Radioembolization with yttrium-90 glass microspheres for patients with hepatocellular carcinoma: a review

SUMMARY

Clinical studies have evaluated the safety and efficacy of radioembolization with yttrium-90 in patients with unresectable hepatocellular carcinoma (HCC). Citing literature published within the last 5 years, we review the clinical evidence of survival outcomes and safety of yttrium-90 treatment in patients with unresectable HCC. This paper is primarily focused on survival rates following the typical application of yttrium-90 in HCC treatment, and also includes time to progression and safety data. Also discussed are special indications and new developments related to yttrium-90 therapy in HCC, as well as patient selection and its correlation with successful treatment outcomes.

Practice points.

• The use of yttrium-90 has become a valuable clinical option in centers that are specialized in the management of hepatocellular carcinoma.

• Yttrium-90 is an effective therapy that can lead to significant prolongation of survival with relatively little side effects.

• Administration of treatment with yttrium-90 requires a multidisciplinary team that consists of hepatologists, diagnostic and interventional radiologists, and nuclear medicine physicians.

• The key to success with yttrium-90 treatment is a meticulous clinical, radiological and nuclear medical workup as well as the choice of suitable patients.

• In general, only individuals with a good liver function should be chosen for treatment with yttrium-90.

• Yttrium-90 can be used when other treatment options such as transarterial chemoembolization or Sorafenib have failed or are contraindicated.

• Yttrium-90 may also be an option as bridging therapy prior to liver transplantation.

Background

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths and the fifth most common tumor worldwide with increasing incidence. Although most HCC occurs in patients with cirrhosis, up to 20% of patients have no underlying advanced liver disease.

The most commonly used staging system for HCC is the Barcelona Clinic Liver Cancer (BCLC) score, which comprises size, pattern and metastatic setting as well as stage of the underlying liver disease. An updated algorithm by Forner et al. demonstrates the BCLC staging system and treatment strategy. In early stage HCC, resection, transplantation and ablation are potentially curative options, provided the tumor is within the Milan criteria (one nodule <5 cm or three nodules <3 cm); best results are seen in tumors less than 2 cm [1,2]. Still, the vast majority of patients are diagnosed with HCC when only palliative approaches such as transarterial chemoembolization (TACE), selective internal radiation therapy and transarterial radioembolization are options. Patients with metastatic HCC can receive sorafenib as systemic anti-proliferative therapy. In general, patients with advanced cirrhosis (Child–Pugh C) are not good candidates for local ablative or systemic therapies due to the risk of further decompensation. Here, treatment options are restricted to supportive measures [3].

For years, α-fetoprotein levels have been used in conjunction with imaging methods to aid in diagnosing HCC. In a review of tools for the diagnosis, prognosis and personalized treatment of HCC, Zhu et al. highlight newer biomarkers, including Dickkopf-1 and Golgi protein 73. In their paper, the authors consider that the use of a combination of these biomarkers could prove valuable for early diagnosis, staging and prognosis of patients with HCC [4].

The assessment of treatment response is another important consideration for clinicians treating with radioembolization. Enhancement-based criteria such as the European Association for the Study of the Liver (EASL) guidelines should be applied, as they address the limitations of using World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for locoregional therapies [5]. Additionally, a study by Riaz et al. showed that alpha α-fetoprotein response can be used as an ancillary method to assess treatment response following radioembolization as well as an early screening tool for disease progression [6].

Clinical evidence exists for both of the commercially available yttrium-90 radioembolization devices. TheraSphere^® (Biocompatibles, Inc., Ottawa, Ontario, Canada) consists of small-glass microspheres and SIR-Spheres^® (Sirtex Medical, Sydney, Australia) are resin-based microspheres. Currently, no randomized studies have been completed in TheraSphere.

TheraSphere

TheraSphere is a transarterial radioembolization therapy that consists of millions of insoluble glass microspheres (mean diameter ranging from 20 to 30 μm) with yttrium-90 as an integral constituent of the glass. Yttrium-90 is a pure β emitter and decays to stable zirconium-90; it has a physical half-life of 64.1 h, or 2.67 days. The average energy of beta emissions from yttrium-90 is 0.9367 MeV. TheraSphere is available in 6-dose sizes, and each dose provides a preassembled single-use TheraSphere Administration Set. In the European Union and Canada, TheraSphere is used in the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. In the United States, TheraSphere is indicated for radiation treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters. The device is also indicated in the US for HCC patients with partial or branch portal vein thrombosis (PVT)/occlusion, when clinical evaluation warrants the treatment [7]. During TheraSphere treatment, yttrium-90 glass microspheres are delivered through a catheter placed by a physician into the hepatic artery which supplies blood to the liver tumor. The glass microspheres are unable to pass through the hepatic vasculature and become trapped, providing a radiotherapeutic effect within the tumor.

Prior to TheraSphere administration, patients must undergo hepatic arterial catheterization using balloon catheterization or appropriate angiographic techniques to prevent extrahepatic shunting. Tc-99m MAA is administered into the hepatic artery to determine the extent of A-V shunting to the lungs. TheraSphere may be administered once the possibility of extrahepatic shunting has been evaluated and the patient is deemed acceptable for treatment. If such flow is present and cannot be corrected using established angiographic techniques, the patient is disqualified from treatment. Recommended dose range to the liver is 80–150 Gy. The following formula may be used to calculate the amount of radioactivity required to deliver the desired dose to the liver; liver volume and corresponding liver mass are determined using CT and ultrasound scans.

Use of TheraSphere is contraindicated in patients who demonstrate a potential for shunting of the radioactive microspheres to the lungs or gastrointestinal tract. It is also contraindication in pregnancy. Treatment with TheraSphere is associated with common side effects, including mild to moderate fatigue, pain and nausea that may occur within the first week after treatment; symptoms are similar to those of the common flu. In a large European study of 108 patients treated with TheraSphere, Hilgard et al. reported that grade 1/2 transient fatigue syndrome was the most commonly (61%) reported adverse event [8]. Some patients may experience loss of appetite and temporary changes in liver blood tests. Rare but more severe side effects may include gastrointestinal ulceration, pulmonary edema and fibrosis. As stated above, patients are screened to determine eligibility and mitigate risks in advance of treatment [9].

Clinical evidence

Studies show that radioembolization with yttrium-90 is a promising therapy for patients with advanced HCC whose treatment options are limited. Clinical studies evaluating the safety and efficacy of TheraSphere (yttrium-90 glass microspheres, referred to hereinafter as yttrium-90) for patients with unresectable HCC are presented below, including key studies in the typical application of yttrium-90 in HCC and those that show new developments in the use of yttrium-90 in HCC (Table 1). Also discussed is patient selection for radioembolization. References to TACE within this literature are specific to conventional TACE (cTACE). Drug-eluting bead TACE is not reviewed.

Table 1. . Studies of yttrium-90 (TheraSphere®) in hepatocellular carcinoma patients.

Author (year)	n	Entry criteria	Response rate (%)		Median TTP	Median OS (months)
			WHO	EASL
Yttrium-90 for the treatment of intermediate-advanced HCC
Mazzaferro et al. (2013)	52	Cirrhosis with preserved liver function HCC, intermediate-advanced	40.4	40.4	11	15
Hilgard et al. (2010)	108	Nonresectable HCC BCLC C stage		42	10	16.4
Lambert et al. (2011)	20	Unresectable HCC				12.3
Pracht et al. (2012)	18	Lobar HCC and ipsilateral PVT	Disease control rate: 83.3%			Not reached
Lewandowski et al. (2009)	50	Unresectable HCC or metastatic cancer	51	69
Riaz et al. (2011)	84	Unresectable HCC tumors angiographically isolatable	59	81	13.6	26.9
Salem et al. (2013)	273	Diagnosis of HCC by biopsy or imaging ECOG 0–2, bilirubin <3.0 mg/dl	42	57	10.8/8.4†	17.2/7.7†
Yttrium-90 in comparative studies with TACE for the treatment of intermediate to advanced HCC
Carr et al. (2010)	99	HCC, not eligible for resection, RFA, LTX	Disease control rate: 76%			11.5
Salem et al. (2011)	123	Unresectable HCC	49		13.3	20.5
Memon et al. (2013)	42	Patients previously treated with TACE or yttrium-90			13.3
Salem et al. (2013)	29	ECOG 0–2, treatment naïve
Yttrium-90, radiation lobectomy
Edeline et al. (2013)	34	HCC and underlying cirrhosis	63, mRECIST, 26, RECIST		21.7	13.5
Gaba et al. (2009)	20	Unresectable HCC, ECOG ≤3	55, WHO 70, RECIST			36.6, censored to transplant or resection
Vouche et al. (2013)	83	Right unilobar HCC, cholangiocarcinoma, colorectal cancer				34.4, BCLC B 9.6, BCLC C
Yttrium-90, downstaging
Lewandowski et al. (2009)	43	Unresectable HCC without PVT or extrahepatic metastases		33.3	35.7, censored 41.6, uncensored

^†Overall Child–Pugh A and Child–Pugh B, respectively.

BCLC: Barcelona Clinic Liver Cancer; EASL: European Association for the Study of the Liver; ECOG: Eastern Cooperative Oncology Group; HCC: Hepatocellular carcinoma; LTX: Liver transplantation; OS: Overall survival; PVT: Portal vein thrombosis; RECIST: Response Evaluation Criteria in Solid Tumors; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization; TTP: Time to progression.

• Yttrium-90 for the treatment of intermediate-advanced HCC

Hilgard et al. described safety and long-term survival following treatment with yttrium-90 in 108 patients with HCC and liver cirrhosis. Yttrium-90 was administered mainly by lobar infusion. Treatment response was determined by computed tomography imaging using RECIST and WHO criteria with EASL/National Cancer Institute amendments. The Kaplan–Meier method was used to estimate time to progression (TTP) and overall survival (OS). Mean treatment dose was 120 (±18) Gy. Overall, 3% of patients had complete responses, 37% had partial responses, 53% had stable disease and 6% had primary progression. Median OS was 16.4 months; this was also the survival rate for BCLC-B patients when survival was stratified by tumor stage. TTP was 10 months for all patients. Transient fatigue syndrome was the most frequently reported adverse event; no lung or visceral toxicity was reported [8].

In a prospective Phase II study by Mazzaferro et al., 52 patients with intermediate-advanced HCC (BCLC B and C) were assessed for TTP following treatment with yttrium-90; tumor response, safety and OS were also evaluated. All patients had Eastern Cooperative Oncology Group status 0–1 and were Child–Pugh Class A–B7. Median liver lobe dose per treatment was 101 Gy. Median TTP was 11 months; no difference was observed between patients with/without PVT. Median OS was 15 months; a nonsignificant trend did favor patients without PVT. Complete responses were observed in 9.6% (five responses) of patients. Tumor responses had a significant correlation with absorbed tumor dose; response was predicted by a threshold of 500 Gy tumor dose. Within 6 months, varying degrees of reduced liver function occurred in 36.5% of patients [10].

Lambert et al. conducted a retrospective review of HCC patients referred to Ghent University Hospital for yttrium-90 treatment. The group evaluated safety, response (using modified RECIST) and survival (Kaplan Meier); they also examined urinary excretion following treatment. Although 29 patients were treated (mean activity, 2.17 GBq), 20 were evaluable according to mRECIST criteria. Of those, 15% had complete responses, 35% had partial responses, 30% had stable disease and 20% had disease progression. Median survival was 12.3 months; 14 months for Child–Pugh A/BCLC-B patients. Four patients had severe adverse events, one was related to treatment. The urinary evaluation showed that 0.0025% of the administered activity was excreted within the first 12 h after administration [11].

Pracht et al. assessed the efficacy and safety of yttrium-90 in 18 patients with advanced, unresectable HCC with ipsilateral PVT. Patients were seen for follow-up every 3–6 months and mean follow-up time was 13 months. Overall, 2 patients had complete responses, 13 had partial responses, 1 had stable disease and 2 had progressive disease, yielding an 89% disease control rate. Downstaging was achieved in four patients, and all of these patients received surgery (transplantation or resection). All patients tolerated yttrium-90 well, and adverse effects were grade 3 or less (CTCAEv3.0 scale) [12].

Lewandowski et al. assessed the safety and efficacy of yttrium-90 extended shelf-life glass microspheres (TheraSphere, 12-day shelf life) in 50 patients with HCC. Mean radiation dose delivered was 126 Gy. There was a mean increase in embolic load of 111%; increase from 3.6 to 7.3 million microspheres. Toxicities following treatment included fatigue (28 patients), abdominal pain (19 patients) and nausea/vomiting (6 patients). One patient had grade 3/4 bilirubin toxicity and two patients had gastroduodenal ulcers. Response rates of 51% (WHO guidelines) and 69% (EASL guidelines) were observed [13].

Riaz et al. evaluated the efficacy and safety of radiation segmentectomy (≤2 hepatic segments) with yttrium-90 in 84 patients with unresectable HCC. The group sought to calculate radiation dose upon segmental delivery. Assuming uniform distribution of the microspheres, the median calculated segment dose was 521 Gy. Assuming nonuniform distribution (incorporating a hypervascularity ratio), the median dose delivered to tumor and normal infused hepatic volume was 1214 and 210 Gy, respectively. Treatment response for tumor size and necrosis was seen in 59 and 81% of patients, respectively. Median TTP was 13.6 months. Median survival was 26.9 months. Grade 3/4 biochemical toxicities (bilirubin, albumin, aspartate aminotransferase (AST) and alkaline phosphatase) were seen in eight patients (9%) following treatment [14].

Salem et al. conducted a single-center, prospective, study of long-term outcomes in 291 patients following radioembolization with yttrium-90. Of the 291 patients, 273 had imaging follow-up. The WHO and EASL overall response rates were 42 and 57%, respectively. Median survival times were significantly different for Child–Pugh A and B patients: 17.2 and 7.7 months, respectively (p = 0.002). Child–Pugh B patients with PVT had poorer outcomes, 5.6 months median survival. Toxicities following treatment included fatigue (57%), pain (23%) and nausea/vomiting (20%). Grade 3/4 bilirubin toxicity was reported in 19% of patients [15].

• TACE vs yttrium-90 for the treatment of intermediate-advanced HCC

Carr et al. compared the therapeutic equivalence of conventional TACE and yttrium-90 in survival of patients with unresectable HCC. The study included 932 patients total: 691 receiving cisplatin-based TACE, 99 receiving yttrium-90 and 142 not receiving any therapy; the 142 patients had been referred for therapy but it was determined that because of poor liver function or metastases they would not benefit from the aforementioned therapies. Median survival was 11.5 and 8.5 months for the yttrium-90 and TACE groups, respectively; patients in the yttrium-90 group had slightly milder disease (small but significant difference). Survival was comparable for the two treatments when subgroup analyses were conducted on: patients with bilirubin <1.5 mg/dl, absence of PVT and α-fetoprotein plasma levels <25 U/dl and patients with PVT and those with high α-fetoprotein plasma levels [16].

Using data from 463 HCC patients treated over 9 years, Salem et al. reported that yttrium-90 treatment resulted in longer TTP and reduced toxicity when compared with conventional TACE. Response rates were 49 and 36% for yttrium-90 and TACE, respectively; TTP was 13.3 and 8.4 months; Median survival times were 20.5 and 17.4 months (not statistically different). Survival was similar in patients with intermediate-stage disease (BCLC B) when yttrium-90 and TACE were compared (17.5 and 17.2 months, respectively). Upon univariate analysis, Child–Pugh A T3 and BCLC C patients appeared to have improved survival following yttrium-90 treatment (35.7 and 19.2 months, respectively) vs TACE (22.1 and. 9.3 months, respectively). TACE resulted in more frequently reported abdominal pain and increased transaminase activity (p < 0.05) [17].

Memom et al. prospectively evaluated 96 patients with early-/intermediate-stage HCC who had experienced disease progression following treatment with conventional TACE or yttrium-90. The group sought to understand the characteristics of patients with progressing HCC. Among these patients, 52 and 48% had Child–Pugh class A and B/C disease, respectively. Of the patients who had progressed and had advanced-stage disease, 63% were Child–Pugh class B/C. Patients who progressed after receiving TACE had a higher local disease progression rate than those who had progressed after receiving yttrium-90 (p = 0.006 and p = 0.016, respectively). Thirteen patients went on to receive systemic agents or enter clinical trials [18].

Salem et al. conducted a prospective, observational quality of life (QoL) study in HCC patients receiving yttrium-90 (29 patients) and conventional TACE (27 patients). Child–Pugh and performance statuses were comparable at baseline; patients receiving TACE had lower tumor burdens (p = 0.018) and less-advanced disease (based on United Network for Organ Sharing [UNOS], p = 0.03, and BCLC, p = 0.02). Patients receiving yttrium-90 had significantly better QoL even though their HCC was more advanced; this included social well-being (p = 0.019, effect size (ES) = 0.67), functional well-being (p = 0.031, ES = 0.60), and embolotherapy-specific scores (p = 0.018, ES = 0.67) [19].

• Radiation lobectomy

Edeline et al. conducted a retrospective study of liver volume changes in 34 patients with HCC and cirrhosis who had been treated with yttrium-90. Inclusion criteria were unilateral treatment, no prior surgery, and computed tomographic scans allowing for volumetric assessments. Volumetric and response assessments were performed at baseline and 3 months on treated, tumor, and contralateral liver volumes. Whole liver volume was also assessed. There was a 26% response rate according to RECIST and 63% according to modified RECIST. Median OS was 13.5 months. Median TTP was 21.7 months. Median treated volume decreased from 938 to 702 ml while median contralateral volume increased from 724 to 920 ml. Total liver volume remained stable [20].

Gaba et al. examined the hepatic lobar volume (HLV) measurements, response rates and survival in 20 patients with liver cancer (HCC [17] and peripheral cholangiocarcinoma [3]) following right-lobe radioembolization with yttrium-90. Baseline absolute right and left HLV was 955 and 719 cm³, respectively. Following radioembolization, absolute right HLV was 460 cm³ (atrophied) and absolute left HLV was 1004 cm³ (hypertrophied). There were no grade 3/4 bilirubin toxicities. Response to treatment ranged from 55 to 70% by size criteria. Five-year survival was 46% in these HCC patients [21].

Vouche et al. conducted a time-dependent analysis of HLV following treatment with yttrium-90 in 83 patients with right-unilobar cancer: 67 with HCC, 8 with cholangiocarcinoma and 8 with colorectal cancer. At 1 month, right-lobe atrophy, left-lobe hypertrophy and future liver remnant hypertrophy were all observed (p = 0.003, p < 0.001 and p < 0.001). After more than 9 months, percentage of future liver remnant hypertrophy was 45% (p < 0.001). Five patients (3 HCC, 1 colorectal cancer and 1 cholangiocarcinoma) were able to undergo successful right lobectomy and 6 patients with HCC received liver transplantation [22].

• Downstaging

Lewandowski et al. compared yttrium-90 with TACE for rates of transarterial downstaging in 86 patients with HCC (from UNOS T3 to T2 status). The group also examined response rates, TTP, event- and recurrence-free survival, and OS. Median tumor size was 5.6 cm (yttrium-90) and 5.7 cm (TACE). Partial response was seen in 61% of patients receiving yttrium-90 vs 37% for TACE. Downstaging from T3 to T2 was achieved in 58% of yttrium-90 patients vs 31% of TACE patients. Using UNOS criteria, TTP was 33.3 months for yttrium-90 and 18.2 months for TACE. A significant difference was seen in event-free survival, with 17.7 months for yttrium 90 vs 7.1 months for TACE (p = 0.0017). OS was also better with yttrium-90 vs TACE; censored data showed 35.7 vs 18.7 months and uncensored data showed 41.6 vs 19.2 months [23].

• Ideal patient selection for yttrium-90 in the treatment of HCC

Studies have shown that certain patient characteristics correlate with a more successful outcome following radioembolization with yttrium-90. Several studies have demonstrated that preserved, normal liver function is one of the key factors associated with long-term survival of HCC patients. In the prospective study of long-term outcomes of yttrium-90 radioembolization described above, Salem et al. found that patients with Child–Pugh A disease, with and without PVT, achieved the greatest benefit from yttrium-90 treatment. Child–Pugh B patients with PVT reported poor survival outcomes.

Tumor hypervascularity is a fundamental requirement for treating HCC patients with yttrium-90. Assessing tumor hypervascularity relative to the normal parenchyma allows a treating physician to calculate dose to normal parenchyma. By using tumor hypervascularity to calculate dose to normal parenchyma, Chiesa et al. found that a dose (using both glass and resin microspheres) to normal parenchyma not exceeding 70 Gy was safe [24]. In two separate studies, Garin et al. found that when tumor dose is increased to >205 Gy while maintaining dose to normal parenchyma lower, there is a response and survival benefit [25,26].

Conclusion

Studies have demonstrated that radioembolization with yttrium-90 is a safe treatment that can improve survival for patients with intermediate to advanced stage HCC. For these patients who do not meet criteria for curative procedures and can have limited treatment choices, radioembolization with yttrium-90 is a promising option. In studies, patients with BCLC B and BLCL C have shown a trend toward higher response rates and better QoL vs those of TACE. Studies in BCLC B patients have demonstrated survival rates up to 16.4 months, and studies conducted with both BCLC B and BCLC C have demonstrated survival up to 15 months.

In patients with BCLC A–C disease, radiation segmentectomy with yttrium-90 has demonstrated a median survival of 26.9 months. Yttrium-90 radioembolization also outperformed TACE as a bridge to downstaging HCC patients from UNOS T3 to T2.

Studies have shown that performing a radiation lobectomy with yttrium-90 yields extensive contralateral hypertrophy, high response rates, prolonged survival and a significant increase in contralateral to total functional liver volume ratio, and that it may offer an intriguing option for bridge to resection.

Finally, although further studies would bolster these assertions, preserved liver function and dosimetry seem to be important considerations when treating with yttrium-90, as both can help predict response and survival outcomes.

Yttrium-90 treatment will likely increase its role as integral part of the therapeutic options in the management of HCC. As this entity is biologically diverse the targeted therapies that are currently being developed will only be effective in subgroups. As radioembolization can be employed in almost all tumor subgroups, this ensures its broad applicability. At the same time it is well tolerated when used in patients with good liver function.