Reduction of Hepatopulmonary and Intrahepatic Shunts after Treatment with Sorafenib in Hepatocellular Carcinoma Patients.

PURPOSE: To investigate the reduction of elevated shunts after treatment with sorafenib in hepatocellular carcinoma (HCC) patients planned for transarterial radioembolization (TARE). MATERIALS AND METHODS: Sixteen HCC patients treated with sorafenib were investigated. Shunts were evaluated by SPECT/CT after Technetium-99 m Tc-macroaggregated albumin injection. RESULTS: All patients had high LSF (median 43.5%, range 28-86), and two (12.5%) of them had widespread intrahepatic shunts with concomitants elevated (36%) and acceptable (18%) lung shunt fraction (LSF). The mean duration of the sorafenib use was 134.4 ± 59.2 days. While one patient (6.25%) developed hand-foot syndrome, minor side effects were seen in all patients. After sorafenib use, LSF fell below 20% in eight patients, and TARE was applied to all of them. There was strong negative correlation between the failure of shunt reduction and presence of macrovascular invasion (ρ = - 0.775) and infiltrative tumour type (ρ = - 0.775). CONCLUSION: Sorafenib use may be beneficial in some selected HCC patients with elevated shunts. Expected results may not be obtained in patients with infiltrative tumour type or macrovascular invasion, but patients with nodular tumour type with the absence of macrovascular invasion may be appropriate candidates for shunt reduction with ensuring subsequent TARE. Further investigations with sufficient patient population and standardized protocols of follow-up periods are needed to clarify the values for sorafenib use in HCC patients with evaluated shunts.

Survival and Toxicities after 90Y Transarterial Radioembolization of Metastatic Colorectal Cancer in the RESIN Registry.

Background Patients with unresectable, chemorefractory hepatic metastases from colorectal cancer have considerable mortality. The role of transarterial radioembolization (TARE) with yttrium 90 (90Y) microspheres is not defined because most reports are from a single center with limited patient numbers. Purpose To report outcomes in participants with colorectal cancer metastases treated with resin 90Y microspheres from a prospective multicenter observational registry. Materials and Methods This study treated enrolled adult participants with TARE using resin microspheres for liver-dominant metastatic colorectal cancer at 42 centers, with enrollment from July 2015 through August 2020. TARE was used as the first-, second-, or third-line therapy or beyond. Overall survival (OS), progression-free survival (PFS), and toxicity outcomes were assessed by line of therapy by using Kaplan-Meier analysis for OS and PFS and Common Terminology Criteria for Adverse Events, version 5, for toxicities. Results A total of 498 participants (median age, 60 years [IQR, 52-69 years]; 298 men [60%]) were treated. TARE was used in first-line therapy in 74 of 442 participants (17%), second-line therapy in 180 participants (41%), and third-line therapy or beyond in 188 participants (43%). The median OS of the entire cohort was 15.0 months (95% CI: 13.3, 16.9). The median OS by line of therapy was 13.9 months for first-line therapy, 17.4 months for second-line therapy, and 12.5 months for third-line therapy (χ2 = 9.7; P = .002). Whole-group PFS was 7.4 months (95% CI: 6.4, 9.5). The median PFS by line of therapy was 7.9 months for first-line therapy, 10.0 months for second-line therapy, and 5.9 months for third-line therapy (χ2 = 8.3; P = .004). TARE-attributable grade 3 or 4 hepatic toxicities were 8.4% for bilirubin (29 of 347 participants) and 3.7% for albumin (13 of 347). Grade 3 and higher toxicities were greater with third-line therapy for bilirubin (P = .01) and albumin (P = .008). Conclusion Median overall survival (OS) after transarterial radioembolization (TARE) with yttrium 90 microspheres for liver-dominant metastatic colorectal cancer was 15.0 months. The longest OS was achieved when TARE was part of second-line therapy. Grade 3 or greater hepatic function toxicity rates were less than 10%. Clinical trial registration no. NCT02685631 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Cost-utility analysis of selective internal radiation therapy with Y-90 resin microspheres in hepatocellular carcinoma.

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.

NEMESIS: Noninferiority, Individual-Patient Metaanalysis of Selective Internal Radiation Therapy with 90Y Resin Microspheres Versus Sorafenib in Advanced Hepatocellular Carcinoma.

In randomized clinical trials, no survival benefit has been observed for selective internal radiation therapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess, through a metaanalysis, whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is noninferior to sorafenib and to compare safety profiles for patients with advanced HCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify randomized clinical trials comparing SIRT, as monotherapy or followed by sorafenib, with sorafenib monotherapy among patients with advanced HCC. The main outcomes were OS and frequency of treatment-related severe adverse events (≥grade 3). The per-protocol population was the primary analysis population. A noninferiority margin of 1.08 in terms of hazard ratio was prespecified for the upper boundary of 95% confidence interval for OS. Prespecified subgroup analyses were performed. Results: Three randomized clinical trials, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411 of 635 (64.7%) patients allocated to SIRT and 522 of 608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was noninferior to sorafenib (10.2 and 9.2 mo [hazard ratio, 0.91; 95% confidence interval, 0.78-1.05]). Treatment-related severe adverse events were reported in 149 of 515 patients (28.9%) who received SIRT and 249 of 575 (43.3%) who received sorafenib only (P < 0.01). Conclusion: SIRT as initial therapy for advanced HCC is noninferior to sorafenib in terms of OS and offers a better safety profile.

Dosimetric characterization of a novel 90Y source for use in the conformal superficial brachytherapy device.

PURPOSE: To characterize the dose distribution in water of a novel beta-emitting brachytherapy source for use in a Conformal Superficial Brachytherapy (CSBT) device. METHODS AND MATERIALS: Yttrium-90 (90Y) sources were designed for use with a uniquely designed CSBT device. Depth dose and planar dose measurements were performed for bare sources and sources housed within a 3D printed source holder. Monte Carlo simulated dose rate distributions were compared to film-based measurements. Gamma analysis was performed to compare simulated and measured dose rates from seven 90Y sources placed simultaneously using the CSBT device. RESULTS: The film-based maximum measured surface dose rate for a bare source in contact with the surface was 3.35 × 10-7 cGy s-1 Bq-1. When placed in the source holder, the maximum measured dose rate was 1.41 × 10-7 cGy s-1 Bq-1. The Monte Carlo simulated depth dose rates were within 10% or 0.02 cm of the measured dose rates for each depth of measurement. The maximum film surface dose rate measured using a seven-source configuration within the CSBT device was 1.78 × 10-7 cGy s-1 Bq-1. Measured and simulated dose rate distribution of the seven-source configuration were compared by gamma analysis and yielded a passing rate of 94.08%. The gamma criteria were 3% for dose-difference and 0.07056 cm for distance-to-agreement. The estimated measured dose rate uncertainty was 5.34%. CONCLUSIONS: 90Y is a unique source that can be optimally designed for a customized CSBT device. The rapid dose falloff provided a high dose gradient, ideal for treatment of superficial lesions. The dose rate uncertainty of the 90Y-based CSBT device was within acceptable brachytherapy standards and warrants further investigation.

Tumor burden and liver function in HCC patient selection for selective internal radiation therapy: SARAH post-hoc study.

Aim: To determine whether a liver tumor burden ≤25% and well-preserved liver function (albumin-bilirubin grade 1) are appropriate criteria for identifying patients with unresectable hepatocellular carcinoma who may benefit from selective internal radiation therapy (SIRT) using 90yttrium resin microspheres versus sorafenib. Patients & methods: Post-hoc analysis of patients in the intention-to-treat population of the SARAH trial (SIRT vs sorafenib) with ≤25% tumor burden and albumin-bilirubin grade 1. Primary end point: overall survival. Results: Median overall survival was 21.9 months (95% CI: 15.2-32.5, n = 37) with SIRT and 17.0 months (11.6-20.8, n = 48) with sorafenib (hazard ratios: 0.73; 95% CI: 0.44-1.21; p = 0.22). Conclusion: A combination of good liver function and low tumor burden may be relevant for selection of hepatocellular carcinoma patients for SIRT.

Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION: EudraCT 2009-012576-27, NCT0112 6645.

Sorafenib Reduced Significantly Heptopulmonary Shunt in a Large Hepatocelullar Carcinoma.

An 81-year-old man with a large hepatocellular carcinoma was referred in our institution for Y radioembolization (RE). The preliminary arteriography using Tc-macroaggregate albumin demonstrated an important hepatopulmonary shunt. It was an exclusion criterion for RE due to high risks of lung radiations. Then, the patient was treated with sorafenib during 4 months, stopped because of grade 3 toxicity. A second liver arteriography was performed, and Tc-macroaggregate albumin imaging showed an important reduction of the lung shunt. Transient therapy with sorafenib permitted to close the lung shunt and was a bridge for RE.

90 Y-ibritumomab-tiuxetan as a therapeutic alternative for follicular lymphoma (FL): A single-center experience.

BACKGROUND: Follicular lymphoma (FL) is the most frequent indolent lymphoma subtype in adults. Maintenance therapy with rituximab is frequently applied to FL patients with complete or partial response following initial chemoimmunotherapy. However, radioimmunotherapy with 90 Y-ibritumomab-tiuxetan represents a therapeutic alternative. METHODS: To compare the clinical and the prognostic impact of both therapies, a study collective of n = 56 patients diagnosed with indolent B-cell lymphoma was retrospectively investigated. The study collective was subdivided into two groups: n = 36 patients treated with rituximab maintenance therapy vs n = 20 patients treated with 90 Y-ibritumomab-tiuxetan. RESULTS: No prognostic differences for performance status, FLIPI score, gender, or B-symptoms were found for 90 Y-ibritumomab-tiuxetan or rituximab maintenance therapy. Overall survival rates and progression-free survival did not differ between both maintenance therapies. CONCLUSION: Our retrospective single-center analysis of two patient groups without major differences in prognostic parameters revealed similar outcome with two different maintenance therapies. Hence, 90 Y-ibritumomab-tiuxetan therapy might offer a valuable alternative treatment option for FL patients with partial response. However, large prospective trials are needed to confirm the reported findings.

Safety and Efficacy of Transarterial Radioembolization Combined with Chemoembolization for Bilobar Hepatocellular Carcinoma: A Single-Center Retrospective Study.

BACKGROUND: Radioembolization induced liver disease (REILD) is a possible sequela of transarterial radioembolization (TARE), particularly in cases of whole-liver treatment. To mitigate this problem, the safety and efficacy of combined transarterial chemoembolization (TACE) and TARE were evaluated for patients with bilobar hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Nineteen patients (mean age 60 years; range 27-82 years) treated for HCC between June 2012 and September 2014 were included in the analysis. Each patient was treated with combined TARE and TACE for bilobar HCC, with or without portal vein thrombosis. The hepatic lobe with large HCC was treated with TARE, and the other lobe with small HCC(s) was treated with TACE. Laboratory and clinical data were investigated to determine REILD occurrence. Survival data were analyzed to compare the treatment efficacy of alternative treatment modalities, including TACE and sequential TARE. RESULTS: All patients underwent TARE for a dominant tumor in one lobe and TACE for small nodule(s) in the other lobe of the liver. The mean yttrium-90 microspheres used in TARE were 2.8 GBq (range; 1.0-3.5 GBq), and the mean doses of doxorubicin and iodized oil were 24.5 mg and 5.2 mL, respectively, for TACE. No statistical differences were noted between laboratory data measured before and after treatment, and no procedure-related major clinical complications occurred. The median time-to-progression of patients was 10.0 months, and the median overall survival was 27.3 months. CONCLUSION: Combined radioembolization and chemoembolization appears to be a safe and effective treatment modality for bilobar HCC.

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

BACKGROUND: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. METHODS: SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. FINDINGS: Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. INTERPRETATION: In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. FUNDING: Sirtex Medical Inc.

Update on Embolization Therapies for Hepatocellular Carcinoma.

PURPOSE OF REVIEW: The purpose of the review is to summarize the latest applications for embolotherapy in the management of patients with HCC according to BCLC stage. RECENT FINDINGS: While traditionally reserved for patients with unresectable HCC and stage B disease, there is an important role for embolization therapies in earlier stage patients as an adjunct to ablation, bridging, or downstaging therapy, as a means to improve safety of resection, and potentially as an arterial ablative option in the case of radioembolization. Newer applications of radioembolization such as radiation segmentectomy have the potential to provide cure in localized unifocal disease, and transarterial chemoembolization-portal vein embolization and radiation lobectomy may provide a combination of treatment and future liver remnant hypertrophy for planned hepatic resection. There is also an increasing role for embolization in the treatment of stage C disease, and recent data suggest it can be used in combination with sorafenib with the potential for survival benefit over sorafenib alone, even in the case of portal vein tumor thrombus. Embolization therapies play an increasingly important role in patients with BCLC stage A-C hepatocellular carcinoma. While different therapies may be offered on a patient-specific basis, there are limited prospective RCT data to support superiority of one technique over another.

A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids.

PURPOSE: To develop a novel conformal superficial brachytherapy (CSBT) device as a treatment option for the patient-specific radiation therapy of conditions including superficial lesions, postsurgical positive margins, Dupuytren's contractures, keloid scars, and complex anatomic sites (eyelids, nose, ears, etc.). METHODS AND MATERIALS: A preliminary CSBT device prototype was designed, built, and tested using readily available radioactive seeds. Iodine-125 (125I) seeds were independently guided to the treatment surface to conform to the target. Treatment planning was performed via BrachyVision Planning System (BPS) and dose distributions measured with Gafchromic EBT3 film. Percent depth dose curves and profiles for Praseodymium-142 (142Pr), and Strontium-90/Yttrium-90 (90Sr-90Y) were also investigated as potential sources. Results achieved with 90Sr-90Y and electron external beam radiation therapy were compared and Monte Carlo N-Particle eXtended 2.6 simulations of 142Pr seeds were validated. RESULTS: BPS was able to predict clinical dose distributions for a multiple seeds matrix. Calculated and measured doses for the 125I seed matrix were 500 cGy and 473.5 cGy at 5 mm depth, and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively. Results of 90Sr-90Y tests demonstrate a more conformal dose than electron EBRT (1.6 mm compared to 4.3 mm penumbra). Measured 142Pr doses were 500 cGy at surface and 17.4 cGy at 5 mm depth. CONCLUSIONS: The CSBT device provides a highly conformal dose to small surface areas. Commercially available BPS can be used for treatment planning, and Monte Carlo simulation can be used for plans using beta-emitting sources and complex anatomies. Various radionuclides may be used in this device to suit prescription depths and treatment areas.

Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Conventional transarterial chemoembolization (cTACE) is used to treat patients with hepatocellular carcinoma (HCC). Radioembolization is a minimally invasive procedure that involves implantation of radioactive micron-sized particles loaded with yttrium-90 (Y90) inside the blood vessels that supply a tumor. We performed a randomized, phase 2 study to compare the effects of cTACE and Y90 radioembolization in patients with HCC. METHODS: From October 2009 through October 2015, we reviewed patients with HCC of all Barcelona Clinic Liver Cancer (BCLC) stages for eligibility. Of these, 179 patients with BCLC stages A or B met our enrollment criteria and were candidates for cTACE or Y90 therapy. Patients were assigned randomly to groups that received Y90 therapy (n = 24; 50% Child-Pugh A) or cTACE (n = 21; 71% Child-Pugh A). The primary outcome was time to progression (TTP), evaluated by intention-to-treat analysis. Secondary outcomes included safety, rate of response (based on tumor size and necrosis criteria), and Kaplan-Meier survival time. We performed inverse probability of censoring weighting and competing risk analyses. RESULTS: Patients in the Y90 radioembolization group had significant longer median TTP (>26 mo) than patients in the cTACE group (6.8 mo; P = .0012) (hazard ratio, 0.122; 95% confidence interval [CI], 0.027-0.557; P = .007). This was confirmed by competing risk and inverse probability of censoring weighting analyses accounting for transplantation or death. A significantly greater proportion of patients in the cTACE group developed diarrhea (21%) than in the Y90 group (0%; P = .031) or hypoalbuminemia (58% in the cTACE group vs 4% in the Y90 group; P < .001). Similar proportions of patients in each group had a response to therapy, marked by necrosis (74% in the cTACE group vs 87% in the Y90 group) (P = .433). The median survival time, censored to liver transplantation, was 17.7 months for the cTACE group (95% CI, 8.3-not calculable) vs 18.6 months for the Y90 group (95% CI, 7.4-32.5) (P = .99). CONCLUSIONS: In a randomized phase 2 study of patients with HCC of BCLC stages A or B, we found Y90 radioembolization to provide significantly longer TTP than cTACE. Y90 radioembolization provides better tumor control and could reduce drop-out from transplant waitlists. ClinicalTrials.gov no. NCT00956930.

Intra-Arterial Radionuclide Therapies for Liver Tumors.

Intra-arterial radionuclide therapies serve essentially as internal radiation treatment options for both primary and metastatic liver tumors, which imply delivering implantable radioactive microspheres into branches of hepatic arteries that feed liver tumors to provide a high dose of targeted radiation to tumor tissue, while sparing the healthy liver tissue from hazardous effects of radiation. The principle of this therapeutic option depends on the unique preferential arterial supply of malignant liver tumors in contrast with mostly portal venous supply of normal hepatocytes as well as excess amount of arterial neovascularization in the tumor bed. Therefore, intra-arterial radionuclide therapy can provide very high radiation exposure to tumor tissue, which is impossible to reach with external radiation therapy due to serious side effects and moreover, radiation can be targeted to tumor tissue selectively with less side effects. Yttrium-90 (Y-90), a high-energetic beta emitter is the most preferred radionuclide, which is used to label microspheres. Two types of Y-90 microspheres are commercially available that are made of resin and glass. Many studies in the literature have demonstrated that Y-90 microsphere therapy is an efficient and safe locoregional therapeutic option for unresectable primary and metastatic liver tumors such as hepatocellular carcinoma and liver metastases from colorectal cancer and breast cancer as well as neuroendocrine tumors. Furthermore, limited number of studies has reported its use in some relatively uncommon metastatic liver tumors from melanoma, pancreatic, renal, and lung cancer. Besides Y-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, Rhenium-188 microspheres, Holmium-166 chitosan, and Holmium-166 microspheres have been introduced as alternative radiopharmaceuticals for intra-arterial therapy for liver tumors.

Complete Remission of Unresectable Hepatocellular Carcinoma After Combined Sorafenib and Adjuvant Yttrium-90 Radioembolization.

Sorafenib has improved the median overall survival of unresectable or otherwise untreatable hepatocellular carcinoma (HCC) of ∼3 months, compared to supportive cares. Complete response, although rare, has been reported. The authors reported herein a case of complete biochemical and radiological remission of advanced unresectable HCC with lymph node metastasis and tumoral portal vein thrombosis treated by 5 months therapy with sorafenib followed by adjuvant Yttrium-90 radioembolization. At 12 months follow-up, there is no evidence of HCC recurrence.

A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib.

BACKGROUND & AIMS: Sorafenib (SOR) is the standard of care for patients with hepatocellular carcinoma (HCC) and portal vein invasion (PVI), based on the results of phase 3 trials. However, radioembolization (RE) using yttrium-90 microspheres has been shown to achieve higher response rates and better survival in large cohorts and phase 2 trials. This study aimed to compare survival of HCC patients with PVI treated by RE or SOR. METHODS: Survival among patients with HCC and PVI treated with RE or SOR in four Spanish hospitals between 2005 and 2013 was analysed retrospectively. Kaplan-Meier survival curves were plotted and baseline variables tested for prognostic value using the log-rank test. A multivariate prognostic model including variables identified in the univariate analysis and adjusted by a propensity score based on factors that may determine the probability of exposure to RE was generated using Cox regression analyses. RESULTS: After a median follow-up of 6 months, 60 deaths had occurred: 38 and 22 in SOR and RE groups respectively. Median survival was 6.7 months (95%CI 5.2-8.1 months) for the entire cohort, and 8.8 months (95%CI 1.8-15.8) in the RE group and 5.4 months (95%CI 2.7-8.1) in the SOR group (P = 0.047). The difference in survival was still statistically significant when 13 patients in the RE group who started SOR after a median time of 8 months were censored from the analysis. CONCLUSIONS: In a cohort of patients with HCC and PVI treatment with RE was associated with a more prolonged survival compared with SOR.

Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common liver neoplasm and the fifth most common cancer worldwide. Moreover, its incidence has increased dramatically since the mid-2000s. While surgical resection and liver transplantation are the main curative treatments, only around 20% of people with early hepatocellular carcinoma may benefit from these therapies. Current treatment options for unresectable hepatocellular carcinoma include various ablative and trans-arterial therapies in addition to the drug sorafenib. OBJECTIVES: To determine the benefits and harms of yttrium-90 microsphere trans-arterial radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other similar systemic or locoregional therapies for people with unresectable hepatocellular carcinoma. SEARCH METHODS: We reviewed data from the Cochrane Hepato-Biliary Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded. We also checked reference lists of primary original studies and review articles manually for further related articles (cross-references) up to December 2015. SELECTION CRITERIA: Eligible studies included all randomised clinical trials comparing yttrium-90-90 microsphere radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other systemic or locoregional therapies for unresectable hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS: The two review authors independently extracted the relevant information on participant characteristics, interventions, study outcomes, and data on the outcomes for this review, as well as information on the design and methodology of the studies. The two review authors assessed risk of bias of the included trials using pre-defined risk of bias domains. We used Trial Sequential Analysis to control the risk of random errors. We assessed the methodological quality with GRADE. MAIN RESULTS: Two randomised clinical trials with 68 participants fulfilled our inclusion criteria. Both trials were at high risk of bias, and we rated the evidence as very low quality. One of the included trials compared radioembolisation versus chemoembolization for intermediate stage hepatocellular carcinoma as classified by the Barcelona Clinic Liver Cancer (BCLC) staging system, while the other included trial was an interim analysis of a randomised trial assessing radioembolisation combined with sorafenib versus sorafenib monotherapy in participants with BCLC-advanced stage hepatocellular carcinoma. The available data were insufficient to perform the planned analyses. Neither of the two trials reported data on all-cause mortality, cancer-related mortality, or time to progression of the tumour. The trial comparing radioembolisation with chemoembolization reported quality of life and serious adverse events, and there were no statistically significant differences between the trial groups with regard to these outcomes at week 12. On the basis of the two included randomised clinical trials, single-session radioembolisation appeared to be as safe as multiple sessions of chemoembolization for intermediate stage hepatocellular carcinoma and had a similar impact on quality of life, but data were too sparse to exclude even major differences. Radioembolisation followed by sorafenib appeared to be as well tolerated as sorafenib alone for advanced stage hepatocellular carcinoma, but data were too sparse to exclude even major differences. We also identified five ongoing studies evaluating the topic of our review. AUTHORS' CONCLUSIONS: There was insufficient evidence to assess the beneficial and harmful effects of yttrium-90 microsphere radioembolisation for people with unresectable hepatocellular carcinoma. Further randomised clinical trials are mandatory to better assess the potential beneficial and harmful outcomes of yttrium-90 microsphere trans-arterial radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies versus placebo, no treatment, or other systemic or locoregional therapies for people with unresectable hepatocellular carcinoma.

Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis.

PURPOSE: Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or (90)Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. METHODS: We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. RESULTS: A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. CONCLUSION: SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials.

Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability.

Synergy between yttrium-90 (90Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with 90Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with 90Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with 90Y radioembolization for treatment of liver cancer.