Streamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation

doi:10.1016/j.jhep.2020.02.024

Journal of Hepatology

Volume 72, Issue 6, June 2020, Pages 1151-1158

https://doi.org/10.1016/j.jhep.2020.02.024 Get rights and content

Highlights

•
Transarterial radioembolization with Y90 is now established as an effective locoregional therapy for patients with HCC.
•
A pre-treatment Tc-99m MAA (MAA) scan is routinely performed to estimate the possible radiation dose shunted to the lungs.
•
Herein, we show that the MAA scan can be removed from the treatment algorithm in certain patients with small HCCs.

Background & Aims

Pre-treatment Tc-99m macroaggregated albumin (MAA) scans are routinely performed prior to transarterial radioembolization (TARE) to estimate lung shunt fraction (LSF) and lung dose. In this study, we investigate LSF observed in early hepatocellular carcinoma (HCC) and provide the scientific rationale for eliminating this step from routine practice.

Methods

Patients with HCC who underwent Y90 from 2004 to 2018 were reviewed. Inclusion criteria were early stage HCC (UNOS T1/T2/Milan criteria: solitary ≤5 cm, 3 nodules ≤3 cm). LSF was determined using MAA in all patients. Associations between LSF and baseline characteristics were investigated. A “no-MAA” paradigm was then proposed based on a homogenous group that expressed very low LSF.

Results

Of 1,175 patients with HCC treated with TARE, 448 patients met inclusion criteria. Mean age was 65.6 years and 303 (68%) were males. A total of 352 (79%) had solitary lesions and 406 (91%) unilobar disease. Two-hundred and forty-three (54%), 178 (40%) and 27 (6%) patients were Child-Pugh class A, B and C, respectively. Median LSF was 3.9% (IQR 2.4–6%). Median administered activity was 0.9 GBq (IQR 0.6–1.4), for a median segmental volume of 170 cm³ (range: 60–530). Median lung dose was 1.9 Gy (IQR: 1.0–3.3). The presence of a transjugular intrahepatic portosystemic shunt (TIPS; n = 38) was associated with LSF >10% (odds ratio 12.2; 95% CI 5.2–28.6; p <0.001). Median LSF was 3.8% (IQR: 2.4–5.7%) and 6% (IQR: 3.8–15.3%) in no-TIPS vs. TIPS patients (p <0.001).

Conclusion

LSF is clinically negligible in patients with UNOS T1/T2 HCC without TIPS. When segmental injections are planned, this step can be eliminated, thereby reducing time-to-treatment, number of procedures, and improving convenience for patients traveling from faraway.

Lay summary

Transarterial radioembolization is a microembolic transarterial treatment for hepatocellular carcinoma. In our study, we found that early stage patients, where segmental injections are planned, exhibited low lung shunting, effectively eliminating the risk of radiation pneumonitis. We propose that the lung shunt study be eliminated in this subgroup, thus leading to fewer procedures, a cost reduction and improved convenience for patients.

Graphical abstract

Introduction

Transarterial radioembolization with yttrium-90 (TARE) is a minimally invasive treatment for hepatocellular carcinoma (HCC).¹ In brief, TARE involves injecting radiated microspheres into hypervascular lesions. While indications include small to infiltrative tumors with vascular invasion, this technique may be limited by extrahepatic deposition and elevated lung shunt fraction (LSF). In recent years, TARE use in early disease (United Network for Organ Sharing [UNOS] T1/T2) for bridging/transplantation has increased, providing cohort and randomized data demonstrating prolonged time-to-progression, complete pathological necrosis, curative potential, and long survival outcomes.[2], [3], [4] This has led to TARE being adopted as the arterial HCC therapy of choice at certain centers.⁵ As part of normal pathophysiology, HCC vascularity results in arteriovenous shunts that bypass capillaries and flow directly to the lung.⁶^,⁷ Hence, there is a theoretical risk that microspheres could induce radiation pneumonitis (RP).

The current standard for TARE involves arteriography with technetium-99 m macroaggregated albumin (MAA) 1-3 weeks prior to treatment.¹ This helps: i) identify non-target deposition and, ii) quantify LSF. LSF is then incorporated in dose calculation to ensure the risk of RP is mitigated. However, this step results in an added procedure, increases cost, and delays time-to-treatment. In this study, we present data supporting the proposal that a subgroup of patients with early stage HCC (UNOS T1/T2/Milan) exhibit clinically negligible LSF, and that there is sufficient rationale to eliminate this step from treatment algorithms and routine clinical practice. We believe this would decrease time-to-treatment, lower costs, increase patient safety by minimizing unnecessary procedures, and facilitate treatment for patients traveling long distances.

Section snippets

Patients and methods

In this institutional review board approved study, we reviewed our prospectively acquired database on 1,175 patients with HCC treated with TARE between January 2004 and December 2018. This time period was selected in order to ensure sufficient follow-up (>1 year) that would permit clinical observation of RP. Inclusion criteria were early stage HCC UNOS T1/T2 (Milan Criteria: solitary tumor ≤5 cm, 2 or 3 lesions, all ≤3 cm). Patients who had Barcelona Clinic Liver Cancer stage B, portal vein

Baseline characteristics

A total of 448 patients with HCC and T1/T2 tumors were treated with TARE between January 1, 2004 and December 31, 2018 (Table 1). Mean age was 65.6 years, 303 (68%) were males, 225 (50%) had HCV while 37 (8%), 56 (12%), 58 (13%) and 72 (16%) had HBV, alcoholic disease, non-alcoholic steatohepatitis (NASH) and other etiologies (e.g. hemochromatosis, alpha-1 anti-trypsin deficiency and cryptogenic HCC), respectively. A total of 352 (79%) had solitary lesions, while 96 (21%) exhibited multifocal

Discussion

Since the introduction of TARE, hepatic arterial infusion of MAA has been the standard method used to estimate LSF. While large, infiltrative tumors with vascular invasion frequently exhibit lung shunting, this is not the case with smaller tumors.¹⁸^,¹⁹ The advent of TARE radiation segmentectomy and bridge to liver transplantation has brought into question the utility of the LSF in small, focal disease.¹³^,²⁰ This stems from the observation that, unlike large HCCs, smaller lesions do not exhibit

Financial support

The authors received no financial support to produce this manuscript.

Authors' contributions

Ahmed Gabr, MD (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Validation; Visualization; Writing – original draft; Writing – review & editing). Srirajkumar Ranganathan (Data curation; Formal analysis; Investigation; Writing – review & editing). Samdeep Mouli (Data curation; Formal analysis; Investigation; Resources; Supervision; Writing – review & editing). Ahsun Riaz (Data curation; Formal analysis; Investigation; Supervision;

Conflict of Interest

AR, RJL and RS are advisors to BTG. SM receive grant support from BTG.

Please refer to the accompanying ICMJE disclosure forms for further details.

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Cited by (29)

Measurement of the Tumor-to-Normal Ratio for Radioembolization of Hepatocellular Carcinoma: A Prospective Study Comparing 2-Dimensional Perfusion Angiography, Technetium-99m Macroaggregated Albumin, and Yttrium-90 SPECT/CT
2024, Journal of Vascular and Interventional Radiology
To calculate the preradioembolic tumor-to-normal (T:N) ratio in hepatocellular carcinoma (HCC) using 2-dimensional (2D) perfusion angiography and compare it with that calculated using technetium-99m macroaggregated albumin (^99mTc MAA) single-photon emission computed tomography (SPECT)/computed tomography (CT).
This prospective single-arm study enrolled 15 participants with HCC who underwent 2D perfusion angiography immediately before the enrollment and with the microcatheter located at the same location as ^99mTc MAA injection, after which SPECT/CT was performed. Quantitative digital subtraction angiography was used to calculate the area under the curve for the tumor and normal hepatic parenchyma and subsequently calculate the T:N ratio. The T:N ratio was calculated from the ^99mTc MAA SPECT/CT and post–yttrium-90 bremsstrahlung SPECT/CT using dosimetry software.
The mean participant age was 64.1 years ± 9.8, and the study included 14 (93%) men and 1 (7%) woman. The mean tumor size was 4.1 cm (SD ± 2.4), and all participants received segmental treatments with glass microspheres. The mean T:N ratio calculated by ^99mTc MAA SPECT/CT was 2.28 (SD ± 0.89) vs 2.25 (SD ± 0.99) calculated by 2D perfusion angiography (P = .45). For the 13 participants who underwent selective internal radiation therapy (transarterial radioembolization), there was no significant difference between the T:N ratios calculated by 2D perfusion angiography and post-⁹⁰Y SPECT/CT (2.25 [SD ± 1.05] vs 1.91 [SD ± 0.39]; P = .12).
The T:N ratio calculated by 2D perfusion angiography correlated well with that calculated by ^99mTc MAA SPECT/CT.
Evolution of Personalized Dosimetry for Radioembolization of Hepatocellular Carcinoma
2023, Journal of Vascular and Interventional Radiology
Yttrium-90 transarterial radioembolization (TARE) has progressed from a salvage or palliative lobar or sequential bilobar regional liver therapy for patients with advanced disease to a versatile, potentially curative, and often highly selective local treatment for patients across Barcelona Clinic Liver Cancer stages. With this shift, radiation dosimetry has evolved to become more tailored to patients and target lesion(s), with treatment dose and distributions adapted for specific clinical goals (ie, palliation, bridging or downstaging to liver transplantation, converting to surgical resection candidacy, or ablative/curative intent). Data have confirmed that “personalizing” dosimetry yields real-world improvements in tumor response and overall survival while maintaining a favorable adverse event profile. In this review, imaging techniques used before, during, and after TARE have been reviewed. Historical algorithms and contemporary image-based dosimetry methods have been reviewed and compared. Finally, recent and upcoming developments in TARE methodologies and tools have been discussed.
Lung shunt fraction calculations before Y-90 transarterial radioembolization: Comparison of accuracy and clinical significance of planar scintigraphy and SPECT/CT
2023, Diagnostic and Interventional Imaging
To determine the accuracy and clinical significance of planar scintigraphy lung shunt fraction (PLSF) and single-photon emission computerized tomography (SPECT) computed tomography (CT) lung shunt fraction (SLSF) before Y-90 transarterial radioembolization.
Seventy patients (46 men, 24 women; mean age, 64 ± 9.5 [SD] years) who underwent 83 treatments with Y-90 transarterial radioembolization for primary or secondary malignancies of the liver with a PLSF ≥ 7.5% were retrospectively evaluated. The patients mapping technetium 99 m (Tc-99 m) macroaggregated albumin (MAA) PLSF and SLSF were calculated and compared to the post Y-90 delivery SLSF. A model using modern dose thresholds was created to identify patients who would require dose reduction due to a lung dose ≥ 30 Gy, with patients who required >50% dose reduction considered to be delivery cancelations.
A significant difference was found between mean PLSF (14.7 ± 11.6 [SD]%; range: 7.5–84.1%) and mean SLSF (8.7 ± 8.5 [SD]%; range: 1.7–73.5) (P < 0.001). The mean realized LSF (7.1 ± 3 [SD]%; range:1.5–17.6) was significantly less than the PLSF (P <0.001) but not the SLSF (P = 0.07). PLSF significantly overestimated the realized LSF by more than the SLSF (8.5 ± 5.3 [SD] % [range: -0.1–21.7] vs. 0.8 ± 3.6 [SD] % [range: -5–13.2], respectively) (P < 0.001). Based on the clinical significance model, 20 patients (20/83, 24.1%) would have required dose reduction or cancelation when using PLSF but would not require even a dose reduction when using the SLSF. Significantly more deliveries would have been be canceled if PLSF was used as compared to SLSF (22/83 [26.5%] vs. 6/83 [7.2%], respectively) (P < 0.001).
SLSF is significantly more accurate at predicting realized LSF than PLSF and this difference is of clinical significance in a number of patients with a PLSF ≥ 7.5%.
Implementation of radiation segmentectomy for early-stage hepatocellular carcinoma
2022, The Lancet Gastroenterology and Hepatology
Surveillance and Monitoring of Hepatocellular Carcinoma During the COVID-19 Pandemic
2021, Clinical Gastroenterology and Hepatology
Citation Excerpt :
Patients scheduled for Y-90 radioembolization commonly undergo angiography 1–2 weeks prior to treatment to evaluate for significant shunting that would make patients ineligible for Y-90 therapy. However, lung shunt fraction is negligible in early-stage patients receiving segmental Y-90 so this step may be eliminated,46 which would reduce health care utilization and potential COVID-19 exposure. There is concern for serious COVID-19 infection in those receiving conventional transarterial chemoembolization (cTACE) (with cytotoxic agents) because of systemic absorption with increased myelosuppression, and therefore the International Liver Cancer Association recommends other forms of LRT over cTACE (eg, bland embolization, drug-eluting bead–TACE, Y-90).47
The Coronavirus disease 2019 (COVID-19) pandemic is expected to have a long-lasting impact on the approach to care for patients at risk for and with hepatocellular carcinoma (HCC) due to the risks from potential exposure and resource reallocation. The goal of this document is to provide recommendations on HCC surveillance and monitoring, including strategies to limit unnecessary exposure while continuing to provide high-quality care for patients. Publications and guidelines pertaining to the management of HCC during COVID-19 were reviewed for recommendations related to surveillance and monitoring practices, and any available guidance was referenced to support the authors’ recommendations when applicable. Existing HCC risk stratification models should be utilized to prioritize imaging resources to those patients at highest risk of incident HCC and recurrence following therapy though surveillance can likely continue as before in settings where COVID-19 prevalence is low and adequate protections are in place. Waitlisted patients who will benefit from urgent LT should be prioritized for surveillance whereas it would be reasonable to extend surveillance interval by a short period in HCC patients with lower risk tumor features and those more than 2 years since their last treatment. For patients eligible for systemic therapy, the treatment regimen should be dictated by the risk of COVID-19 associated with route of administration, monitoring and treatment of adverse events, within the context of relative treatment efficacy.
Repeat Evaluation of Lung Shunt Fraction is Unnecessary: A Retrospective Observational Study of Successive Lung Shunt Fractions from Variable Arterial Distributions in Patients Undergoing Radioembolization of Primary and Secondary Liver Tumors
2021, Journal of Vascular and Interventional Radiology
Citation Excerpt :
With the development of same-day or single session protocols, the current standard practice surrounding the radioembolization of hepatic tumors is evolving (19,21). In certain patient populations, it has been suggested that lung shunt calculations may be eliminated completely (22). Recent literature has demonstrated that LSFs in non-HCC patients are low, supporting the elimination of repeat calculations in patients with metastatic disease (23).
To evaluate whether the recalculation of lung shunt fraction (LSF) is necessary prior to next-stage or same lobe repeat radioembolization.
Retrospective chart review was performed for patients who underwent radioembolization between February 2008 and December 2018. Eighty of 312 patients had repeat mapping angiograms and LSF calculations. A total of 160 LSF calculations were made using planar imaging (155, [97%]) and single-photon emission computed tomography (5 [3%]) technetium-99m macroaggregated albumin hepatic arterial injection imaging. The mean patient age was 61.8 years ± 12.7; 69 (86%) patients had metastatic disease and 11 (14%) had hepatocellular carcinoma.
Patients had a median LSF of 5% (interquartile range [IQR] 3%–9%) with a median absolute difference of 1.25 (IQR 0.65–3.4) and a median of 76 days (IQR 42.5–120 days) between repeat LSF calculations. There was a median change in LSF of 0.2% between mapping studies (P = .11). There was no statistical significance between the repeat LSFs regardless of the arterial distribution (P = .79) or between tumor types (P = .75). No patients exceeded lung dose limits using actual or predicted prescribed dose amounts. The actual median lung dose was 2.6 Gy (IQR 1.8–4.4 Gy, maximum = 20.5) for the first radioembolization and 2.0 Gy (IQR 1.3–3.7 Gy, maximum = 10.1) for the second radioembolization.
No significant difference in LSF was identified between different time points and arterial distributions within the same patient undergoing repeat radioembolization. In patients who receive well under 30-Gy lung dose for the initial treatment and a 50-Gy cumulative lung dose, repeat radioembolization treatments in the same patient may not require a repeat LSF calculation.

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Research ArticleStreamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation

Highlights

Background & Aims

Methods

Results

Conclusion

Lay summary

Graphical abstract

Introduction

Section snippets

Patients and methods

Baseline characteristics

Discussion

Financial support

Authors' contributions

Conflict of Interest

J Vasc Interv Radiol

Gastroenterology

J Vasc Interv Radiol

J Vasc Interv Radiol

Int J Radiat Oncol Biol Phys

Gastroenterology

Clin Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

J Vasc Interv Radiol

Int J Radiat Oncol Biol Phys

J Eur Soc Ther Radiol Oncol

J Vasc Interv Radiol

Value Health

Tech Vasc Interv Radiol

Radiation segmentectomy: potential curative therapy for early hepatocellular carcinoma

Radiology

Research Article
Streamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation