is the SIRFLOX trial (NCT00724503), an international, multicentered, randomized, controlled study evaluating the combination of SIR-Spheres and FOLFOX-6m chemotherapy (oxaliplatin, leucovorin, and 5-fluorouracil) compared with FOLFOX alone in patients with nonresectable liver metastases from primary CRC who have not yet received chemotherapy for advanced disease.

Investigators were also allowed to add bevacizumab (Avastin) to either arm at their discretion. The study has completed enrollment (532 patients), and results are expected to be available in early 2015.17 “It is hypothesized that the addition of SIRSpheres will improve progression-free survival in the SIR-Spheres + FOLFOX arm compared with FOLFOX,” stated Marwan Fakih, MD, professor of Medical Oncology and Experimental Therapeutics and director of GI Medical Oncology at City of Hope Comprehensive Cancer Center in Duarte, California. According to Fakih, “The sample size to achieve an 80% power in confirming this hypothesis is 450 patients, so with over 530 patients enrolled, the study is well powered.”

Providing further detail on the two treatment arms, Fakih explained, “Patients on the SIR-Spheres arm receive SIR-Spheres during the first cycle of FOLFOX (day 4) and the dose of oxaliplatin is attenuated on cycles 1 to 3 of treatment to reduce the risk of severe bone marrow suppression. In the event that an institute elects to use bevacizumab as part of the treatment arms on SIRFLOX, bevacizumab is added starting with cycle 1 on the FOLFOX arm and starting with cycle 4 on the FOLFOX + SIR-Spheres arm.” More than 100 hospitals have participated over the past 6 years, including 21 sites in the United States, and enrollment was completed in April 2013. The primary endpoint is progression-free survival (PFS), while secondary endpoints include response rate, overall survival (OS), and liver PFS. Fakih stated that the first reports on PFS data are expected in early 2015.

Pishvaian pointed out that Sirtex has already presented favorable interim safety data, and he expects that the final results from SIRFLOX will provide further confirmation of this. Among 122 patients, the safety profile was comparable to or better than standard chemotherapy; the most common adverse events were nausea (59%), vomiting (31%), diarrhea (47%), constipation (22%) and abdominal pain (18%).^17,18

Both Fakih and Pishvaian noted that a similar international study, the FOXFIRE trial, is also currently enrolling patients. Data analysis from these two frontline studies will be pooled to further increase the power of the studies and to definitively determine the OS endpoint.

Fakih explained that combining SIR-Spheres with standard chemotherapy is an important strategy that may have the potential to downstage hepatic metastases and increase resectability rates, or even prolong disease control. He believes that if these trials confirm the efficacy of this combination, “It will result in a shift in the standard of care and move the application of SIRT from the later lines of treatment to the front line in liver metastases [that are] dominant [in] CRC.” Pishvaian also believes that these studies will provide “critical data to see whether this paradigm actually improves survival.”

Although experts in the field agree that SIRSpheres should help to downstage tumors and increase the proportion of patients who are eligible for resection, in a recent special report for Clinical Oncology News, N. Joseph Espat, MD, professor, director of the Cancer Center, and chief of surgical oncology at Boston University, observed that there is still a common misconception that surgical resection is not possible after SIRT.¹⁶

“The data on surgical resection after SIR-Spheres [are] really limited, but at the same time, it does seem promising from the point of view of safety,” stated Pishvaian. Espat and Pishvaian both pointed out that there have been a series of anecdotal reports of patients who have successfully undergone surgical resection after SIRT. Pishvaian believes that Sirtex has been gathering these anecdotes together, with a view to publishing them in the near future.

References

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