Transarterial Chemoembolization with Epirubicin-Loaded Microspheres for Hepatocellular Carcinoma: A Prospective, Single-Arm, Multicenter, Phase 2 Study (STOPPER Trial)

Baseline screening included patient demographics, physical exam, tumor and treatment history, Child–Pugh score, Eastern Cooperative Oncology Group (ECOG) evaluation, electrocardiogram, non-contrast and contrast-enhanced MRI to evaluate intrahepatic tumors, non-contrast chest CT scan to exclude extrahepatic lesions, and laboratory tests. Laboratory tests included routine blood tests, hepatic, renal and coagulation function tests, hepatitis testing, alpha-fetoprotein, and a pregnancy test, if appropriate.

Inclusion criteria for the study were patients aged 18–75 years diagnosed with HCC according to the diagnostic criteria for liver cancer in the Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in 2017 [28]. Additional inclusion criteria were preserved liver function (Child–Pugh class A or B7), an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, a single tumor < 7 cm in the diameter or multiple tumors with maximum three lesions with individual diameters < 7 cm and a total diameter < 10 cm [29, 30], diagnosed with HCC for the first time or recurrence after curative-intent therapy (liver resection or ablation), and no history of chemotherapy, radiotherapy, or transarterial embolization for HCC.

Patients were excluded from the study if they had vascular invasion, extrahepatic spread, diffuse lesions (tumor burden of the whole liver > 50%), combined with arteriovenous shunt, invasion of the main trunk or primary branch of the portal vein. Patients were excluded if they had advanced liver disease (bilirubin levels > 2 mg/dL, aspartate aminotransferase, or alanine aminotransferase > 5 times the upper limit of normal value), renal failure, insufficient renal function (creatinine levels > 2 mg/dL) or any contraindications for TACE, epirubicin administration or magnetic resonance imaging (MRI) examination. In addition, pregnant women, breastfeeding women, or those who were unable to use reliable contraceptives during treatment or within 12 months after the end of the treatment and have participated in the trials of other drugs or devices within the past 30 days were excluded. Patients were also excluded based on the judgment of the investigators.

Standard DEB-TACE procedures were performed by senior interventional radiologists in each center. DEB-TACE procedures were routinely performed with cone-beam CT guidance. The volume and size of epirubicin-loaded microspheres was based on the safety of the treatment, the tumor size and/or the vascular structure with the dose of epirubicin at the discretion of the treating physician. In patients with large tumor (> 5 cm), or with potential risk of arterioportal or hepatic venous shunting, 100 μm microspheres would be recommended. In patients with small tumor (< 3 cm) and without arterioportal or hepatic venous shunting, 40 μm microspheres would be recommended. Otherwise, 75 μm microspheres would be considered. Evaluation of procedure and device-related adverse events was performed peri-operatively, and follow-up assessments were performed 30 days, 3 months, 6 months and 12 months after the first DEB-TACE procedure.

Follow-up assessment included physical examination, ECOG and Child–Pugh scores, laboratory tests, electrocardiogram (at 3 months), non-contrast and contrast-enhanced MRI for evaluation of intrahepatic tumors, and non-contrast chest CT scan, concomitant medications prescribed since the last follow-up, adverse events that occurred since the previous assessment, and survival status (at 6 and 12 months).

Every 30 days following DEB-TACE treatment, each site conducted a post-treatment evaluation and determined whether another DEB-TACE procedure was necessary. If deemed necessary, the next treatment was completed within 14 days after the follow-up procedure with up to four DEB-TACE treatments permitted for each patient within 6 months following the first treatment. If the patient received four embolization treatments, the 30 days post-treatment evaluation was not performed and the 6 month follow-up after the first treatment would be conducted instead.

The primary effectiveness outcome measure was 6-month objective response rate (ORR), which was defined as the percentage of patients who achieved either complete response (complete disappearance of lesions) or partial response. An independent Core Laboratory blindly assessed tumor response using EASL and mRECIST criteria (at baseline, 30-day, 3-month, 6-month and 12-month post-initial treatment) based on the plain scan and enhanced MRI performed. Thirty days after each DEB-TACE treatment, the site conducted a post-treatment evaluation and determined whether the next DEB-TACE treatment would be performed according to the patient’s condition.

The secondary outcome measures included 30-day ORR, 3-month ORR, time to tumor progression (TTP), time to extrahepatic spread, 12-month progression-free survival (PFS), 12-month overall survival rate, and the frequency of treatment-associated AEs or serious adverse events (SAEs), and the latter having a Grade 3 or higher score using based on the Common Terminology Criteria for Adverse Events (v5.0). ORR was assessed based on MRI using both the European Association for the Study of the Liver (EASL) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria [31, 32]. TTP was defined as the length of time from the initiation of treatment to either the date of first disease progression or the date of death due to any cause, whichever occurred earlier. Time to extrahepatic spread was defined as the length of time from the initiation of treatment to the development of extrahepatic spread via imaging assessment.

The primary hypothesis was that the ORR for the DEB-TACE procedure at 6 months for the present study would exceed the performance goal (PG). The null (H₀) and the alternative (H₁) hypotheses for this primary outcome measure were as follows: H₀: P_e ≤ PG; H₁: P_e > PG; where P_e was the expected 6-month ORR (%). A standard approximation test was used to assess the one-sided hypotheses of the primary outcome measure, considering the superiority of the DEB-TACE procedure to PG, if the one-sided lower 97.5 confidence bound ORR at 6 months for the DEB-TACE procedure was more significant than PG. The sample size was determined based on the primary effectiveness outcome measure, considering a power of ≥ 85.0%, a one-sided significance level of α = 2.5%, a PG for 6 month ORR = 45.0%, and an expected 6 month ORR of 60.0%, resulting in a total of 98 patients being required for the 6 month assessment. Considering an assumed attrition rate of 10.0% (loss to the 6-month follow-up), it was determined that approximately 109 patients needed to be enrolled in the study.

A total of 109 patients with HCC were enrolled and included in the intent-to-treat population (Fig. 1). One patient who was diagnosed with cholangiocarcinoma instead of HCC after enrollment and the first DEB-TACE procedure and not included in the final per-protocol analysis reported below. All 108 patients in the per-protocol group completed the 30 day follow-up assessment. Three (2.8%) of the 108 patients were not eligible for the 3 month follow-up due to either undergoing transplantation (n = 2) or withdrawal from the study (n = 1). At 6 months, an additional three patients were not available for follow-up as a result of death, failure to complete imaging evaluation, and lost to follow-up resulting in data for 102 (94.4%) patients being assessed at 6 months. Ninety-two patients completed the 12-month follow-up. Baseline characteristics for the per-protocol population are reported in Table 1. Patients had a mean of 1.56 tumors with 36 (33.3%) having multiple tumors.

The 108 patients in the per-protocol group underwent a total of 199 DEB-TACE procedures. Forty-two (38.9%) had a single DEB-TACE procedure and 47 (43.5%), 13 (12.0%) and six (5.6%) patients underwent two, three or four total DEB-TACE procedures respectively following the initial treatment.

The characteristics of embolization treatment in this study are shown in Table 2. For the first treatment, 24 (22.2%) of patients received 40 μm microspheres, 67 (62.1%) received 75 μm microspheres and 24 (22.3%) received 100 μm microspheres. Sixty-six patients received a second treatment. Except for two patients who received two different-sized (100 μm/2 ml and 100 μm/3 ml; 40 μm/3 ml and 75 μm/3 ml) microspheres during the same procedure, other patients just received the same-sized microspheres in both treatments. Hence, 15 (22.7%), 35 (53.1%) and 18 (27.2%) received 40 μm, 75 μm and 100 μm microspheres, respectively (Table 2). For the 19 patients undergoing a third treatment of 19 patients, 15.8%, 63.1%, and 21.1% received 40 μm, 75 μm and 100 μm microspheres. For the six patients having a fourth treatment 16.7%, 33.3% and 50.0% received 40 μm, 75 μm and 100 μm microspheres. The epirubicin dose was similar across all treatment groups ranging from 47.3 ± 14.0 mg to 52.5 ± 17.6 mg (Table 2). Bilateral hepatic arterial chemoembolization was performed in five (4.6%), five (7.6%), one (5.3%), and two (33.3%) of patients for procedures cycles 1, 2, 3, and 4, respectively. Unilateral hepatic artery chemoembolization was performed for the remainder of the patients in the study. There were no reports of device defects for any of the procedures.

Six-month ORR was 73.3% based on the EASL criteria, and 71.3% based on mRECIST criteria (Fig. 2). The 30-day ORR was 79.6% for both criteria and the 3-month ORR was 80.0 or 81.0% for the EASL and mRECIST criteria, respectively. The complete response, partial response, stable disease, and progressive disease rates were also comparable for both criteria. Supplement Table 1 reports tumor measurements at baseline and by follow-up visit. The 12-month overall survival rate (Fig. 3) was 94.3% (95% CI 89.9–98.8%). Sixteen patients were censored prior to 12 months. This included seven deaths and nine patients who were withdrawn from the study, including two patients who received a transplant, two patients who were lost to follow-up, two patient who withdrew from the study and three patients for whom no 12-month follow-up data was reported.

The median TTP and median time to extrahepatic spread were all not reached (NR; 95% CI NR–NR). The 12-month probabilities for TTP were 60.7% (95% CI 51.9–71.1%) using the EASL criteria and 61.8% (95% CI 53.0–72.1%) using the mRECIST criteria. At the 6-month follow-up, the extrahepatic spread was observed in 9.5% of patients and increased to 21.1% at the 12-month follow-up. After tumor progression or extrahepatic spread, 48.1% (52/108) of patients received subsequent single or combined therapies (Table 4). Supplemental Tables 2 and 3 report Child–Pugh scores and ECOG performance status at baseline and by follow-up visit.

There were no unanticipated adverse device events during the study. Six (5.5%) deaths were reported in the study population during the observation period. This included two deaths due to liver cancer metastases to the whole body and one each due to liver cancer, liver cancer metastasis to bone, cerebral hemorrhage, and biliary obstruction. No deaths were considered to be device or procedure related.

There was a total of 709 treatment-associated AEs reported during the 12-month post-initial procedure study observation period. The most commonly reported AEs include 132 reports of Grade 1 or 2 post-embolization syndrome, 58 complaints of abdominal pain, 26 incidences of pyrexia, 24 complaints of constipation, 14 instances of abnormal hepatic function, and 14 incidences of abdominal distension.

A total of 53 SAEs were reported within 12 months after the DEB-TACE procedure (Supplement Table 4), of which 30 were reported to be likely to definitely relate to the treatment (Table 3). This included 9 each reported for the microspheres and epirubicin and 12 procedure related SAEs. None of these resulted in death. SAEs reported as being likely to definitely related to the microspheres included five liver abscesses, and one each liver cancer recurrence, ascites, anemia, and post-embolization syndrome.