It took nearly 25 years, but advances in technology — an investigator’s insight — and a device company’s “leap of faith” have led to a major step forward in the treatment of unresectable hepatocellular carcinoma (HCC).

After decades of negative studies looking at selective internal radiation therapy (SIRT) for primary HCC, the DOORwaY90 study took a new approach: Researchers used personalized advanced dosimetry to target primary tumors in the liver using SIR-Spheres Y-90 resin microspheres (Sirtex Medical) and demonstrated remarkable response rates and duration of response.

The findings prompted the first expanded approval for SIR-Spheres since the device’s initial approval for unresectable liver metastases from primary colorectal cancer in 2002.

The FDA expanded the indication in July 2025, making SIR-Spheres the first SIRT device to be approved in the US for both metastatic CRC of the liver and the first-line treatment of primary HCC tumors.

“After more than two decades, the device is reaching its maturity after having been used without reaching its maximum potential,” Armeen Mahvash, MD, co-principal investigator of the DOORwaY90 study, told Medscape Medical News.

And that may open the door to new uses of SIRT, he said.

SIRT: The Long Road to Progress

SIRT, also known as radioembolization, was first explored in the 1980s. That first SIR-Spheres approval in 2002 was for combination radioembolization with intra-arterial chemotherapy, although intra-arterial chemotherapy is no longer used.

A similar device — TheraSphere Y-90 lass microspheres (Boston Scientific) — had also received an FDA humanitarian device exemption in 1999 based on probable benefit for HCC. The retrospective LEGACY trial led to TheraSphere earning FDA premarket approval for solitary primary HCC in 2021, while Boston Scientific’s EPOCH trial failed to result in an approval of the device for metastatic CRC. This was due to no clinically significant survival benefit having been observed among treated patients, said Mahvash, who was also an investigator on the EPOCH trial.

The devices consist of microspheres — tiny beads about 32 microns in diameter or about a third of the width of a human hair — that are infused by the millions via hepatic arteries to deliver high doses of the radioactive element yttrium-90 to tumors while minimizing effects on healthy surrounding tissue.

During the early studies of these devices, the technology for assessing the radiation dose achieved during treatment was limited.

Better Dose Calculations, Better Outcomes

Prior studies, such as the 2017 SARAH trial and 2018 SIRveNIB trial didn’t rely solely on modern dosimetry. Instead, they most commonly used “methods that lacked complexity in calculations,” which likely resulted in inadequate radiation doses — and negative study results, said Mahvash, an interventional radiologist at MD Anderson Cancer Center, Houston.

He also noted that more modern approaches weren’t commonly used at the time.

Over the years, researchers and clinicians “kind of lost confidence in whether the treatment worked or not,” he said.

With advancing technology, the ability to overcome earlier limitations in dose calculations emerged. For example, studies began to demonstrate that partition model dosimetry provided better dose calculation vs the simpler body surface area model typically used in earlier studies.

Mahvash, drawing on his mechanical engineering background, then began looking more closely at the doses given during radioembolization to see if more careful dosing calculations could make a difference in outcomes.

Having achieved some success with the approach at MD Anderson, thanks to modern software that supported advanced dose calculations, he began working with Sirtex Medical and a physicist colleague at MD Anderson to design a new study that incorporated newer technology and techniques. The prospective, multicenter, open-label DOORwaY90 study began enrolling patients at 18 centers in 2021 with Mahvash and physicist S. Cheenu Kappadath, PhD, as co-principal investigators.

A New Kind of Trial

One unique feature of DOORwaY90 was the greater use of partition model dosimetry, Mahvash explained.

Using the more advanced techniques and modern software, he and his colleagues worked with each of the sites that enrolled patients into the trial to create a “rational dose plan for each patient.”

“We also imaged each patient after treatment to confirm if the dose delivered matched the plan,” he said. “This told us whether we were actually doing what we planned to do to achieve the dose intended.”

Another unique feature of the study was that patients who didn’t receive the intended dose could be retreated, he noted.

Investigators enrolled 100 patients with unresectable/unablatable HCC. Partition model dosimetry was used to determine optimal dosing, and patients were assessed using posttreatment dosimetry at baseline and at regular intervals for up to 1 year.

Two patients were found to have received an inadequate dose and were retreated.

Of 65 patients included in a preplanned interim analysis, 64 had responded and the co-primary endpoint of best overall response rate (ORR) was 98.5%. At 1-year follow-up after treatment, none of those who responded had experienced disease progression, Mahvash said.

The 98.5% best ORR and 100% duration of response far exceeded the 40% primary response rate and 60% sustained response rate the FDA had required for approval, Mahvash noted.

“This study moves the field of radioembolization forward with reproducible dosimetry outcomes and a strong safety profile linked to very positive clinical results,” he stated in a press release at the time the interim study results were published. “This will give multidisciplinary care teams the confidence to recommend SIR-Spheres for HCC treatment.”

Asked if there are lessons to be gleaned from the journey to this expanded approval, Mahvash said that Sirtex Medical “took a leap of faith and showed that this type of study, which never had been done before, can be done successfully.” 

“It’s about applying good science, collaboration with industry and other clinicians and researchers, and a willingness to be flexible and do something different as technology evolves,” he said.

A Launching Pad for SIRT Expansion

The success of DOORway90 could serve as “kind of a launching pad for similar successes in this space,” Mahvash added.

One possible new indication for radioembolization is the treatment of primary cholangiocarcinoma.

“That is definitely a potential use,” he said, noting that SIRT is currently used off-label for cholangiocarcinoma.

Studies have also been conducted in kidney cancer, including the ongoing RENEGADE trial at UCLA, which is evaluating TheraSphere for early-stage renal cell cancer.

Boston Scientific is also looking at TheraSphere in combination with immunotherapy for HCC in studies, including the ROWAN study evaluating local tumor control in patients with HCC treated with TheraSphere followed by durvalumab and tremelimumab.

In a September 2024 paper published in Therapeutic Advances in Medical Oncology, Arian Mansur of Harvard Medical School, Boston, and colleagues added prostate cancer and lung cancer to the list of potential SIRT targets.

The authors also highlighted emerging advances in radioembolization, such as the development of Holmium-166 — a neutron-activated isotope used as an alternative to Y-90 for SIRT — and the expansion of the use of SIRT from “a palliative option for the treatment of hepatic tumors…to its inclusion as an option with curative intent.”

“Growing advances in radioembolization and its dosimetry continue to expand the treatment options for patients with liver tumors. Novel indications for radioembolization are emerging and offer a promising treatment for future research and clinical applications,” they concluded.

Mahvash disclosed receiving research support and/or consulting fees from Sirtex Medical, Boston Scientific, and Siemens Healthineers. Mansur reported having no disclosures.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.