Comparing stereotactic ablative radiotherapy (SABR) versus re-trans-catheter arterial chemoembolization (re-TACE) for hepatocellular carcinoma patients who had incomplete response after initial TACE (TASABR): a randomized controlled trial

As mentioned above, TACE is effective for managing HCC patients with early to intermediate stage. However, TACE alone cannot achieve satisfactory complete tumor response rate, demonstrating median response and complete response rates after TACE was 38% (range 3–86%) and 0 (range 0–35%), respectively [37]. The unsatisfactory complete response suggested the concept of combining local therapy to improve local control.

In this regard, TACE combined with RFA has been reported to be useful in local tumor control [38, 39]. Recently, image-guided high-precise radiotherapy, i.e., SABR, has been reported to play a role in managing incomplete TACE [27]. However, evidence from randomized phase III studies is largely lacking.

Hence, the main reason to conduct SABR for unresectable HCC patients who had incomplete response after TACE is to increase treatment response and to prolong patient survival [24, 26, 28, 40‐45]. In addition, post-TACE embolized materials were also useful to guide dose delivery of SABR, enhancing targeting precision.

Taken together, conducting a randomized clinical trial to test the role of SABR in eradicating HCC – particularly for post-TACE residual tumors – is strongly encouraged [29‐31]. As a result, the present phase-III trial intends to compare clinical outcomes between TACE plus SABR and TACE plus re-TACE for HCC patients who had post-TACE residual tumors.

The present study will be conducted after a formal approval of Institute Review Board (Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medication Foundation; approval number: A10502001). Important protocol modifications, e.g., changes to eligibility criteria or outcome analyses, will be re-submitted to IRB and implemented only after a re-approval of IRB.

Written informed consent will be obtained for each participant. Details of the trial process, including pros and cons of interventions, will be explained by both physician and study nurse. Whole-day contact information of investigators will be provided for all participants and their families. Obtained data will be kept in a security locker. The present protocol is reported according to recommendation of SPIRIT 2013 [46]. Final analyses and results will be submitted for publication on a peer-reviewed journal after completion of the study.

The present study will be conducted at a single regionally academic institute (i.e., Dalin Tzu Chi Hospital, Chia-Yi, Taiwan). Inter-institute cooperation for enrolling potential patients may be done under formal supervision of IRBs.

Several inclusion criteria will be as follows.

We will recruit patients who have incomplete response after their initial TACE. All recruited patients will be allocated randomly to the SABR or re-TACE group (Fig. 1).

SABR, or alternatively named Stereotactic Body Radiotherapy (SBRT), is a rapidly developing modern radiotherapy technique for liver tumors [47, 48]. TrueBeam™ (Varian Medical Systems, CA, USA) will be used to deliver SABR by using an extremely conformal radiation dose distribution and rapid fall-off of the peripheral dose, leading to a large sparing of surrounding normal tissues.

To achieve high precision, Image-guided Radiotherapy (IGRT) with respiratory-gated or breath-holding technique will be combined with SABR to overcome the effect of positioning uncertainty and respiratory motion. Real-time Position Management™ (RPM) system (Varian Medical System, CA, USA), version 1.7.5, will be used when breath-holding technique cannot be conducted confidentially. A CT scanner will be used for simulation (Somatom Emotion 6, Siemens Medical Solution, Forchheim, Germany). These techniques have been reported to improve treatment precision of irradiating targets that are affected by respiratory motion, such as lung, breast, and liver tumors [49].

SABR will be delivered in 5 fractions within 2 weeks, and the prescription dose will be ranged from 35 to 50 Gy, depending on tumor size, location, and normal tissue constrains. In some situations, treatment course will be prolonged to 8–10 fractions, for example, patients with poor liver function (e.g., Child B8–9) or their tumor location near the adjacent gastrointestinal tract, diaphragm, or the central zone of the liver (i.e., ≤1.5 cm around the main portal vein). The preferred inter-fraction time interval will be 48 h.

No expansion from Gross Target Volume (GTV) to CTV will be performed for most irradiating targets, and margins to generate Plan Target Volume (PTV) from Clinical Target Volume (CTV) will be ≤10 mm. The prescribed isodose should encompass 95% of PTV but 100% of CTV.

Critical organ constrains will be obeyed according to RTOG 1112 protocol [50]. Briefly, the 0.5-cc maximum dose regions of normal structures will be as follows: stomach, duodenum, small and large bowels, < 30 Gy; esophagus, < 32 Gy; and, 5 mm around the spinal cord, < 25 Gy. Bilateral mean kidney dose should be < 10 Gy. Allowed mean liver dose (MLD, the mean dose to the liver minus all GTV) should be kept < 13 Gy (if prescribed dose is 50 Gy) and < 15 Gy (if prescribed dose is 40–45 Gy).

Although the liver is considered as an organ with parallel functional subunits, the central hepatobiliary tract (cHBT) drained into the central hilum is more likely a serial structure. A 15-mm expansion of portal veins will be used as a surrogate for cHBT, and its constrains in 5-fraction SABR will be V26 < 37 c.c. and V21 < 45 c.c., as reported previously [51].

TACE will be conducted by using a catheter to deliver chemotherapeutic agent and embolic materials into the blood vessels that supply to the tumor. Generally the procedure time will be completed within 1–2 h, and the hospitalization course will be 3 days.

Before each TACE, laboratory data will be checked, and abdominal images will be reviewed. Treatment plan will be discussed and determined by radiologists and gastrointestinal physicians. The planned catheter-inserted site will be the groin. A guide wire will be inserted into the femoral artery. A curve Angiographic Catheters (COOK MEDICAL INC., Bloomington, USA) followed by a superselective microcatheter (Terumo®, Tokyo, Japan) will be sent to the target artery in the liver.

As the catheter approach to the target, several series of angiography will be done to identify the lesion sites. After the target site is determined, catheter will be inserted to the feeding artery branch. Chemotherapy agent (Epirubicin, 30 mg), oil-based radio-opaque contrast agent (LIPIODOL® [ethiodized oil], 5–10 ml, according to tumor size), several 1 × 1 mm Sterile Sponge (Gelfoam®), contrast (XENETIX 350 [350 mg/ml], and solution for injection 10 ml) will be mixed together and then injected to the tumor site.

Post-procedure care will be prescribed, including keeping absolute bed rest for 12 h after the procedure. The incision wound will be compressed by a 2-Kg sandbag for 4–6 h for hemostasis. The medical care team will closely monitor vital signs, pulse of the distant limb, and awareness of whether TACE-associated complication occurred, such as nausea, vomiting, and allergic reactions. Proper treatments will be provided if complication occurs.

Computer-generated random numbers will be used for participant allocation. Two factors will be used as stratification factors, i.e., BCLC cancer stage and level of total bilirubin. A 2-by-2 cross table will be used for randomizing and blocking: total bilirubin (< 2 versus 2–3 g/dl) and BCLC (A versus B), with a block size of 4 in each stratification.

Opaque and sealed envelopes will be used for implementing the randomization and allocation sequence. When the participants are ready to be randomized, the study investigator will pull the very next randomization envelope by sequence from the envelope file, which will be locked in secure locker. The study nurse will record associated information on the study randomization list and the participant’s case report form. Finally, the envelope will be opened to reveal the subject’s treatment assignment and second study staff will double check the envelope file in real time to verify correct treatment assignment. An inspection of envelopes will be completed by data and safety monitoring board (DSMB) during routine monitoring visit. Note that blinding in either sides (i.e., physician or participants) cannot be done because of intervention natures.

All participants have full rights to request discontinuing intervention in any stage of trial allocation. For patients treated with SABR, if during-RT follow-up tests suggest impairment of liver function, such as GOT/GPT > 5-fold upper limit of normal range or total bilirubin > 2.0 g/dl, irradiation dose and treatment schedule will be considered to modify for consolidating patient safety.

All participants will be followed up weekly during intervention period via both outpatient department (OPD) visit and phone contact, respectively. For patients with any grade 3 toxicity of CTCAE, in-patient care with aggressive management will be recommended and provided accordingly.

Several strategies will be conducted for achieving an adequate enrolment of study participants. First, IRB-approved recruitment materials, including hard copy and electronic documents, will be posted in suitable platforms of hospitals and communities. Second, enrolment messages will be announced among national-level special societies, including – but not limited – gastrointestinal, surgical oncology, internal oncology, and radiation oncology. Third, inter-institute cooperation for potential patient enrolments may be done under formal supervision of IRBs.

For all participants, relevant concomitant care and interventions for managing medical comorbidities, such as hypertension, type II diabetes mellitus, and hepatitis B/C infection, will be permitted. Permitted targeted therapy for HCC will be allowed to be prescribed subsequently – but not concomitantly – with SABR. However, chemotherapy agents, including intra-venous or oral forms, may be prohibited before a formal agreement of investigator committee.

Participants will be recruited from Dec. 2016 to Dec. 2019. All recruited participants will be followed up according to National Comprehensive Cancer Network (NCCN) guideline [6]. Table 1 shows a follow-up schedule and checklist according to recommendation of SPIRIT 2013 [46]. Follow-up data will be collected per 3 month since the baseline till 2 years. The timing to decide treatment response will be defined at the week 6 from the date of baseline. Other clinical outcome data regarding patient survival, response rate, and treatment toxicity, will be recorded systemically by schedule.

All investigators, including a specific study nurse, will promote participants retention and follow-up by using a team-work manner. A trial-specific information platform will be used. Follow-up data will be checked at least weekly. Loss of follow-up will be aggressively avoided by using multidisciplinary efforts.

The primary outcome measure is freedom from local progression (FFLP) [24]. FFLP will be defined as time with no in-field progressive disease. Response for target lesions will be defined according to the RECIST version 1.1 and modified RECIST (mRECIST) [52]. The target lesions should show intra-tumor arterial enhancement on contrast-enhanced CT or MRI and can be accurately measured in at least one dimension as 1 cm or more [53, 54].

Several tumor responses will be defined by two independent physicians (one hepatic-specific radiologist and one radiation oncologist): complete response (CR), total disappearance; partial response (PR), 30% decrease in single longest diameter (SLD) of contrast-enhanced part; stable disease (SD), neither partial response nor progressive disease met; and, progressive disease (PD), 20% increase of SLD or new lesion(s).

Several secondary outcomes will be measured at 1 and 2 years, as follows: (1), overall survival; (2), progression-free survival; (3), tumor response rate; and (4), toxicity. Post-intervention complete or partial response will be defined as having a tumor response. Treatment-associated toxicity will be classified according to CTCAE, v.4.03 [55]. Toxicity within 3 months after initiation of interventions will be recorded as acute toxicity. And, toxicity that developed after 3 months will be considered as late toxicity. Liver-specific toxicity including classic and non-classic radiation-induced liver disease (RILD) will also be assessed. Degree of toxicities will be documented, such as ascites (i.e., absent, mild to moderate, and severe/refractory) and encephalopathy (i.e., absent, mild [I-II], and severe [III-IV]).

Several image and laboratory studies will be conducted for assessing treatment response and toxicities. First, CT, MRI, or abdominal sonography will be done per 3 months within the first two-year follow-up, then per 6 months thereafter for another 3 years. Second, specific laboratory studies will be followed up regularly, such as AST, ALT, and Bilirubin (both total and direct; Table 1). All adverse and potential harming events will be systemically collected and then analyzed in investigator meetings. Severe adverse events will be reported to IRB within 2 weeks as the IRB-monitoring guideline.

For allocated patients who have incomplete response after SBRT or re-TACE, several re-salvage modalities will be evaluated as the following order: (1), surgical resection; (2), RFA; (3), TACE; (4), SABR; and, (5), conventional RT. Note that re-SABR or conventional RT may not be indicated for patients with post-SABR recurrence because of limitation of normal tissue tolerance.

Data will be collected primarily through the use of a paper-based case report forms (CRF), which will be completed by a specific study nurse and then confirmed by a physician. Subsequently, the data will be keyed in to the electronic research-incorporated database system (i.e., IROIP) that will be securely hosted at the Dalin Tzu Chi Hospital. Two independent investigators will be assigned to audit the process of data collection and correctness of the data. Baseline data will be collected routinely, including age, sex, ethnicity, education, economic, chronic hepatitis, prior treatments of HCC, and relevant medical comorbidities. All collected clinical data will be cross-linked with electronic laboratory data from the hospital HIS system.

According to prior studies, response rates have been reported: 38% in patients treated with TACE alone [37] and 76.6% in those treated with TACE then salvage SABR [44]. As a result, an absolute increase of 30% in response rate will be considered as having a clinical significance. By using probability of type I error (α, 0.05; and, power [1 - β], 80%), 46 patients will be required in both the two study groups, resulting in a total study cases of 92. With an estimate of drop-out rate of 20%, we will enroll an additional 24 patients to counter potential attrition, reaching a final sample size of 120.

For patients with intermediate stage of BCLC classification, most patients received TACE as their local-regional therapies. However, TACE alone seldom achieves satisfactory complete response and demonstrates a dismal 5-year survival rate of < 20% [56]. Recently, modern high-dose SABR achieves 60–100% tumor response rate when combined with TACE [11 17–22]. Phase I and II trials also showed promising results of SABR on local control (1-year, 87%; 2-year, 94.6%) and survival rate (1-year, 55%; 2-year, 68.7%) [24, 25]. Thus, based on these results, SABR has been suggested as an effective modality for HCC patients with early-stage lesions [19, 24, 57, 58], unresectable tumors (i.e., ≤10 cm) [59], and post-TACE residual tumor [20, 44]. However, level 1 evidence from randomized trials for liver SABR is largely lacking.

A lack of level-III evidence is the main barrier for recommending SABR as a standard of care in most international treatment guidelines. As a result, conducting randomized trials to demarcate the role of SABR in HCC patients is warranted, especially in the Asia-Pacific region, where HBV- and HCV-related HCCs are predominated [2, 3].

Previously, the role of conventional external beam radiation therapy has been limited to palliative or salvage setting for large unresectable HCC, portal vein thrombosis, obstructive jaundice, and failure of prior TACE/RFA [6]. Nowadays, recent advances in irradiating technology lead the radiotherapy from palliation to cure in HCC management [47]. Local response rates range from 40 to 90%, and the median survival range from 10 to 25 months when treated with RT with or without TACE [60]. Remarkably, a recently published randomized trial showed that TACE plus conventional external beam radiation therapy can prolong progression-free survival at 12 and 24 weeks in locally advanced HCC patients when compares with sorafenib treatment [61]. Thus, in the present study, conventional RT will be allowed as one of alternative modalities for managing HCC patients who have incomplete response after SABR (the Arm A) or re-TACE (the Arm B) and for those patients who cannot (or do not) receive re-salvage treatment of TACE, SABR, or RFA.

Study enrolment has been started since Dec. 2016. Participant recruitment is expected to be completed in Dec. 2020.

The major limitation of the present study is small sample size. The relatively small sample size may increase the likelihood of a Type II error that skews the results.