Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Shi, 2022

Type of study: RCT, single center

Setting and country: Eastern Hepatobiliary Surgery Hospital. Shanghai, China

Funding and conflicts of interest: The research has received funding from the “Clinical

science and technology innovation project of Shenkang

Hospital Development Center” (SHDC12020104),

Shanghai Jiading District Fund’(2016-QN-001), and

“Shanghai Municipal Health Commission Program”

(202140362). The funding contributed to the job in the

collection, analysis, and interpretation of data, in the

writing of the report, and in the decision to submit the

article for publication.

The authors state no further conflicts of interest.

Inclusion criteria:

• Adults who were diagnosed with HCC in BCLC stage 0 or A,
• and had pathologically proved MVI in the surgical specimen,
• and received marginal resection

Exclusion criteria:

• previous anti-tumour treatment
• spontaneous rupture of tumour
• re-resection for recurrence
• delayed recovery from surgery (over 30 days)

N total at baseline: 76

Intervention: 38

Control: 38

Important prognostic factors²:

age ± SD:

I: 56.42 (+/- 10.44)

C: 55.74 (+/- 10.19)

Sex:

I: 86.8 % M

C: 84.2 % M

Groups comparable at baseline?

Yes, no differences between the two groups in terms of baseline characteristics and potential confounders.

Describe intervention (treatment/procedure/test):

Stereotactic body radiotherapy (SBRT). A total dose of 35 Gy was delivered in a week.

Describe  control (treatment/procedure/test):

Surgery alone (SA): Conventional open partial hepatectomy.

Length of follow-up:

Follow-up was measured at 1, 3 and 5 years. The median follow-up period was 55 months.

Loss-to-follow-up:

None

Incomplete outcome data:

None

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival

The one-, three-, and five-year OS rates were

100%, 89.5%, and 75.0% in the SBRT group versus

100.0%, 68.4%, and 53.7% in the SA group, respectively

(p = 0.053).

Disease free survival

The one-, three-, and five-year DFS rates were 92.1%, 65.8%, and 56.1% in the SBRT group versus 76.3%, 36.8%, and 26.3% in the SA group, respectively (p = 0.005).

Adverse events

The overall incidence of radiotherapy-related AE was

31.6% (12 participants).

Local Recurrence

There is no significant difference between

the SBRT group (local recurrence 4/16) and the

SA group (local recurrence 12/28) (p = 0.236).

Distal intra-hepatic recurrence

The recurrence rate

in the SA group (3/28) was not significantly higher than

the rate in the SBRT group (0/16) (p = 0.274). One

participant in the SBRT group and two in the SA group

had extra-hepatic recurrence after intra-hepatic recurrence

in the follow-up period. No singly extra-hepatic

recurrence occurred prior to intra-hepatic recurrence.

Toxicity

Only measured for the SBRT-group: One patient developed abdominal pain, 2 abdominal distention, 2 dyspepsia, 3 nausea, 9 fatigue, 2 liver injury (ALT peak value 91.1 and 104.5 U/ml, respectively), 2 decreased leucocyte count, 2 decreased platelet count, and 1 anorexia.

Méndez Romero, 2023

Type of study: RCT, multi center

Setting and country: Coördination by Erasmus MC Cancer Institute

Funding and conflicts of interest: Funding by Dutch Cancer Society, no conflicts of interest

Inclusion criteria:

• Diagnosis HCC
• (EASL–EORTC Clinical Practice Guidelines 2012)
• Age ≥18 years
• ECOG performance status 0-1
• BCLC stage A, B
• None or cirrhosis Child Pugh A
• Albumin>28 g/l
• Bilirubin <50 µmol/l
• INR <2.3
• AST/ALT <5 times ULN
• Leukocytes >1.5x109/l
• Hb >6 mmol/l
• Preferably platelets ≥50x109/l
• One to three tumors
• Diameter (cumulative) ≤6 cm
•  

Exclusion criteria:

• Uncontrolled portal hypertension.
• Untreated esophageal varices Paquet III or IV
• Ascites
• Encephalopathy
• Acute viral or non-viral hepatitis
• Vascular tumor invasion
• Previous radiotherapy to the liver
• Pregnancy;
• Distance from tumor to luminal organs <0.5 cm

N total at baseline: 28

Intervention: 12

Control: 16

Important prognostic factors²:

age ± median range

I: 62 (50-85)

C: 69 (55-78)

Sex:

I: 10 (83%) M

C: 14 (88%) M

Groups comparable at baseline?

Yes, no differences between the two groups in terms of baseline characteristics

A risk-adapted dose prescription of SBRT was applied with a maximum dose of 6x9 Gy (Canadian protocol), while 6x8 Gy was acceptable as lowest total dose.

Chemoembolization was performed by delivering DEB, i.e., hydrogel-based microspheres

(Biocompatibles UK, Ltd, HepaSphere Biosphere Medical) loaded with the chemotherapeutic agent

doxorubicin. If 1-month, 3-month or 6-month follow-up CT or MRI scan showed residual enhancement of the treated lesion, a second, third or even fourth TACE-DEB procedure was allowed.

Length of follow-up:

Median follow-up 28.1 months

Loss-to-follow-up:

None

Incomplete outcome data:

None

Outcome measures and effect size (include 95%CI and p-value if available):

Time to progression

Median TTP was 12.0 months in the TACE-DEB arm (95% CI, 4.9-15) and 18.8 months in the SBRT arm (95% CI, 7.6-not reached) (HR = 0.45, 95% CI: 0.16-1.32, p=0.15).

Local control

Median time to local recurrence was 12.0 months in the TACE-DEB arm (95% CI, 4.9-not reached). In the SBRT arm it has not been reached (>40 months) HR = 0.15, (95% CI 0.02-1.21 p=0.075).

Overall survival

Median OS time was 36.8 months in the TACE-DEB arm (95% CI, 18.1-not reached) and 44.1 months (95% CI, 20.3-not reached) in the SBRT arm (HR = 0.58, 95% CI 0.18-1.85, p=0.36).

Response rate

Response rates were 81% (56% CR+25% PR) in the TACE-DEB arm and 92% (67% CR+25% PR) in the SBRT arm.

Liver transplantation

Nine patients had been treated with TACE-DEB with the intention of liver transplantation at a later

stage. Ultimately, five of these patients underwent transplantation. Median time from randomization to liver transplant was 10.7 months (range 9.8-17.1 months). The other patients were not transplanted, either because they did not wish to undergo transplantation (two patients) or due to disease progression (two patients). Six patients in the SBRT group were considered for liver transplant, four of whom ultimately received a transplant. Median time from randomization to liver

transplant was 10.3 months (range 5.2-14 months). Due to disease progression, two patients did not undergo a transplant.

Toxicity

Only considering adverse events that may have been related to the treatment delivered, two of the 16 patients in the TACE-DEB arm had between them a total of three episodes (13%) of grade ≥3 toxicity. In the SBRT group there were no

such episodes. In the TACE-DEB arm, one patient developed an infection with sepsis within one month after treatment. This was scored as grade 4 and as probably related to the procedure. One patient who developed a hepatobiliary disorder grade 3 (hepatic encephalopathy) between 1 and 3 months after treatment was also scored as possibly related. In the same period, the same patient,

developed an increase in bilirubin. This was possibly related and scored as grade 3 (grade 2 at base line).

Power analysis for this study calculated a needed sample size of 100 patients, but due to slow recruitment the study was closed after 30 patients. Two of the 30 included patients were retrospectively considered to be ineligible. Both these patients were randomized in the SBRT arm.

Comito, 2022

Type of study: RCT, single center

Setting and country: Humanitas Research Hospital, Rozzano, Italy

Funding and conflicts of interest:

No external funding received, no conflicts of interest declared

Inclusion criteria:

Patients diagnosed with unresectable HCC by histology or non-invasive European Association for the Study of the Liver criteria following prior TAE or TACE with radiologically defined residual disease. Patients also had to be appropriate candidates for locoregional treatment with stage BCLC A-B HCC (without evidence of active extrahepatic disease, including vascular thrombi) and Child–Pugh Class A or B liver disease without existing encephalopathy or ascites.

Exclusion criteria:

Patients were excluded from the trial in the event of concurrent malignancy, uncontrolled infection, severe anomalies in blood tests, previous abdominal

irradiation and Grade _3 hemorrhagic complications within 4 weeks of enrollment in

the study.

N total at baseline: 40

Intervention: 21

Control: 19

Important prognostic factors²:

Sex:

I: 71 % M

C: 79 % M

Groups comparable at baseline?

Yes, no significant differences between the groups

In patients randomized to SBRT, a blank and contrast-enhanced 4D-simulated CT was acquired, and, when available, image fusion with magnetic resonance

imaging and/or choline positron emission tomography for better target definition was

performed. The clinical target volume (CTV) corresponded to the gross tumor volume, as

delineated on pretreatment imaging. The planning target volume (PTV) corresponded to the clinical target volume plus a 7–10 mm isotropic expansion. Tumor motion was managed through 4D CT and abdominal compression. SBRT was delivered in 3 to 6 fractions: the dose schedule was adapted on an individual basis in terms of the number of fractions

and total delivered dose in order to prioritize with respect to dose–volume constraints for normal tissues, particularly the dose to the residual healthy liver.

Patients randomized in the TAE/TACE arm were treated

with TAE or conventional TACE according to the first embolization treatment received before the randomization. For TAE, the superselective catheterization of feeding vessels with

microcatheters (Renegade High Flow; Boston Scientific, Natick, MA, USA) was obtained to

perform subsegmental embolizations. Embolization was performed using small, precise

and tightly calibrated microparticles (40 +/- 10 and/or 100 +/-  25 µm in diameter) with a hydrogel core and a nanothin coating of Polyzene-F (Embozene Color-Advanced Microspheres;

CeloNova BioSciences, Newnan, GA, USA). The injection of 40 µm microspheres

was performed until blood flow interruption or the administration of 4 mL. In the case of

the residual enhancement and/or patency of feeding arteries, 100 _m microparticles were

administered. In patients treated with TACE, 5 mL of iodized oil (Lipiodol) and 50 mg of epirubicin dissolved in 5 mL of non-ionic contrast media were used, followed by particle administration. The procedure was considered completed only when vascular shutdown was confirmed and no feeding vessels to the target tumor were detected at final angiography.

Length of follow-up:

Median of 20 (range 3 to 56) months

Loss-to-follow-up:

One patient was lost before randomization

Incomplete outcome data:

None

Outcome measures and effect size (include 95%CI and p-value if available):

Local control

The use of SBRT was significantly correlated with superior LC as compared to TAE/TACE (median not reached versus. 8 months,

p = 0.0002; HR: 0.15 (CI95% 0.04–0.4)), corresponding to a 1-year LC of 84% versus. 23%

Progression free survival

Patients treated with SBRT experienced significantly longer PFS in comparison with patients treated with TAE/TACE (median 9 versus 4 months, p = 0.016; HR: 0.43 (CI95% 0.21–0.87)).

Distant Recurrence-Free Survival

Median DRFS was 14 months (95% CI 5–21) in the TAE arm and 9 months (95% CI 7–16) in the SBRT arm (p = 0.494).

Overall survival

Median OS was 31 months (95% CI 22–53) in the SBRT arm and 30 months (95% CI 17–35) in the TAE/TACE arm (p = 0.472). OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively.

Patterns of failure

At the time of our analysis, local progression occurred in 21 patients following TAE/TACE (n = 15) or SBRT (n = 6).

Toxicity

The occurrence of toxicity was infrequent (n = 5, 13%) and mainly consisted of grade 1–2 nausea and abdominal pain in 4 out of 5 patients (3 in the SBRT arm occurred during radiation treatment and 1 in the TAE/TACE arm occurred within 24 h of the embolization session). Only one patient experienced acute grade 3 sepsis complicated by pleural effusion following TACE. Overall, no grade >3 toxicity was observed in any treatment arm.

All included patients have received one or more TAE/TACE course, and were unresponsive.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts

blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Shi, 2022

Definitely yes

Reason: Randomization was carried out using the random sequence method of Excel on the computer, keeping a 1:1 ratio.

Definitely no

Reason: Participants and study staff were unmasked to treatment allocation. Blinding was not applied.

Definitely no

Reason: Patients and healthcare providers were not blinded. It is not mentioned whether the data collectors, outcome assessors and data analysts were blinded.

Definitely yes

Reason: There was no loss to follow-up.

Definitely yes

Reason: All relevant outcomes were reported.

Definitely yes

Reason: No other problems noted

HIGH

Reason: Lack of blinding, and unclear whether data collectors, outcome assessors and data analysts were blinded

Méndez Romero, 2023

Probably yes

Reason: In this open-label, prospective, multicenter, randomized,

phase 2 trial, we randomized patients 1:1 between TACEDEB (standard arm) and SBRT (experimental arm).

Definitely no

Reason: Unblinded study (open label)

Definitely no

Reason: Patients and healthcare providers were not blinded. It is not mentioned whether the data collectors, outcome assessors and data analysts were blinded.

Definitely yes

Reason: There was no loss to follow-up.

Definitely yes

Reason: All relevant outcomes were reported.

Definitely no

The study was powered for 100 participants, but after 30 participants was stopped due to slow inclusion.

HIGH

Lack of blinding, and unclear whether data collectors, outcome assessors and data analysts were blinded, trial underpowered and stopped prematurely due to slow inclusion

Comito, 2022

Definitely yes

A computer-generated minimization program that incorporates a random element was used to ensure that the treatment groups were balanced for gender and Child-Pugh class

Definitely no

Reason: Unblinded study (open label)

Definitely no

Reason: Patients and healthcare providers were not blinded. It is not mentioned whether the data collectors, outcome assessors and data analysts were blinded.

Definitely yes

Reason: There was no loss to follow-up.

Definitely yes

Reason: All relevant outcomes were reported.

Definitely no

The study inclusion was stopped prematurely due to slow accrual/number of events was met earlier than expected

HIGH

Reason: Lack of blinding, and unclear whether data collectors, outcome assessors and data analysts were blinded, trial was stopped prematurely