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Globally, hepatocellular carcinoma is the second most common cause of cancer deaths. It remains challenging to intensify cancer treatment without impairing liver function.
The objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is to examine the hypothesis that transarterial radioembolization (TheraSphere yttrium-90 glass microspheres) combined with standard first-line treatment with sorafenib will improve outcomes over treatment with sorafenib alone in unresectable hepatocellular carcinoma. The STOP-HCC study is the largest international, multicenter, prospective study of intra-arterial treatment in combination with sorafenib in unresectable hepatocellular carcinoma. Here we report the study design.
STOP-HCC is a prospective, phase 3, open-label, randomized controlled study conducted across up to 105 sites in North America, Europe, and Asia. Eligible adults have unresectable hepatocellular carcinoma and a life expectancy of at least 12 weeks, 1 or more unidimensional measurable lesions, Child-Pugh score 7 points or less, and Eastern Cooperative Oncology Group Performance Status score 1 or lower, and are candidates for treatment with sorafenib. Presence of branch portal vein tumor thrombosis is permitted. Patients were randomly assigned in a 1:1 ratio to receive either sorafenib alone or transarterial radioembolization followed by sorafenib within 2 to 6 weeks. The primary outcome is overall survival. Secondary outcomes are time to progression, time to untreatable progression, time to symptomatic progression, tumor response, quality of life, and adverse event occurrence. The study is an adaptive trial, comprising a group-sequential design with 2 interim analyses with 520 patients, and an option to increase the sample size to 700 patients at the second interim analysis. The sample size of 520 patients allows for 417 deaths to give 80% power to detect an increase in median overall survival from 10.7 months for the sorafenib group (based on the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) to 14.2 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.754) with 2-sided alpha of .05. The increased sample size of 700 patients allows for 564 deaths to give 80% power to detect a smaller difference in median overall survival from 10.7 months for the sorafenib group to 13.7 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.781).
Enrollment for the study completed in September 2017. Results of the first and second interim analyses were reviewed by the Independent Data Monitoring Committee. The recommendation of the committee, at both interim analyses, was to continue the study without any changes.
The STOP-HCC study will contribute toward the establishment of the role of combination therapy with transarterial radioembolization and sorafenib in the treatment of unresectable hepatocellular carcinoma with and without branch portal vein tumor thrombosis.
ClinicalTrials.gov NCT01556490; https://clinicaltrials.gov/ct2/show/NCT01556490 (Archived by WebCite at http://www.webcitation.org/7188iygKs).
RR1-10.2196/11234
Primary liver cancer (hepatocellular carcinoma [HCC] and intrahepatic bile duct cancer) is the fifth most common cancer in men and ninth most common in women worldwide [
Early-stage disease is often asymptomatic and unlikely to be diagnosed unless patients are enrolled in a surveillance program. Most HCC is diagnosed after patients have progressed beyond early-stage disease and, thus, they receive palliative treatments (intra-arterial treatment, systemic therapies, and external radiation), with the goal to improve life expectancies and maintain a good of quality of life. Median survival in this group of patients varies widely, ranging from approximately 3 months for patients with metastatic disease and portal vein thrombosis to up to 33 months for patients with good prognosis [
Patients with unresectable HCC are primarily treated with locoregional therapies and systemic agents. The systemic treatment sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals Inc, Wayne, New Jersey, USA) is the only approved systemic therapy in the first-line treatment of patients with unresectable HCC [
The use of sorafenib in clinical practice was assessed in over 3000 patients in the global observational registry study of sorafenib, Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment With Sorafenib (GIDEON) [
After the marketing of sorafenib was approved in North America, numerous studies that evaluated other molecular therapies did not demonstrate their superiority or noninferiority to sorafenib [
Transarterial radioembolization (TARE) could be an alternative to TACE treatment [
There is more rationale to combine sorafenib with TARE than with TACE. First, TARE is better tolerated than TACE, which may allow a higher dose and longer length of therapy with sorafenib. Additionally, sorafenib may be potentially more synergistic with yttrium-90, as antiangiogenic agents potentiate the effects of radiation on tumor regression [
Several small nonrandomized studies that investigated combination treatment with TARE and sorafenib reported favorable results among patients with BCLC A and B status. Median overall survival ranged between 12 and 20 months, and disease control was achieved in up to 100% of patients [
Two large randomized multicenter trials were designed to evaluate combination treatment with TARE and sorafenib, with the primary end point of overall survival. The Evaluation of Sorafenib in Combination With Local Micro-Therapy Guided by Primovist Enhanced MRI in Patients With Hepatocellular Carcinoma (SORAMIC) trial compared sorafenib alone against TARE using resin yttrium-90 microspheres combined with sorafenib in patients with advanced HCC [
The TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is the largest phase 3 prospective study of TARE in combination with sorafenib in unresectable advanced HCC. Compared with the SORAMIC trial, STOP-HCC has a larger sample size and so should have greater statistical power to detect a difference in overall survival; additionally, STOP-HCC uses glass yttrium-90 microspheres and is being conducted worldwide. At the time the STOP-HCC study was designed (in 2011), sorafenib was the only systemic agent approved for use as first-line treatment in HCC and, since then, there have been several trials reporting positive outcomes [
The STOP-HCC study, also known as the BTG TS-103 study, was registered with ClinicalTrials.gov (NCT01556490) on March 13, 2012.
Patients aged >18 years with unresectable hepatocellular carcinoma (HCC; confirmed by histology or noninvasive American Association for the Study of Liver Diseases criteria) who have a life expectancy ≥12 weeks.
Measurable disease defined as at least one unidimensional measurable lesion by computed tomography or magnetic resonance imaging (according to Response Evaluation Criteria in Solid Tumors v1.1).
Child-Pugh score ≤7 points and Eastern Cooperative Oncology Group Performance Status score of ≤1.
Eligible to receive standard-of-care sorafenib.
Platelet count >50×109/L or >50% prothrombin activity; hemoglobin ≥8.5 g/dL (≥85.0 g/L); bilirubin ≤2.5 mg/dL (≤42.8 μmol/L); alanine aminotransferase and aspartate aminotransferase <5 times the upper limit of normal; amylase or lipase ≤2 times the upper limit of normal; serum creatinine ≤1.5 times the upper limit of normal; international normalized ratio for prothrombin time <2.0.
Eligible for curative treatment (eg, ablation or transplantation).
Main portal vein thrombosis (branch portal vein thrombosis is permissible).
Extrahepatic disease, except lung nodules and mesenteric or portal lymph nodes ≤2.0 cm each.
Must not have tumor replacement >70% of total liver volume based on visual estimation by the investigator or must not have tumor replacement >50% of total liver volume in the presence of albumin <3 g/dL (<30 g/L).
History of previous or concurrent cancer other than HCC unless treated curatively ≥5 years prior to entry.
Contraindication to TheraSphere administration according to package label.
Patients infected with HIV can be considered; however, they must be well managed and well controlled with an undetectable viral load.
Contraindications to sorafenib, angiography, and selective visceral catheterization.
Concurrent treatment with substrate agents for cytochrome P450 2B6, uridine diphosphate glucuronosyltransferase 1A1 or 1A9, and P-glycoprotein; rifampicin; St John’s wort; phenytoin; carbamazepine; phenobarbital; dexamethasone; other systemic anticancer agents (eg, docetaxel, doxorubicin, or irinotecan); other locoregional therapies (other than study treatment).
Prior treatment with transarterial chemoembolization (TACE) or bland embolization must have occurred >2 months prior to randomization and must have been applied to a treatment field or lobe that is not to be treated under this protocol. For patients with tumor progression in the treatment field or lobe previously treated with TA(C)E, vessels feeding the tumor(s) must be assessed for adequate blood flow using angiography (cone beam computed tomography strongly recommended), and the TACE or bland embolization must have been applied >6 months prior to randomization.
Prior receipt of external beam radiation treatment to the chest, liver, or abdomen.
STOP-HCC is an ongoing phase 3, randomized, parallel-group, multicenter, prospective, open-label study evaluating treatment with TheraSphere microspheres in patients with unresectable HCC in whom sorafenib therapy is already planned. Patients were recruited at up to 105 sites in the United States, Canada, Europe, and Asia. Eligible patients were randomly assigned in a 1:1 ratio to the sorafenib and TARE+sorafenib groups. The sorafenib group receives planned sorafenib according to the product label. The TARE+sorafenib group receives TheraSphere microspheres prior to the initiation of sorafenib. All patients are followed prospectively from randomization to death until the predefined number of deaths, to allow the final analysis to be conducted, have occurred.
Site investigators are from departments of radiology, nuclear medicine, and interventional radiology. Investigators are experienced in radioembolization with radioactive microsphere products. For sites with investigators with low or no experience with TheraSphere microspheres, before inclusion in the trial, the site team must have completed training that included 3 to 5 administrations of TheraSphere microspheres. Administration of TheraSphere microspheres is generally considered to be an outpatient procedure in the United States and Canada and an inpatient procedure in Europe and Asia. The physical location for aftercare and recovery was determined by individual institutional policies and facility configurations. The sites are collecting the data.
An Independent Data Monitoring Committee (IDMC), led by the IDMC chairperson, was established to oversee the conduct of the study. The IDMC met periodically to review enrollment, protocol deviations, and safety events. In addition, the IDMC conducted and reviewed an initial feasibility safety analysis and will evaluate the overall survival data at interim analyses for consideration of stopping the study for efficacy and for the option to increase the sample size at the second interim analysis. The IDMC is tasked to make formal recommendations to the study sponsor at the time of the feasibility safety analysis, at the time of the interim analyses, and during the conduct of the study based on detailed decision rules specified in the IDMC charter. An IDMC member or designate can act as the study independent medical monitor. The IDMC will evaluate the final study report.
On day –14 to day 0, the following assessments were conducted: review of eligibility criteria, demographics, medical history, physical examination, medication and prior treatment history, serum pregnancy test for women, ECOG Performance Status, hematology (white blood cells, hemoglobin, hematocrit, and platelets), coagulation (prothrombin time, partial thromboplastin time, and international normalized ratio for prothrombin time), chemistry panel, liver function tests, tumor markers for HCC (alpha-fetoprotein), triple-phase magnetic resonance imaging and spiral computed tomography (CT) of abdomen, Child-Pugh score, spiral CT of chest and pelvis, quality-of-life questionnaire, assessment and report of adverse events, and review and recording of concurrent medications. Informed consent was obtained at screening.
Eligible patients were randomly assigned on day 0 using a computer-generated randomization scheme, and investigators had the option to randomly assign patients using either a Web-based electronic system or telephone. To create a balance between the 2 study groups, patients were stratified based on region (North America and Europe vs Asia), ECOG Performance Status (0 vs 1), and presence or absence of branch portal vein tumor thrombosis (PVTT). Randomly assigned patients who were unable to receive the planned study treatment continued to be followed under their assigned study group and will be included in the statistical analysis.
Patients randomly assigned to the sorafenib group start sorafenib as soon as possible after randomization, in accordance with the product labeling. Doses are adjusted over several visits as needed. Every 8 weeks after randomization, assessments are conducted as
Clinical trial schema for the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study. TARE: transarterial radioembolization; TS: TheraSphere microspheres.
TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study schedule of assessments and events.
Interventions and Assessments | Sorafenib group: initiate treatment weeks 1-4; continue therapy weeks ≥5 | TAREa+sorafenib group | Follow-up every 8 weeks ±14 daysc (for both groups) | ||||
First workup and TARE treatment: Weeks 1-4 | Second workup and TARE treatment for patients with bilobar disease: Weeks 5-8 | Sorafenib treatment: initiate and continue sorafenib treatment >2 to <6 weeks after TARE | Workup and retreatmentb for patients with hepatic progression | ||||
Administer sorafenibd | ✓ | ✓ | ✓c | ||||
Calculate liver volume and mass | ✓ | ✓ | |||||
Hepatic angiogram, 99mTc-MAA scanf, calculate TARE dose, administer TAREg | ✓ | ✓ | ✓ | ||||
ECOGh Performance Status | ✓ | ✓ | ✓ | ✓i | |||
Hematologyj, coagulationk, chemistry panel, liver function tests | ✓l | ✓l | ✓ | ✓m | |||
Tumor markers for hepatocellular carcinoma (alpha-fetoprotein) | ✓ | ✓ | ✓m | ||||
Triple-phase MRIn/spiral CTo abdomen, Child-Pugh score, spiral CT chest and pelvis, quality-of-life questionnaire | ✓m | ||||||
Assess and report adverse events, review and record concurrent medication | ✓ | ✓ | ✓ | ✓ | ✓m | ||
Final end point, efficacy and safety documentation, and exit patient | ✓i |
aTARE: transarterial radioembolization.
bAdditional TARE workup and administration in lesions amenable to further TARE.
cThe follow-up visits should be scheduled from the day of randomization. A window of ±14 days is permissible from the scheduled date.
dAccording to package insert at weeks 1-4 for sorafenib group patients and after all initial TARE administrations for TARE+sorafenib group patients only.
eSorafenib to be stopped 7 days before subsequent TARE administration in disease progression and restarted 2 weeks after TARE is administered.
f99mTc-MAA scan: technetium-99m macroaggregated albumin.
gAdditional TARE may be administered only after progression if lesions are amenable to treatment.
hECOG: Eastern Cooperative Oncology Group.
iBoth before and after progression of disease resulting in termination of further treatment.
jHematology tests: white blood cells, hemoglobin, hematocrit, and platelets.
kCoagulation tests: prothrombin time, partial thromboplastin time, and international normalized ratio for prothrombin time.
lIf treatment commences within 14 days of randomization, the clinical laboratory assessments are not required to be repeated.
mPrior to progression of disease resulting in termination of further treatment.
nMRI: magnetic resonance imaging.
oCT: computed tomography.
All patients in the study have liver volume measurements and mass calculations with triple-phase CT (
Patients deemed unsuitable for such treatment can proceed to treatment with sorafenib as described above. For eligible patients, TARE is started within 28 days of randomization, prior to the initiation of sorafenib.
Patients with unilobar disease receive a lobar TARE. Patients with bilobar disease receive TARE to the first lobe, and then TARE to the second lobe after at least 28 days after the first treatment but still within 5 to 8 weeks after randomization.
The treatment approach for TARE with TheraSphere microspheres is lobar. Target liver mass and volume are determined by the positioning of the delivery catheter in the hepatic vasculature and the resulting liver area (Couinaud segments) infused. Since there is considerable individual variation in hepatic vascular anatomy, the determination of target liver mass and volume depends on the variant encountered. TheraSphere microspheres are administered at a dose of 120 Gy ±10% to each lobe. If radiation exposure to the lungs exceeds 30 Gy (or 50 Gy cumulative across all planned infusions, estimated during the dose calculation), the TARE dose is reduced to a minimum dose of 90 Gy ±10%. If, after consideration of dose reduction, radiation exposure to the lung continues to be more than 30 Gy (or 50 Gy cumulative), TARE is not administered and sorafenib treatment is initiated. 99mTc-MAA angiography and 99mTC-MAA SPECT or SPECT/CT can be repeated after 4 weeks of continuous treatment with sorafenib to reassess lung shunting. If radiation exposure to the lung is less than 30 Gy for a single treatment (or 50 Gy cumulative over all planned infusions) within a target dose of 90 to 120 Gy ±10%, TARE can be administered.
Sorafenib treatment is initiated at least 2 weeks and up to 6 weeks following administration of TARE (
During follow-up, patients in the TARE+sorafenib group who had hepatic progression with lesions amenable to TARE can be retreated under investigator judgment. In that case, sorafenib is discontinued 7 days prior to TARE (equivalent to approximately 5 to 7 half-lives) and resumed 2 weeks after TARE.
For TARE with TheraSphere microspheres, the catheter is placed under image guidance at the same position as for 99mTc-MAA administration. Prophylaxis with a gastric inhibitor (H2 blocker) is recommended.
After the first 20 patients in the TARE+sorafenib group received both TheraSphere microspheres and sorafenib and completed at least 2 weeks of sorafenib therapy, a feasibility safety assessment was conducted. The IDMC reviewed the safety results of both groups in an unblinded fashion. Stopping further enrollment to trial could have been considered if there was either (1) an unanticipated patient death definitely or probably related to the sequential administration of TARE followed by sorafenib, or (2) a pattern of serious toxicity clearly related to the sequential administration of TARE followed by sorafenib as assessed by the IDMC experts based on the severity of disease of the study population.
The primary outcome measure of the STOP-HCC study is overall survival time. The secondary outcomes are time to progression, time to untreatable progression, time to symptomatic progression, tumor response, quality of life, and adverse events. Definitions of these outcomes are as follows:
The following additional efficacy variables will be assessed.
Adverse events, serious adverse events, and unanticipated adverse device effects are collected throughout the study and assessed using version 4.0 of the National Cancer Institute Common Terminology for Adverse Events [
The STOP-HCC study is a phase 3 adaptive trial using a group-sequential design with overall survival as the primary efficacy end point. The study was designed to detect a 3.5-month increase in median overall survival, from 10.7 months in the sorafenib group to 14.2 months in the TARE+sorafenib group (HR 0.754), using a log-rank test. Due to uncertainty in the expected treatment effect, we planned a sample size reestimation, which would allow the sample size to increase in order to detect a 3.0-month increase in median overall survival time, from 10.7 months in the sorafenib group to 13.7 months in the TARE+sorafenib group (HR 0.781).
A maximum of 417 deaths would yield 80% power to detect the target difference in median overall survival (HR 0.754) with a 2-sided alpha of .05 using a group-sequential design with 2 interim analyses. It was estimated that a maximum of 520 patients would need to be recruited over 60 months, with an 18-month additional follow-up period. This includes an adjustment to take account of an assumed 5% of patients who would be lost to follow-up and for whom a date of death was not recorded, and an assumed additional 5% of patients who would be erroneously randomly assigned because they did not meet the eligibility criteria at randomization.
The IDMC will evaluate the overall survival data during 2 interim analyses, which are planned at the observance of approximately, but no less than, 188 and 250 events, with a 2-sided
Sample size modification will be considered at the second interim analysis according to a simplification of the promising zone approach described in Mehta and Pocock [
The final analysis, without a sample size modification, is planned when approximately, but no less than, 417 deaths have occurred. A 2-sided
If the sample size increases after the second interim analysis, the final analysis is planned when approximately, but no less than, 564 deaths have occurred, which gives 80% power to detect an improvement in median overall survival from 10.7 to 13.7 months using a log-rank test with a 2-sided
All efficacy end points will be analyzed using a modified intention-to-treat population, defined as patients who met the study eligibility criteria and were randomly assigned. The per-protocol population is defined as the patients in the modified intention-to-treat population without any major protocol deviations that could affect efficacy evaluation; analysis using the per-protocol population will be according to the treatment actually received. The safety population included all randomly assigned patients who received study treatments at least once; analysis will be according to the treatment actually received.
For the primary end point, the Kaplan-Meier method will be used to estimate overall survival curves, and the log-rank test will be used to compare groups. For all secondary end points, comparison between groups will be conducted at a 2-sided alpha of .05, with analyses occurring only at final analysis to determine statistical significance between the groups. For the secondary time-to-event end points (time to progression, time to untreatable progression, time to symptomatic progression, and time to deterioration in quality of life), the Kaplan-Meier method will be used to estimate curves, and comparisons between groups will be conducted using the log-rank test. Tumor response rates will be compared between groups using the continuity-adjusted Newcombe-Wilson test.
Univariable Cox regression analyses of the primary efficacy end point, overall survival, and all other time-to-event end points (ie, time to progression, time to untreatable progression, time to symptomatic progression, and time to deterioration in quality of life) will be conducted with the following baseline factors, one at a time, together with randomized group: age group, race, ethnicity, unilobar versus bilobar disease, region, ECOG Performance Status, presence of branch PVTT, duration from date of initial diagnosis of HCC to randomization, tumor burden, presence of extrahepatic lesions, Child-Pugh score, BCLC stage, HCC etiology, prior oncologic treatment for HCC, bilirubin, albumin, albumin-bilirubin score, and alpha-fetoprotein. This will allow an assessment of each of these factors on the study outcomes.
To address the poolability of data across regions, study sites, and sex, multivariable Cox regression analyses of the time-to-event end points will be conducted with the following factors, together with treatment group, and the factors from the univariable analyses that have a 2-sided
Logistic regression analyses of binary end points (ie, objective response rate and disease control rate) will be conducted in the same way as the Cox regression analyses described above.
Enrollment for the study completed in September 2017. Results of the first and second interim analyses were reviewed by the IDMC; the recommendation of the committee, at both interim analyses, was to continue the study without any changes.
TARE has gained a place in various guidelines and consensus recommendations for the treatment of unresectable HCC. A consensus panel report by the Radioembolization Brachytherapy Oncology Consortium states that TARE can be considered for patients with unresectable hepatic primary cancer or metastatic hepatic disease with liver-dominant tumor burden, and a life expectancy of at least 3 months [
PVTT is the most common form of macrovascular invasion in HCC, and it is a common complication [
We expect the STOP-HCC study to be the largest study of sorafenib alone versus sorafenib combined with TARE. We chose overall survival as the primary end point; overall survival is the primary end point recommended by the American Association for the Study of Liver Diseases Panel of Experts for the design of clinical trials in HCC patients because it is the most clinically relevant and the one that is least subject to investigator bias [
When the study was designed there was no standard second-line treatment available. Now that at least three new drugs are available in second-line treatment (regorafenib, cabozantinib, and the checkpoint inhibitor nivolumab), it is possible that postprogression treatment may affect overall survival. Subsequent treatments that are equally effective in the treatment arms would not be expected to affect the absolute overall survival benefit of the experimental treatment but will make the relative improvement in overall survival smaller, provided that the subsequent therapies used in both treatment arms follow the current standard of care [
Another factor that may affect overall survival is the tolerance to the treatment. In the randomized controlled trials of TACE versus TACE plus sorafenib (Sorafenib or Placebo in Combination With Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma [SPACE], Sorafenib in Combination With Transarterial Chemoembolisation in Patients With Unresectable Hepatocellular Carcinoma [TACE 2], and Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib [TACTICS] trials [
Overall survival should be improved by the control of the different risks of progression. Treatment failure could be the consequence of new intrahepatic lesions, intrahepatic growth, and new extrahepatic lesions (including portal vein thrombosis). TARE should mitigate the first two risks and sorafenib, the third risk.
Finally, survival in HCC patients is confounded by underlying cirrhosis and hepatitis, so while there may be a treatment effect, there are other elements at play that determine survival.
Although the SORAMIC trial did not show an improvement in overall survival, there are some design differences between that trial and the STOP-HCC trial: the STOP-HCC study has a larger sample size and so should have greater statistical power to detect an overall survival difference, the TARE devices used in the 2 studies are different (resin yttrium-90 microspheres vs glass yttrium-90 microspheres), and the SORAMIC trial was conducted in Europe and Turkey with 38 sites, whereas STOP-HCC is being conducted in North America, Europe, and Asia with approximately 100 sites.
We chose secondary end points to determine whether improvement in response affects overall survival and quality of life. The secondary end points of time to progression, time to symptomatic progression, and tumor response rate are also recommended by the American Association for the Study of Liver Diseases Expert Panel [
Limitations of the study include the unblinded design, but other limitations were minimized as much as possible. Blinding for the sorafenib group would have been difficult to achieve due to its well-known and extensive toxicity profile. There are uncertainties in the assumptions of median overall survival for the sample size calculation (eg, since the population enrolled may include more PVTT patients than expected, and the literature suggests that a larger difference in median overall survival may exist for PVTT patients vs non-PVTT patients), hence the choice of an adaptive study design, which allows the sample size to be increased to detect a smaller difference in median overall survival. The STOP-HCC study addresses this issue in terms of providing a large patient population in a well-designed trial.
It is important to establish an effective, tolerable, and affordable treatment to improve patient survival for unresectable HCC. One challenge in the treatment of patients with HCC at the advanced stage is providing an efficient treatment of the cancer without impairment of liver function and quality of life. TARE has a limited toxicity profile when used appropriately and, consequently, a low impact on sorafenib dose intensity and duration and is, thus, an attractive concomitant treatment. Enrollment for the STOP-HCC study completed in September 2017 [
IRB approval of the global principal investigator's site, Northwestern.
technetium-99m macroaggregated albumin
Barcelona Clinic Liver Cancer
computed tomography
Eastern Cooperative Oncology Group
Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment With Sorafenib
hepatocellular carcinoma
hazard ratio
independent data monitoring committee
magnetic resonance imaging
portal vein tumor thrombosis
Response Evaluation Criteria in Solid Tumors
Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol
Evaluation of Sorafenib in Combination With Local Micro-Therapy Guided by Primovist Enhanced MRI in Patients With Hepatocellular Carcinoma
Sorafenib or Placebo in Combination With Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma
single-photon emission computed tomography
TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma
transarterial chemoembolization
Sorafenib in Combination With Transarterial Chemoembolisation in Patients With Unresectable Hepatocellular Carcinoma
Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib
transarterial radioembolization
The authors thank all the individuals who participated in the design of the study (TheraSphere STOP-HCC Protocol Study Group), the IDMC, and Tuli Ahmed, Accelera Communications, LLC (King of Prussia, PA, USA) and Gretchen Pezza, BTG International, Inc (West Conshohocken, PA, USA) who provided medical writing support. The TheraSphere STOP-HCC Protocol Study Group consisted of the following members: H Kevin Kim and Bassel El-Rayes (Emory University Hospital, Atlanta, GA, USA); Jorg Schlaak (University Hospital, Essen, Germany); Stephen Cohen (Fox Chase Cancer Center, Philadelphia, PA, USA); Jean-Luc Raoul (Centre Eugène Marquis, Rennes, France); Jonathan Strosberg, Bulent Arslan, and Ravi Shridhar (H Lee Moffitt Cancer Center, Tampa, FL, USA); Matt Johnson and Mary Maluccio (Indiana University, Indianapolis, IN, USA); Dan Brown (Thomas Jefferson Hospital, Philadelphia, PA, USA); Jeff Geschwind, David Cosgrove, and Michael Choti (Johns Hopkins University, Baltimore, MD, USA); Andrew Zhu (Massachusetts General Hospital, Boston, MA, USA); Lewis Roberts (Mayo Clinic, Rochester, MN, USA); Bill Rilling (Medical College of Wisconsin, Milwaukee, WI, USA); Ravi Murthy and Ahmed Kaseb (MD Anderson, Houston, TX, USA); Vincenzo Mazzaferro (Istituto Nazionale Per Lo Studio e La Cura dei Tumori, Milan, Italy); Laura Kulik, Mary Mulcahy, Riad Salem, Bob Lewandowski, and Al Benson III (Northwestern Memorial Hospital, Chicago, IL, USA); Mark Bloomston, Tony Saab, and Hooman Khabiri (Ohio State University Medical Center, Columbus, OH, USA); Daniel Sze (Stanford University, Palo Alto, CA, USA); Wells Messersmith and Jan Durham (University of Colorado, Denver, CO, USA); Nicholas Fidelman (University of California San Francisco, San Francisco, CA, USA); and HuaChing Zhao (MedTrials Inc, Media, PA, USA).
TheraSphere is a registered trademark of Theragenics Corporation used under license by Biocompatibles UK Ltd, a BTG International Group Company. TheraSphere microspheres are manufactured for Biocompatibles UK Ltd.
This study was sponsored by Biocompatibles UK Ltd, a BTG International Group Company. The sponsor was involved in the design of the study. The sponsor funded professional medical writers for the writing of the manuscript. All authors met International Committee of Medical Journal Editors authorship criteria. NC, JB, EB, BH, and FM are employed by BTG International Group Companies; NC and BH own company stock. JE received research grants from and acted as a consultant for BTG. DC was compensated for work on a speakers’ bureau for BTG and advisory board for Bristol-Myers Squibb. LK has been compensated for work on advisory boards for Bristol-Myers Squibb, Bayer, Gilead Sciences, and Eisai and as a nonpromotional speaker for BTG. RS receives research grant funding from and is a consultant to BTG.