Introduction

Over the past decade, there has been an increasing use of transarterial radioembolization (TARE) using yttrium-90 (Y-90) glass microspheres in patients with hepatocellular carcinoma (HCC) across the Barcelona Clinic Liver Cancer (BCLC) classification spectrum. Since the previous publication of clinical and dosimetric considerations for TARE with Y-90 glass microspheres, additional published work has demonstrated the critical role of personalized dosimetry, optimizing dosing and patient selection in achieving improved clinical outcomes [1,2,3]. Additionally, several investigations demonstrated that increasing tumor-absorbed dose increases the likelihood of achieving complete pathologic necrosis, without compromising safety, while limiting toxicity by minimizing normal liver tissue exposure [4, 5]. These investigations have led to the inclusion of TARE in the updated BCLC staging system for treatment of single-HCC lesions ≤ 8 cm [6]. The decision to use single-compartment or multicompartment dosimetry in these studies underscores the importance of matching the appropriate TARE treatment approach with specific patient characteristics and treatment goals [1,2,3]. Given the number of new trials, recent publications, and their rapid impact on clinical practice, the TheraSphere Global DSC was reconvened to evaluate these new data and to update the recommendations [7].

Methods

The committee, comprised of interventional radiologists, radiation oncologists, nuclear medicine physicians, clinical scientists, medical oncologists, and physicists, reconvened for four 2-h virtual meetings, with an additional offline review in preparation for the process of updating the recommendations. During the first meeting, the committee reviewed the prior recommendations, recently published literature, and discussed updates. To identify literature since the prior recommendations, a PubMed search using a combination of the following search terms was conducted: transarterial radioembolization, TARE, brachytherapy, internal radiation therapy, SIRT, Y90, yttrium-90, TheraSphere, hepatocellular carcinoma, and HCC. The committee also considered whether new data warranted changing the degree of recommendation and/or the strength of consensus from the previous recommendations (Tables 1 and 2). Briefly, per the Delphi method, consensus was defined during virtual meetings as outlined in Table 2; strong disagreements by members were recorded and highlighted within the recommendation as caveats, where applicable. During the second and third meetings, committee members reviewed the revised recommendations and discussed each change collectively. Between the meetings, the lead author (RS) revised the recommendations based upon committee discussion and comments. The fourth and final meeting was a comprehensive review of the recommendations and a review of the draft manuscript. Steering committee members then had the opportunity to review and refine the manuscript independently, and final comments were incorporated into the manuscript by the lead author. All authors formally endorsed the manuscript and its recommendations prior to submission.

Table 1 Degree of recommendation
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Table 2 Strength of consensus
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The reviewed literature included all published studies of TARE with glass microspheres for HCC since January 1, 2019; additional studies outside of this timeframe were reviewed if suggested by steering committee members. Publications addressing technical challenges rather than clinically oriented approaches were not included in the review. The recommendations included in this updated document incorporate both the critical literature review and the expert opinion and experience of members of the committee. All recommendations made in Tables 3, 4, 5, 6, and 7 are subject to regulatory and clinical standards within each country.

Table 3 Scenario 1: radiation segmentectomy recommendations using Y-90 glass microspheres
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Table 4 Scenario 2: radiation lobectomy recommendations using Y-90 glass microspheres
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Table 5 Scenario 3: multifocal unilobar HCC without macrovascular invasion recommendations using Y-90 glass microspheres
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Table 6 Scenario 4: multifocal bilobar HCC without macrovascular invasion recommendations using Y-90 glass microspheres
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Table 7 Scenario 5: HCC with macrovascular invasion recommendations using Y-90 glass microspheres
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In light of the changing paradigms and treatment goals associated with Y-90 glass microsphere TARE, the committee agreed to expand the clinical scenarios from four to five, separating multifocal unilobar and bilobar disease recommendations, and to revise the definition of each. The scenarios subsequently addressed in the updated recommendations are as follows:

Curative intent:

  • Radiation segmentectomy: Localized disease (one or multiple tumors located in ≤ 2 segments), with contemporary and modern treatment approaches delivering superselectively to subsegments of liver, referred to as angiosomes (i.e., hepatic territory perfused by a specific branch of the hepatic artery), with the intent of delivering an ablative dose to tumor and normal tissue. Radiation segmentectomy no longer narrowly defined as ≤ 2 segments but rather inclusive of smaller hepatic segmentectomy

  • Radiation lobectomy: Unilobar disease, with the ultimate goal of disease control and contralateral lobar hypertrophy in the context of small future liver remnant (FLR), as a bridge to surgery (resection)

Palliative intent:

  • Multifocal unilobar disease without macrovascular invasion or portal vein thrombosis (MVI/PVT), with the goal of palliation and delay in progression; in select patients, intent may be conversion to curative options

  • Multifocal bilobar disease without MVI/PVT, with the goal of palliating and delaying progression, usually in combination or in sequence with systemic treatment

  • HCC with MVI/PVT, with the goal of palliating and delaying progression; in select patients, intent may be conversion to curative options

Key definitions used throughout this document were defined in the original publication and are reprinted below for ease of reference [7]:

  • Mean absorbed dose: Quantity is expressed in gray (Gy) in order to describe the average energy (J) deposited within a volume of interest (VOI) within a specific given mass (kg). The mean absorbed dose is referred to as “Dose” and is distinctly different than “Activity” or “Dosage” (GBq) [8, 9].

  • MIRD schema: The Medical Internal Radiation Dose (MIRD) schema is applicable to both the single-compartment and multicompartment dosimetry models. The mean absorbed dose (D) in any specific VOI (i.e., perfused volume, lobe, tumor or normal tissue) with mass of any VOI, denoted as M, with the assumption that D is distributed uniformly in each volume with permanent microsphere implantation and no biological clearance [10, 11]. Using this schema, D in a VOI is computed as:

    where A is the net activity of 90Y implanted in the VOI, and F is the lung shunt fraction. As an example, if 2.2 GBq of glass microspheres was infused with a residual of 1% and a lung shunt of 5%, the net implanted activity in the liver tissue would be 2.2 × (0.99) × (0.95) = 2.07 GBq, and 2.07 GBq would represent the final activity within a MIRD formula for determining final tissue dose.

    $${D}_{\left(\mathrm{Gy}\right)}=\frac{{A}_{(\mathrm{GBq})}\times ({50}_{(\mathrm{Gy}/\mathrm{kg}/\mathrm{GBq})}\left(1-F\right))}{{M}_{(\mathrm{kg})}}$$

  • Single-compartment model: A MIRD dosimetry model that assumes the 90Y microspheres (and therefore absorbed dose) are distributed uniformly within the VOI. In this model, only a uniform averaged D value over the VOI is calculated, without consideration of Y-90 activity distribution within the tumor and normal parenchyma. In reality, hypervascular tumors will absorb more microspheres and receive a higher dose, while the normal hepatic tissue will absorb fewer spheres and receive a lower dose [12,13,14].

  • Multicompartment model: A MIRD-based dosimetry approach where D is determined in more than one VOI, such as the tumor VOI and the normal parenchyma VOI. The lung also represents another compartment to which D can be estimated (based on a single-compartment model). Partition modeling refers to the multicompartment dosimetry approach reporting the tumoral and non-tumoral doses separately with a single averaged tumor to averaged non-tumoral uptake ratio (T:N ratio) [10].

Results

Relevant publications from the literature review, including additional suggestions by the committee, resulted in the inclusion of 31 new publications [1,2,3,4,5,6, 16, 17, 19, 20, 24,25,26, 28,29,30,31, 35, 36, 41, 47, 48, 50,51,52,53,54,55,56,57,58] and formed the basis for updates to the recommendations.

Clinical scenarios

Scenario 1: radiation segmentectomy for HCC

Radiation segmentectomy has been previously defined as the administration of Y-90 to ≤ 2 Couinaud segments with curative intent. In practical terms, this translates to subselective or superselective radioembolization. In most scenarios, a superselective, subsegmental infusion covering significantly ≤ 1 is achieved [15, 16]. For radiation segmentectomy, the percentage total liver volume that is treated should be considered. As long as a minimal amount of tissue is exposed, radiation segmentectomy may be considered in the setting of prior surgical resection (particularly if robust post-surgical hypertrophy has been observed). In the presence of stable but reduced hepatic function, radiation segmentectomy should be undertaken using caution and consideration of alternate options [3, 17,18,19]. Details are included in Table 3.

The objective is ablative dosing for both tumoral and non-tumoral compartments as both are expendable in this scenario [3]. The strength of these recommendations was an A in the previous version and remains an A with a strong degree of consensus from the committee; this recommendation was further reinforced by the findings of the prospective RASER study [20]. Partition dosimetry was not recommended by the panel in this scenario.

Scenario 2: radiation lobectomy for HCC

In unilobar HCC patients, resection is often not possible due to small FLR. For these patients, radiation lobectomy may be an option, as delivery of a high dose of radiation to one lobe may trigger the hypertrophy-atrophy complex, inducing hypertrophy in the contralateral lobe and thereby increasing the functional liver volume while controlling tumor growth in the treated lobe (Table 4) [21,22,23,24]. The increased FLR may allow for subsequent curative resection.

Depending on patient biology and mapping results, either single-compartment or multicompartment dosimetry approaches may be used [1, 21, 25, 26]. Hepatobiliary scintigraphy (HBS), including 99mTc-iminodiacetic acid (HIDA) or 99mTc-mebrofenin, and the use of Eovist/Primovist contrast media in magnetic resonance imaging are emerging investigational techniques that are being implemented for regional functional assessment of the FLR before and after Y-90 treatment. Additional data are needed to support a strong recommendation of their use as a standard of care in radiation lobectomy and resection planning [27,28,29]. The strength of these recommendations was previously a B with strong consensus from the committee; despite these additional studies and data, the committee deemed the data to be insufficient to raise the grade to A and maintained the grade of B with strong consensus.

Scenario 3: multifocal unilobar HCC without macrovascular invasion (MVI/PVT)

For patients with multifocal unilobar disease without MVI/PVT, radioembolization can be used for palliation and prevention of disease progression (Table 5). In this population, the goal should be to maximize tumor dose while preserving liver function. The committee recommends that radioembolization be used for Child–Pugh A patients and that a multidisciplinary tumor board review be conducted, especially for Child–Pugh B patients who have more severe hepatic dysfunction [1, 23, 30,31,32]. In select cases, this group of patients may be considered for resection if they exhibit responses and hypertrophy features of radiation lobectomy.

Previously, multifocal unilobar and bilobar diseases were grouped together and granted a B grade with a strong committee consensus; this newly created unilobar disease section has been given a grade of B with strong committee consensus.

Scenario 4: multifocal bilobar HCC without MVI/PVT

In multifocal bilobar HCC without MVI/PVT, the primary goals of treatment are frequently palliation, delaying disease progression, and sequencing with other liver-directed therapies and/or systemic treatment (Table 6). As with other clinical scenarios, the goal should be to maximize the dose of radiation delivered to the tumor while minimizing the dose to remaining normal liver parenchyma. Previously, multifocal unilobar and bilobar diseases were grouped together and given a grade of B with a strong committee consensus; this newly created bilobar disease section has been given a grade of B with strong committee consensus.

Scenario 5: HCC with MVI/PVT

Patients with portal vein thrombosis (MVI/PVT), indicative of advanced HCC, generally have a poor prognosis. Such patients are not usually considered transplantation or resection candidates and may not achieve optimal outcomes with chemoembolization [1, 33,34,35]. With careful patient selection and dosimetric planning, radioembolization may achieve a long-term durable response without compromise of hepatic function in this population (Table 7) [1, 34,35,36,37,38,39]. The committee recommended a shift in defining which patients with MVI/PVT should be selected for treatment with Y-90 glass microsphere TARE, narrowing from previous broader recommendations to those who are Child–Pugh A5 or A6 (except in the case of segmental MVI/PVT where radiation segmentectomy may be considered [1, 34,35,36]. Multicompartment dosimetry is preferred in these patients to ensure that the maximum tumor-absorbed dose (TAD) is achieved while minimizing the dose to the normal tissue–absorbed dose (NTAD) and allowing the assessment of MVI/PVT targeting evaluation during pretreatment planning [1, 35, 40]. As with the approaches discussed earlier, an adequately high specific activity (the amount of radioactivity per microsphere at the time of administration) is important to achieve a desired TAD in the MVI/PVT with potentially limited microsphere deposition [1]. Given data from this and other recent studies, the committee chose to increase the degree of recommendation from B to A, with a moderate degree of committee consensus.

Discussion

Results from over 30 manuscripts and abstracts published since 2019 prompted an update to treatment recommendations for Y-90 glass microsphere–based TARE in HCC patients; these included the DOSISPHERE-01, LEGACY, and TARGET studies [1,2,3]. While previous studies highlighted the improved overall survival in patients achieving complete response upon imaging, data from the recent DOSISPHERE-01 and TARGET studies further established associations between TAD, tumor response, and overall survival [1, 2]. For patients with limited disease, ablative Y-90 TARE remains the most effective and well-tolerated treatment option in eligible patients. Important new updates to the recommendations based on recent publications include more specific dosimetric recommendations for radiation segmentectomy and lobectomy, separating multifocal unilobar and bilobar diseases into different sets of recommendations and providing context in which Y-90 glass microsphere TARE should be used for patients with portal vein thrombosis. Additional multicompartment dosimetry updates included proposed new thresholds for tumor and NTAD and incorporated the impact of underlying liver function [3, 4, 41,42,43]. Multiple publications focused on the utility of 99mTc-MAA imaging to estimate Y-90 glass microsphere distribution confirm the distribution of treatment and whether to select tumor or NTAD as the primary driver in choosing the appropriate Y-90 activity using multicompartment dosimetry [1, 41, 43].

Ablative dosing approaches in radiation segmentectomy

Recent publications, including LEGACY and its companion publications, have reported on higher selective treatment-absorbed doses for radiation segmentectomy [3, 4, 42]. Higher absorbed dose in selective ablative Y-90 glass microsphere TARE led to increased rates of complete pathologic necrosis, e.g., ≥ 400 Gy; complete and extensive pathologic necrosis have been shown to be associated with reduced recurrence in patients bridging to transplant [5, 42]. However, a maximum perfused volume-absorbed dose has not yet been identified. Recent publications also refined guidance for albumin-bilirubin (ALBI)-1/Child–Pugh A and ALBI-2/Child–Pugh B patients from up to 2 Couinaud segments to specific volume recommendations [17]. The use of cone-beam CT or angio-CT with selective intra-arterial contrast enhancement provides the best preprocedural volume definitions for accurate dosimetry calculations, provides the most accurate arterial flow assessing for non-target flow and coverage of microsatellites, and ensures dose target accuracy [19].

Improving conversion to resection

Recent studies and published recommendations have demonstrated the utility of personalized dosimetry in converting unresectable patients to candidates for resection [1, 3, 4, 21, 23, 25, 44]. Some recent publications showed that such an approach not only increased overall tumor response, but approximately doubled response rates when the TAD exceeded 300 Gy [1, 3]. In one of these investigations, multicompartment dosimetry used in multifocal unilobar HCC with or without MVI/PVT offered superior conversion of unresectable HCC compared to standard lobar single-compartment dosimetry (36% versus 4%, respectively) [1]. Single-compartment dosimetry using radiation lobectomy or modified lobectomy imparts local tumor control and contralateral lobe hypertrophy as a bridging strategy prior to resection. Collectively, these data demonstrated that treatment efficacy outcomes exhibit a continuum of improvement as TAD is escalated [3, 4, 21, 23]. Select studies provide guidance on the NTAD maximum and support evaluation of liver function, i.e., baseline bilirubin, prior to selecting NTAD targets [41]. Treatment outcome data regarding the use of NTAD to guide Y-90 glass microsphere activity selection are limited; further clinical data is needed to strengthen recommendations.

Differing treatment approaches for unilobar and bilobar HCC

Based on approvals of new systemic treatment options, the committee decided to divide unilobar and bilobar diseases without MVI/PVT into two separate clinical scenarios [30]. Systemic therapy is the current standard of care for advanced disease; however, it is important to consider TARE early in treatment planning, as it plays an important role in providing a cytotoxic effect, while ensuring tumor control, preserving liver function, and keeping future treatment options available [45, 46]. In these patients, multicompartment dosimetry is preferred to adequately assess TAD and NTAD relative to the extent of disease and liver function. Select centers have published Y-90 glass microsphere TARE experience in patients undergoing bilobar treatment, demonstrating that a multicompartment dosimetry approach is appropriate and beneficial in bilobar HCC [35, 43, 47].

The NTAD values proposed for unilobar treatment, 50–90 Gy based on baseline bilirubin levels, are higher than those recommended for bilobar patients, 40–70 Gy. However, additional clinical data are needed to better define the appropriate range for bilobar patients [41, 43]. In the case that multicompartment dosimetry is not feasible and single-compartment dosimetry is used, a lower target (i.e., 120 Gy to the perfused volume) is recommended for bilobar HCC patients; planning for such treatment should include careful evaluation of clinical status and liver function when evaluating possible treatment options. A more conservative approach to TAD and NTAD is recommended in the palliative setting as compared to in patients where treatment intent includes downstaging or conversion to resection.

Treatment goals for HCC with MVI/PVT

In HCC patients with MVI/PVT, treatment goals (i.e., potential downstaging or conversion to resection) and careful patient selection should drive the decision as to whether TARE should be used as monotherapy or in conjunction with systemic treatment. In both DOSISPHERE-01 and TARGET, Y-90 glass microsphere TARE was evaluated in patients with MVI/PVT as monotherapy [1, 2]. Patients in DOSISPHERE-01 were selected based on a dual targeting of tumor and MVI/PVT, crucial to tumor control and resolution of MVI/PVT [1]. Over 40% of patients with MVI/PVT in DOSISPHERE-01 who were treated with multicompartment dosimetry were converted to resection, compared to no patients in the single-compartment dosimetry arm. In the presence of ongoing cirrhotic liver function decline, systemic agents may be considered early on in treatment and in combination with Y-90 following a multidisciplinary review; however, further investigation is needed to better determine specific timing and treatment algorithms [48, 49]. Multicompartment dosimetry is the preferred treatment option in this patient population.

Future directions

As noted throughout the recommendations, there remain several areas which require additional investigations to better understand optimized patient selection and outcomes. The investigational research areas identified by the committee as high interest and requiring additional data and publications to inform clinical practice are detailed in Table 8. The committee encourages the collection and publication of clinical data to further provide evidence relating to the updated recommendations in these key areas of Y-90 glass microsphere TARE for HCC patients. Here, we briefly discuss two of these areas in which research is currently being or was recently conducted: the use of functional assessments in treatment planning and increasing reproducibility of dosimetric approaches.

Table 8 High-priority investigational research areas
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Functional assessments in treatment planning

In a parallel advancement in treatment planning for Y-90 glass microsphere TARE patients with insufficient FLR, functional assessments have been proposed in addition to volume assessments. Traditionally, the timing to undergo resection has focused solely on hypertrophy of the contralateral lobe; however, mounting evidence suggests a role for hepatobiliary scintigraphy to assess regional adequate liver function in confirming treatment candidacy [27,28,29]. Though the time course of function and volume recovery are parallel, functional recovery lags behind volume. Functional assessment may better drive key clinical decisions regarding treatment success, such as follow-up duration, the need for additional Y-90 treatment, and surgical timing or additional observations. Additional investigation is necessary to confirm the utility of functional assessment in making such treatment decisions.

Variability and reproducibility of dosimetry

One oft-cited concern with using more complex dosimetry-based approaches is the prediction reproducibility in the treatment phase; however, there are now several tools available to help address these challenges. Several commercial dosimetry software options are available, streamlining calculation of multicompartment dosimetry. Advancements in catheter technique in addition to refinement of the use of 99mTc-MAA imaging to estimate Y-90 glass microsphere distribution have led to improved clinical utility [50,51,52,53]. NTAD exhibits better reproducibility, which provides confidence in its use as a safety threshold. Although reproducibility in TAD may be suboptimal, it has been shown to be predictive of patient outcomes (such as tumor response and overall survival) in DOSISPHERE-01, TARGET, and other recent single-center publications [1, 2, 50, 51, 53]. To date, publications evaluated all patients to ascertain reproducibility. However, it may be appropriate to screen out patients in whom multicompartment tumor dosimetry predictions may be unreliable; in those cases, defaulting to MIRD is recommended. Recent publications note that variability may be driven by a limited sample size of published data, operator experience, and variability of tumor flow (and hence T:N) in the presence of multifocal disease, suggesting further optimization of patient selection is needed to improve accuracy and reproducibility of multicompartment dosimetry [52].

Conclusions

While Y-90 glass microsphere TARE is a key tool in the HCC treatment arsenal, appropriate patient selection, multidisciplinary review, and consideration of alternative or combination treatment in the algorithm are critical to achieving optimal patient outcomes. A number of advancements have been incorporated into the updated HCC treatment recommendations for Y-90 glass microsphere TARE presented here in an effort to improve patient selection, toxicity profiles, and outcomes.