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- Semin Intervent Radiol
- v.38(4); 2021 Oct
- PMC8497083
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Semin Intervent Radiol. 2021 Oct; 38(4): 482–487.
Published online 2021 Oct 7. doi:10.1055/s-0041-1735570
PMCID: PMC8497083
PMID: 34629718
Seminars in Radioembolization
Guest Editors, Robert J. Lewandowski, MD, FSIR and William Rilling, MD
Stephen J. Williams, MD,1 William S. Rilling, MD,1 and Sarah B. White, MD, MS1
Author information Copyright and License information PMC Disclaimer
Abstract
Objective Transarterial radioembolization (TARE) offers a minimally invasive and safe treatment option for primary and metastatic hepatic malignancies. The benefits of TARE are manifold including prolonged overall survival, low associated morbidities, and improved time to progression allowing prolonged treatment-free intervals. The rapid development of new systemic therapies including immunotherapy has radically changed the treatment landscape for primary and metastatic liver cancer. Given the current climate, it is critical for interventional oncologists to understand the benefits of TARE relative to these other therapies. Therefore, this report aims to review quality-of-life outcomes and the cost comparisons of TARE as compared with systemic therapies.
Keywords: transarterial radioembolization, health-related quality of life, yttrium 90, hepatocellular carcinoma, transarterial chemoembolization, interventional radiology
The Assessment of Quality of Life in Medical Literature
Quality of life (QoL) outcomes are considered an increasingly important treatment endpoint, particularly in inoperable, chronic, or otherwise incurable medical conditions.123With interventions such as transarterial radioembolization (TARE), in the treatment of advanced primary or secondary hepatic malignancies, the therapeutic goal often includes maximizing symptom-free intervals while minimizing current symptomatology.
Health-related quality of life (HRQoL) has become a useful metric in the comparison of treatment options for advanced hepatocellular carcinoma (HCC), particularly in the palliative setting, where curative options are not feasible. While QoL concerns are prevalent among patients with advanced disease, many trials lack a validated disease-specific assessment model which hinders evidence-based treatment decisions.4When a group of 328 oncology patients enrolled in phase I clinical trials were queried in 2003, 95% of participants reported QoL was at least as important as length of life.1
An ideal HRQoL tool should accurately quantify the physical, social, and psychologic distress associated with a medical condition and/or treatment, while maintaining validity and reliability.4Proposed components of an effective HRQoL tool include the ease of patient self-administration and low burden of response, alongside multiple dimensions which may be used to calculate overall and subset scores. A commonly utilized, non–disease-specific, HRQoL measurement tool is the Short-Form 36 (SF-36). The SF-36 includes 36 individual items over 8 domains scored on a numeric scale (0–100), including well-being (physical and social), vitality, and pain subsets, with higher scores corresponding to decreased disability.5Specific tools also exist to assess pain following medical or surgical therapies, such as the visual analog scale/score (VAS), which requires patients to rate pain on a nonlabeled intensity scale, ranging from “no pain” to “extreme pain.” This point is then measured numerically from the baseline (no pain) and quantified (in millimeter), with ranges from no pain, mild, moderate, or severe pain.6While the SF-36 and VAS offer insight into the general QoL of patients, disease- or treatment-specific tools may be required to offer a more focused measurement of QoL, especially in the setting of radioembolization.
Several disease-specific QoL tools exist which include the following: the Research and Treatment of Cancer Quality of Life Questionnaire—Core 30 (EORTC QLQ-C30), Functional Assessment of Cancer Therapy General (FACT-G), Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep), Functional Assessment of Cancer Therapy Hepatobiliary Symptoms Index (FHSI), and embolotherapy-specific score (ESS). A 2014 review article cited the EORTC QLQ-C30 and the FACT-Hep as the most commonly utilized tools in the assessment of QoL in HCC patients.4The FACT-Hep measurement tool separates physical, social, emotional, and functional well-being, alongside a hepatobiliary cancer subscale. Finally, the ESS is derived from items of the FACT-Hep, including QoL items most applicable to embolization procedures such as pain, treatment side effects, ability to work, diarrhea, and appetite.7
Optimizing QoL is an important priority for all cancer patients, not just those enrolled in clinical trials. Salem et al have implemented an automated digital patient engagement platform for the collection of QoL data in patients undergoing radioembolization. In their report, there was an activation rate of 78.4% among participants, with 92.6% of respondents reporting satisfaction with the measurement tool. At five time points, baseline through 90 days posttreatment, stability was observed in five out of seven FACT-Hep items and ESS at all points of measurement.8
Radioembolization: Quality-of-Life Considerations
Generally, patients undergoing radioembolization are able to maintain their baseline QoL.8A prospective trial utilized multiple QoL assessment tools in 56 patients undergoing transarterial therapy, either radioembolization or chemoembolization (n = 29 and 27, respectively), in the treatment of HCC. It is worth noting that patients within the radioembolization treatment group had more advanced disease compared with the chemoembolization group, as staged by the Barcelona Clinic Liver Cancer (BCLC) system (p = 0.02). Between the two groups, relative to TACE, there was significant improvement in both social and functional well-being components of FACT-G, and ESS (p = 0.019, 0.031, and 0.018, respectively) at 4 weeks post-radioembolization. Although the overall difference in FACT-Hep scores was not statistically significant between the two groups, limitations included a small sample size (effect size = 0.54) with a trend favoring radioembolization.7
Similarly, a prospective study enrolled 30 patients with unresectable HCC, complicated by portal vein thrombosis (all BCLC stage C), who underwent radioembolization. The SF-36 was used at baseline, 1-, 3-, and 6 months after TARE as a measure of HRQoL. Of the eight SF-36 domains, no significant changes in either the physical or mental component scores were observed at any time point compared with baseline, via chi-square analysis. The only exception was a significant increase in the Role-Emotional Score (p = 0.04), within the 1- and 3-month follow-up comparison, which corresponds to decreased disability on the SF-36.5Consequently, investigators suggested that radioembolization is a reasonable treatment option for patients with infiltrative HCC and may alleviate concern for treatment-related decreases in HRQoL.2
The SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma (SARAH) trial compared radioembolization to sorafenib, in a prospective phase III trial. After randomization of 467 patients to either radioembolization or sorafenib, there was no significant difference in median overall survival, with the median survival of radioembolization reported as 8.0 versus 9.9 months with sorafenib (p = 0.18). As part of this trial, QoL via the EORTC QLQ-C30 was assessed at baseline, 1 month, and every 3 months thereafter. When comparing the global health status subscore, where higher values correspond to increased QoL, investigators found a significant increase in the QoL of patients treated with radioembolization versus sorafenib (group effectp = 0.0048, time effectp < 0.0001). When graphed, this difference was due to a sustained decrease in mean global health subscores in the sorafenib group at 3 through 12 months following randomization. Although not directly analyzed for significance, the subscores in the radioembolization group were at least maintained at 6 months.9
Within the respective treatment arms of the SARAH trial, between radioembolization and sorafenib, the rates of serious treatment-related complications were 20 and 36%, respectively.9The most common serious treatment-related complications in both groups included cirrhosis (and associated complications), reduced general status, tumor progression, and hepatic failure. As for the frequency of any treatment-related adverse effects between groups, with a median of five, radioembolization was also favored in this aspect compared with a median of 10 with sorafenib. As for the specific events, namely, fatigue, hepatic dysfunction, increased function enzymes, hematologic abnormalities, diarrhea, abdominal pain, and hand–foot skin reaction, the only event more prevalent in the radioembolization treatment group was increased liver function enzymes (9% in the radioembolization group vs. 7% in the sorafenib group). Many of the above adverse effects were also reported as grounds for treatment discontinuation in 64% of the 216 patients who underwent sorafenib therapy, 78% of which was reported as permanent. These data suggested better overall tolerability of radioembolization over sorafenib therapy.9
In a similarly designed prospective study, the Selective Internal Radiation Therapy Versus Sorafenib (SIRveNIB) trial, researchers randomized 360 patients to either radioembolization (n = 182) or sorafenib (n = 178). While the primary endpoint was overall survival, safety analysis included monitoring and comparison of treatment-related adverse events between the two treatment arms. Of the reported adverse effects graded 3 or higher, the radioembolization group had significantly less relative to sorafenib (p < 0.001). Specific events with significantly increased incidence in the sorafenib group included the following: constipation (p < 0.0051), diarrhea (p < 0.001), alopecia (p < 0.001), palmar-plantar erythrodysesthesia syndrome (p < 0.001), and rash (p < 0.001). Similar to SARAH, researchers again suggested better tolerability of radioembolization compared with sorafenib in the treatment of locally advanced HCC.10
Similar results were reported in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, which randomized patients to receive sorafenib or placebo in a double-blind fashion. Although the trial demonstrated a significant survival benefit, adverse events were significantly prevalent in the sorafenib treatment group including diarrhea, weight loss, hand–foot skin reaction, alopecia, anorexia, and voice changes. Although tolerability was not specifically commented on, this study reinforced treatment-specific adverse events that led to treatment discontinuation in 86 of 226 (38%).11
QoL following TARE has been studied in mixed cohorts of patients. A recent study assessed QoL in 200 patients with a combination of primary and secondary hepatic lesions, including HCC (n = 114), intrahepatic cholangiocarcinoma (n = 33), metastatic colorectal (n = 38), and neuroendocrine (n = 5) malignancies undergoing radioembolization, the majority of which reported as palliative intent (79%). Utilizing the EORTC QLQ-C30, stability in global health subscore was reported in the 23% of patients who had scores for each of the sampling dates (baseline, 1 week, and 15–19 weeks). Mean global health subscore of 60.2% was reported across all points, compared with a baseline of 59.1%, indicating that radioembolization allows patients to maintain their QoL.12
The use of TARE in the treatment of neuroendocrine tumor liver metastases (NETLM) has also been assessed regarding QoL following treatment. In 2016, thirty patients with NETLM were enrolled prospectively and underwent radioembolization, followed by health-related QoL assessment at set intervals (baseline, 1, 3, 6, 12, and 24 months) via the SF-36. When analyzed via pairedt-test, no significant differences were observed at baseline relative to 1-, 3-, or 24-month follow-up. When comparing 6- and 12-month intervals, significant improvement in the mean scores of both mental health and social function domains were reported relative to baseline (p = 0.007,p = 0.019, respectively). Investigators ultimately suggested that patients with neuroendocrine metastasis undergoing radioembolization have preserved QoL up to 24 months.13
The Measurement of Cost-Effectiveness in Medical Literature
Incremental cost-effectiveness ratio (ICER), or cost per quality-adjusted life year (QALY), is a commonly reported value in the cost-effectiveness analysis of medical therapies. During cost-threshold analysis, although largely variable, an ICER of $50,000 is commonly referred to as the threshold of willingness to pay (WTP) per QALY gained in the United States.14Depending on the country, the threshold varies accordingly. The World Health Organization (WHO) recommendations for determining the WTP threshold for cost-effective analysis suggest multiplication of GDP per capita by 3.15For example, the reported WTP threshold in China was reported at $20,301/QALY in 2014.16By setting an ICER specific to the region of interest, investigators make conclusions regarding cost-effectiveness of medical therapies. As the cost for a specific therapy varies per case, sensitivity analyses may be performed to assess the probability of a proposed treatment meeting the WTP threshold. If the ICER exceeds the WTP threshold for a therapy, it is deemed cost ineffective. An understanding of this calculation becomes imperative when reviewing literature relating to the cost-effectiveness of radioembolization.
Cost-Effectiveness of Radioembolization
Cost-Effectiveness of Radioembolization as a Primary or Adjuvant Therapy
In the context of cost-effectiveness, literature most often compares similar treatment modalities for advanced HCC, rarely directly comparing locoregional and systemic therapies. Costs specific, but not exclusive to, radioembolization include mapping angiography, MAA scintigraphy, Y-90 spheres, procedural costs, and management of treatment-related complications. Congruent over multiple studies, compared with other locoregional therapies (transarterial chemoembolization or percutaneous ablation), TARE confers the highest treatment cost estimated at $31,000 and $48,000 for unilobar and bilobar treatments, respectively.17For single-session radioembolization, cost has been recently approximated at $20,818 by time-driven activity-based costing (TDABC), with microspheres accounting for around 80% of costs incurred.18
With adequate preparation, radioembolization also offers the potential of same-day outpatient experience, in contrast with both TACE and systemic therapy.1920On the topic of same-day radioembolization versus a 2-day protocol, costs estimated recently via TDABC analysis did not differ significantly. This was presumed due to the fixed cost of the Y-90 dose itself, which accounted for 76 and 72% of the total cost of 2- and 1-day protocols, respectively.21
For locoregional therapies, costs of chemoembolization and radioembolization have been directly compared based on set treatment paradigms, which account for extent of disease (BCLC) and frequency of expected treatments.17Radioembolization, either unilobar or bilobar, conferred a higher cost relative to chemoembolization in all stages of disease assuming up to six chemoembolization or two radioembolization treatments. Investigators suggested that radioembolization was cost-effective only for the BCLC stage C group, accounting for a statistically significant survival benefit of 4 months when compared with TACE. Of note, this study did not allow for crossover between treatment groups which was noted as limitation to generalizing the reported survival results. As described, in clinical practice, patients often cross over or receive a combination of the two treatment modalities in the setting of unresectable HCC.
Cost-Effectiveness of Radioembolization in Respect to Systemic Treatments for HCC
The cost-effectiveness of radioembolization versus multikinase inhibitors (sorafenib and lenvatinib) have been questioned specifically in HCC patients not eligible for chemoembolization, categorized as BCLC stage B or C. Summative expenses included the costs of drug (Y-90 spheres or kinase inhibitors), hospital expenses, adverse events, curative-intent treatment, clinical follow-up, and end-of-life care. Of note, estimated costs assumed repeat treatment in the radioembolization group. In short, radioembolization as an alternative treatment conferred cost savings ranging from 5.4 to 26.5% in four separate European countries (Italy, France, United Kingdom, and Spain) relative to the treatment with sorafenib or lenvatinib.22When accounting for disease severity, Rognoni et al reported an ICER of €3,302 per QALY gained in 308 patients with intermediate-stage HCC undergoing radioembolization, with further reduction in ICER when advanced-staged patients were treated.23
The median treatment duration is estimated at 5 to 6 months for sorafenib, as suggested by the European Society for Medical Oncology.24Utilizing 2007 data, researchers calculated a ICER of $62,473/life-year gained for sorafenib, compared with best supportive care, in the treatment of advanced HCC.25In similarly designed international studies, ICERs of CA$75,821/life-year gained and $101,399/QALY were reported in Canada and China, respectively.1626Assuming a threshold ICER of $50,000, as reported,14the treatment of advanced HCC with sorafenib does not appear cost-effective.
Most recently, Marqueen et al utilized individual data from the SARAH and SIRveNIB trials, alongside current literature and Medicare reimbursem*nt values, to perform a cost-effectiveness analysis between sorafenib and radioembolization.27Costs of sorafenib and radioembolization were $78,859 and $58,397 respectively, which resulted in a ICER of $1,280,224/QALY gained for sorafenib. It was suggested that the cost of sorafenib was not cost-effective, given the difference of 0.02 QALYs gained over radioembolization. Furthermore, it was noted that a greater than 50% decrease in the cost of sorafenib would be required to reach an ICER of $200,000/QALY gained, the study-specific cost-effectiveness threshold for WTP.
Chiang et al utilized third-party payer data to generate base costs for sorafenib versus atezolizumab plus bevacizumab (Atezo/Bev) in the first-line treatment of unresectable HCC. Reported components included fixed drug costs, drug administration, follow-up imaging, inpatient care, and post-progression therapy costs. Adjusting for inflation, summative base costs for a treatment duration of 2.8 months amounted to $634,668 for sorafenib versus $713,742 for atezolizumab and bevacizumab. For patients receiving Atezo/Bev, the reported ICER was $179,729 per QALY, noting a difference of $79,074 when treating with sorafenib over atezolizumab and bevacizumab.28
In the setting of disease progression on sorafenib, the cost of several secondary systemic agents has also been analyzed relative to the best supportive care (some with the addition of placebo)2930as outlined inTable 1. Notably, the ICER exceeded study-specific ICER thresholds in all reports which suggested against cost-effectiveness for these second-line agents.293031
Table 1
Cost analysis of first-line systemic agents
| Agent | ICER | QALY gained |
|---|---|---|
| Sorafenib | $62,473/life-year gained25 | N/A |
| CA$75,821/life-year gained26 | N/A | |
| $101,399/QALYa16 | 0.18 | |
| $1,280,224/QALYa27 | 0.88 | |
| $100,655/QALYa28 | 0.98 | |
| Atezolizumab/bevacizumab | $179,729/QALYa28 | 1.426 |
| Regorafenib | $224,362/QALYa31 | 0.18 |
| Cabozantinib | $1,040,675/QALYa29 | 0.067 |
| Pembrolizumab | $340,409/QALYa30 | 0.138 |
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Abbreviations: CA, Canadian; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life years.
aICER values exceeded study-specific thresholds for willingness to pay.
Cost-Effectiveness of Radioembolization in the Treatment of other Primary or Secondary Hepatic Malignancies
Although a majority of reports focus on the applications of radioembolization in unresectable HCC, very few reports have focused on the cost-effectiveness of radioembolization in the treatment of other primary or metastatic hepatic lesions. Cost-effectiveness models have been utilized to compare chemotherapy alone and combination of radioembolization and chemotherapy in the treatment of unresectable intrahepatic cholangiocarcinoma.32Researchers included 585 patients, 88% of who received just chemotherapy and 12% received combination therapy. In addition to an overall increase in survival in patients receiving combination therapy (p = 0.02), a median ICER of $50,059/year of added survival was calculated, suggesting borderline cost-effectiveness.
In metastatic colorectal carcinoma, radioembolization is also a treatment consideration. Pennington et al compared radioembolization (n = 224) and best supportive care (n = 29) in the treatment of chemotherapy-refractory colorectal carcinoma with liver metastasis. In the treatment arm, an overall gain of 0.81 QALYs was reported, which equated to an ICER of €28,216. Subsequent probabilistic sensitivity analysis suggested cost-effectiveness in 57% of cases, assuming a WTP threshold of €30,000 per QALY gained.33
The use of radioembolization in the treatment of gastroenteropancreatic neuroendocrine tumors is another therapeutic application, most often when curative surgical management is not possible. In these cases, systemic chemotherapy is an option, with a primary treatment goal of symptomatic relief and tumor regression, with current evidence for the use of somatostatin analogs (lanreotide, octreotide), everolimus, sunitinib, peptide receptor radionuclide therapy (lutetium-177 DOTATATE), or standard chemotherapy.34
A cost-effectiveness analysis was recently performed for somatostatin analogs in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors (stage IV), where 60 patients were treated with octreotide empirically immediately following diagnosis rather than following disease progression. Reporting an increase in 0.44 QALYs, with a calculated ICER of $388,966, octreotide was cost-effective in 1.4% of cases via a probabilistic sensitivity analysis assuming a WTP threshold of $100,000.35A similarly designed Canadian study in 2018 compared everolimus to best supportive therapy in patients with either unrespectable or metastatic neuroendocrine tumors of pulmonary or gastrointestinal origin. Utilizing intention-to-treat data, the RADIANT-4 trial, which randomized 302 patients to either everolimus or placebo,36reported an ICER of CA$145,670 per QALY gained. A probability of cost-effectiveness was 52.1% via probabilistic sensitivity analysis, assuming a WTP threshold of CA$150,000.37
A 2018 review sought to assess the cost-effectiveness of everolimus, lutetium-177 DOTATATE, and sunitinib in the treatment of advanced neuroendocrine tumors, utilizing list prices for the various therapies. For pancreatic neuroendocrine tumors, the treatment with everolimus or sunitinib compared with best supportive care resulted in an ICER of €45,493 and €20,717 per QALY, respectively. For other gastrointestinal and pulmonary neuroendocrine tumors, the ICER of everolimus compared with best supportive therapy was €44,557 per QALY. In the treatment of gastrointestinal neuroendocrine tumor with either everolimus or lutetium-177 DOTATATE versus best supportive care, ICERs of €199,233 and €62,158 per QALY were reported, respectively. Referencing a range of €20,000 to €30,000 per QALY as a cost-effectiveness threshold, as determined by the National Institute for Health and Care Excellence (NICE), authors raised the possibility of sunitinib being cost-effective in the pancreatic neuroendocrine tumor group. The use of everolimus or lutetium-177 in the treatment of the compared subtypes of neuroendocrine tumor did not appear cost-effective.38
Table 2outlines the results of multiple studies evaluating the costs of TARE in the treatment of primary and secondary liver malignancies.
Table 2
Cost analysis in the treatment of primary and secondary hepatic malignancies
| Etiology | Treatment | ICER |
|---|---|---|
| Hepatocellular carcinoma | TARE | €3,302/QALY23 |
| Intrahepatic cholangiocarcinoma | TARE | $50,059/life-year gaineda32 |
| Metastatic colorectal carcinoma | TARE | €28,216/QALY33 |
| Gastroenteropancreatic neuroendocrine tumors | Octreotide | $388,966/QALYa35 |
| Everolimus | CA$145,670/QALY37 | |
| Everolimus | €45,493–€199,233/QALYa38 | |
| Sunitinib | €20,717/QALY38 | |
| lutetium-177 DOTATATE | €62,158/QALYa38 |
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Abbreviations: CA, Canadian; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life years; TARE, transarterial radioembolization.
aICER values exceeded study-specific thresholds for willingness to pay.
Conclusions
Quality of life is an important factor in treatment selection for all cancer patients. In multiple studies, Y-90 radioembolization has shown the ability to maintain or improve HRQoL in patients with advanced HCC as well as liver metastases. Although radioembolization confers a high cost per treatment compared with other regional therapies, use in advanced HCC has shown to be cost-effective as measured by conventional standards. By these same measures, the cost-effectiveness of multiple first- and second-line systemic options appears questionable in the current literature. These advantages should be considered in the multidisciplinary care of patients with advanced hepatic malignancies.
Footnotes
Conflicts of interest S.B.W.—Research support: Guerbet, InSightec, Siemen's; consulting: Cook, NXT, Guerbet, Sirtex; speaking bureau: Penumbra; grant funding: Focused Ultrasound Foundation.
W.S.R.: Consultant for Sirtex, Boston Scientific, Varian, BD/Bard.
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