Selective internal radiotherapy (SIRT) versus transarterial chemoembolization (TACE) for the treatment of intrahepatic cholangiocellular carcinoma (CCC): study protocol for a randomized controlled trial

Contrast-enhanced CT is a widely used method for the primary diagnosis and staging of CCC[22]. CT allows evaluation of the primary tumor and can rule out extrahepatic metastasis[24]. Typical imaging features are nodular, irregularly shaped intrahepatic masses, which show moderate contrast enhancement in the arterial and portal venous phases[22].

Due to its high soft-tissue contrast, MRI with an intravenous contrast medium is the modality of choice for staging of intrahepatic CCC[25, 26]. In analogy to CT, the tumor shows only moderate contrast enhancement in the arterial and portal venous phases and prolonged enhancement in the late phases[27, 28].

Surgical resection is the treatment of choice[5]. When a complete removal (R0-resection) is accomplished, 3-year survival rates of 40 to 60% are reported[31‐38]. However, when the tumor is incompletely removed, the results are not better than those obtained with palliative care[39].

Patients with very few but clearly definable lesions can be treated with local ablative therapies like radiofrequency or microwave ablation. The intention is to completely ablate the tumor, including a safety margin of a least 1 cm[40]. Because 5 cm of liver tissue is the maximum diameter that can be safely ablated with the standard probes available, 3 cm is typically the maximum tumor diameter suggested for ablation.

Survival was proven to be higher with Cisplatin and Gemcitabine compared to Gemcitabine monotherapy[41]. Nonetheless, only 59% of patients in that study had extra- or intrahepatic CCC; the remainder had tumors in papillary tissues and the gallbladder. Therefore, those results were only partially applicable to patients with intrahepatic CCC.

Transarterial chemoembolization (TACE) is based on delivering small particles into the tumor feeding arteries via a catheter to cause embolization or occlusion of the tumor’s arterial supply. The particles also contain a chemotherapeutic agent for specific tumor treatment. In inoperable patients, survival was greater with TACE than with best supportive care[42‐44]. Recently published data indicate that TACE performed with drug-eluting beads (DEB TACE) lead to better local tumor control and both prolonged progression-free survival (PFS) and overall survival (OS) compared to systemic chemotherapy[45]. The rate of side effects was acceptable; thus, TACE was considered a good method for preserving quality of life for as long as possible[42, 45, 46].

SIRT is a locoregional treatment that selectively irradiates liver tumors. The particles are loaded with the beta emitter Yttrium 90 (Y-90) and are delivered to the hepatic artery or its (sub)-segmental branches in order to embolize and selectively irradiate the tumor. Due to the short range of beta radiation, the tumor is predominantly targeted, and most of the normal liver tissue is spared. The procedure is performed once in each liver lobe. SIRT particles are commercially provided by two companies, and both are acceptable for a prospective study protocol. Based on our significant experience with one of these products, we will use SirSpheres® in this study. The most serious complication associated with SIRT is radiation-induced liver disease, which is, in fact, radiation-induced liver failure; this condition leads to death within a few weeks[50, 51]. To minimize this complication, the right and left liver lobes will be treated sequentially, with a between-treatment interval of 4 weeks. The liver lobe with the larger tumor mass will be treated first. The dose for each liver lobe will be calculated according to the body surface method[51, 52]. This is the most frequently used approach for resin spheres (73.5% in a large series of 680 treatments)[53], and it is recommended by the manufacturer, SIRTEX, and by the Radioembolization Brachytherapy Oncology Consortium (REBOC)[52].

Patients randomized to SIRT will receive a preparative intervention, including embolization of the collateral arteries (mainly the gastroduodenal artery and the right gastric artery), and subsequently, an MAA scan will be performed. Follow-up visits will be performed at 4 and 12 weeks after completion of SIRT treatment, and every 3 months thereafter until the clinical endpoints are reached. In cases where local tumor progression is detected and no contraindications exist, SIRT can be repeated once in each lobe. In cases where contraindications exist, the patient is allowed to cross over to TACE if there are no contraindications against TACE.

TACE is a well-established alternative to classic chemotherapy in patients with tumors confined to the liver; in this trial, TACE will serve as the control arm. Numerous different TACE techniques have been reported in the literature for treating HCC and CCC[44, 47, 54]. Since 2006, doxorubicin-loaded DEBs have been commercially available in various sizes. Compared to conventional TACE, which uses Lipiodol mixed with a chemotherapeutic agent, DEBs have been shown to be more effective, with fewer side effects in patients with HCC[55, 56]. Currently, DEB TACE is the only TACE method that is standardized in terms of the embolization material, the chemotherapeutic agent, and the application technique[55, 57]. Because we have considerable experience with DcBeads®, we will continue to use them exclusively throughout the trial to ensure reproducibility. The bead size will be 100 to 300 μm.

An optimal dose of 150 mg doxorubicin per application was determined in a prospective trial in patients with HCC[58]; there will be no dose adjustment made for elevated bilirubin or body surface area. After mixing with nonionic contrast medium, the DcBeads are to be administered slowly, and as selectively as possible with a microcatheter under fluoroscopic control. The mixture will be infused until the flow is sluggish to avoid reflux. In cases of incomplete embolization, additional bland (drug-free) embolization is not permitted. The TACE procedure will be repeated every 6 weeks as this interval has been established in several clinical trials for HCC and intrahepatic CCC[44, 47, 55, 56, 59]. TACE treatment will be carried out until either no viable tumor tissue is detected by MRI or if any contraindications against repeated treatment occur (for example relevant ascites, portal invasion or occlusion of the arterial feeding vessels). Therefore, additional MRI is indicated prior to each TACE treatment. After cessation of TACE treatment, follow up will be carried on in 3-month intervals until the clinical endpoints are reached. In cases where local tumor progression is detected and no contraindications exist, TACE can be repeated. In cases where contraindications exist, the patient is allowed to cross over to SIRT if there are no contraindications against SIRT.

Each follow up will include MRI of the liver, a quality-of-life assessment, documentation of adverse/serious adverse events, a physical examination, and blood tests. All MRI examinations will be performed according to a standardized protocol of MRI sequences, including transversal T1- and T2-weighted images, diffusion-weighted images, and multiphasic contrast-enhanced T1-weighted images. All examinations will be performed on a single 3 T scanner (Skyra®, Siemens Healthcare, Erlangen, Germany).

PFS is directly related to the local treatment result. The local tumor response will be measured with the modified response evaluation criteria in solid tumors (mRECIST) on the basis of the MRI[60]. In an attempt to eliminate any potential bias that could derive from the difference in follow-up intervals, for determination of PFS only the MRI performed at 3, 6, 9 months et cetera, after the first treatment will be used in both groups (Figure 1). However, survival is limited by both tumor progression and liver performance. Because both treatments also affect parts of the normal liver parenchyma, they can potentially lead to liver failure. Additionally, extra-hepatic metastases develop more often in patients with intra-hepatic CCC than in patients with HCC. Therefore, PFS will be the primary endpoint, because it includes the local treatment effect, death by deteriorating liver function due to liver toxicity, and death due to extra-hepatic tumor spread.

OS is also influenced by drug-induced impaired liver function, by extra-hepatic tumor spread, and by secondary treatment strategies applied after the SIRT/TACE treatment. Therefore, OS is considered a secondary endpoint. Time to progression (TTP) serves as another secondary endpoint. The local tumor response will be determined on the basis of the MRI performed at 3, 6, 9 months et cetera, after the first treatment.

As indicated above, the local tumor response will be measured according to the detailed mRECIST criteria on the basis of the MRIs performed at 3, 6, 9 months et cetera, after the first treatment[60]. Progression is defined as tumor progression that cannot be properly treated by the respective local treatment method. The final decision that progression cannot be treated properly with the respective local treatment method will be at the discretion of the investigators after consulting with an internal tumor conference and the interdisciplinary study team (including members from Surgery, Hepatology, Oncology, and Nuclear Medicine). Performance status, evaluated according to the Eastern Cooperative Oncology Group (ECOG), will be assessed during the follow-up visits by physical examination.

To ensure quality execution, patient welfare, and compliance with ethical and legal stipulations, the Interdisciplinary Center for Clinical Trials (IZKS), Mainz, will perform the regulatory tasks (support in the development and review of study-related documents) and statistical analysis (carried out by an independent statistician). These functions will be performed according to the standard operating procedures of IZKS, which are based on the guidelines stated at the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use and good clinical practice.

The analysis of the study will be performed in a purely exploratory manner. Statistically significant results are unlikely unless the difference between the two methods is greater than expected. The main purpose of the analysis is to provide estimates of PFS, OS, and TTP. In particular, the time-to-event data will be analyzed with Kaplan-Meier methods. Descriptive statistics of all analyzed parameters will be provided whenever appropriate.

In the absence of previous randomized trials or data regarding SIRT as a first-line therapy for patients with intrahepatic CCC, it is not possible to perform a reliable power calculation. Therefore, this trial is designed as a pilot study.