Combined Stereotactic Body Radiotherapy and Immunotherapy Versus Transarterial Chemoembolisation in Locally Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis

Abstract

Immunotherapy has achieved modest clinical activity in HCC patients. Propensity score matching analysis was conducted to compare the efficacy and safety of combined stereotactic SBRT-IO versus TACE in patients with locally advanced HCC in a tertiary centre of Hong Kong

Patients with locally advanced HCC who were medically inoperable for, refractory to, or refused to curative surgical interventions were eligible. The primary outcome was PFS; the secondary outcomes were OS, ORR as per mRECIST version 1.1, and TRAEs. Matching pair analysis was performed to compare the clinical outcomes.

A total of 226 patients were eligible. 16 patients in the SBRT-IO group were matched with 48 patients treated with TACE. The median tumour size was 10 cm (range: 2.9-19.6 cm) and 20.3% of the patients had portal vein invasion. The 12-month and 24-month PFS were significantly better in the SBRT-IO group (93.3% vs 16.7% and 77.8% vs 2.1%, respectively, p<0.001); the 12-month and 24-month OS were also better in the SBRT-IO arm (93.8% vs 31.3% and 80.4% vs 8.3%, respectively, p<0.001). The ORR was 87.5% (CR: 50%, PR: 37.5%) in SBRT-IO arm compared to 16.7% (CR: 2.4%, PR: 14.3%) in those receiving TACE alone (p<0.001). There were fewer ≥ grade 3 TRAE (60.4% vs 18.8%, p=0.004) and treatment discontinuations (25% vs 12.5%, p=0.295) due to adverse events in the SBRT-IO arm.

SBRT-IO had significant superior survival and less treatment toxicity than TACE in patients with locally advanced HCC. Our results provide rationale for studying this combination therapy in prospective randomised trials.

Introduction

Recent advances in cancer immunotherapy have profoundly influenced the care of patients with hepatocellular carcinoma (HCC). Programmed cell death protein 1 / programmed death-ligand 1 (PD-1 / PD-L1) targeted therapies have been increasingly used as first-line and second-line treatment of patients with advanced HCC [1-3]. However, response rates are modest; overall the response rates to anti PD-1 monotherapy is around 20%, and even combination therapies of atezolizumab/bevacizumab, pembrolizumab/lenvatinib, or nivolumab/ipilimumab are not higher than 50% [4-6]. Because the primary resistance of HCC may underlie these low response rates, strategies to overcome these primary or secondary resistances to immune checkpoint inhibitors (ICI) using combination therapies such as combined stereotactic body radiotherapy and immunotherapy (SBRT-IO) are under investigations.

Radiotherapy (RT) has been shown to enhance immunotherapeutic effects. RT can prime the immune system by enhancing antigen presentation, promoting the infiltration of cytotoxic T-cells, and reprogramming the tumour microenvironment against the immune evasion of cancer, while ICI can reverse the RT-mediated exhaustion pathway [7]. SBRT-IO has been reported in several cancers, potentially improve the clinical outcome of patients [8-9]. But, evidence on the combination of ICI and SBRT in HCC patients is lacking.

We recently reported encouraging results of SBRT-IO in a small pilot of patients with locally advanced unresectable HCC [10].  This study aimed to compare the clinical outcomes of these patients treated with SBRT-IO versus TACE, the current the standard of care in this population.

Materials And Methods

Study design and population

This was an Institutional Review Board (IRB) approved retrospective study (IRB number: UW-20-674) conducted at a tertiary referral centre of Hong Kong. Data was retrieved from a prospectively collected HCC database at Queen Mary Hospital, Hong Kong. Patients with histological or radiological HCC, who were ineligible for, refractory to, or refused curative surgical interventions, were candidates of loco-regional treatment. All cases were discussed in the multi-disciplinary tumour board. TACE was the standard of care. An experimental treatment of SBRT-IO was offered as an alternative since 2017 based on the potential synergistic effect between SBRT and ICI [10]. While the optimal sequence of combining SBRT and ICI remains controversial, we deliver SBRT prior immunotherapy based on the immune-activation property of radiation to sensitize the tumour for subsequent PD-1 inhibitors [11].   The advantages and disadvantages of these local treatments were informed to patients and the final treatment depends on patients’ decisions. 

The inclusion criteria were as follows: (a) patients were ineligible or refractory to curative surgical interventions; (b) a Child-Pugh (CP) liver score of A5 to B7; (c) tumor nodules ≤ 5; (d) no main trunk of portal vein invasion (Vp4); (e) no prior systemic therapy, and (f) absence of extra-hepatic metastasis, ascites or encephalopathy. There were no limits on the maximum diameters of tumours.

All patients who received SBRT-IO or TACE from January 2010 to May 2020 were included. Propensity score matching was performed using the nearest neighbouring method in 3:1 ratio according to age, sex, tumour size, numbers, and portal vein invasion between the TACE and SBRT-IO groups. 

Transarterial chemoembolisation

TACE was performed by supra-selective cannulation of all the branches supplying the tumour. The emulsion was prepared by mixing lipiodol with cisplatin (1 mg/mL) in a 1:1 ratio using the pumping method, which was then slowly injected under fluoroscopic monitoring according to the size of the tumour and the arterial blood flow. TACE was repeated in eight-week intervals [12].

Stereotactic body radiotherapy and immunotherapy 

For SBRT planning, patients were immobilized via a vacuum foam bag (Vac-LokTM; MEDTEC, Iowa, USA) and active breathing control to reduce the amplitude of liver motion. Imaging was performed on the inhale breath-hold contrast computed tomography (CT). GTV was defined as tumor focus that was visualized on contrast imaging. The clinical target volume (CTV) was defined as GTV plus a margin of 0–3mm. The individualized PTV margins were formulated to compensate the respiratory motion and set-up errors. Cone beam CT was acquired on board before each treatment. The largest tumor was selected as index lesion of SBRT, while maximum three nodules were allowed provided that the liver tolerance dose can be met. The dose was prescribed according to the Radiation Therapy Oncology Group (RTOG) 1112 protocol (23). Total dose of 25Gy to 50Gy in five fractions was allowed per instititional protocol. The prescription isodose should encompass 95% of PTV. The final dose was determined such that a maximum tumoricidal dose could be delivered to tumors while respecting the tolerance dose of OAR to the limits of RTOG 1112. 

Among our patient cohort, a total dose ranging from 25 Gy–37.5 Gy in five fractions was given during 1–2 weeks. At 2 weeks after SBRT, intravenous nivolumab at a dose of 3 mg/kg was started and was given every 2 weeks, median 10 cycles (range: 1-20 doses) were given.

Evaluation of treatment response and decision on treatment discontinuation

Contrast computed tomography was performed every 8-12 weeks in the first two years. All radiological responses were evaluated according to the Modified Response Evaluation Criteria for Solid Tumours (mRECIST) version 1.1. Treatment-related adverse events (TRAEs) were graded using the National Cancer Institute Common Terminology for Adverse Events (CTCAE) version 4.0. Treatments were continued until disease progression, unacceptable toxicities, refusal of patients, or achieved radiological complete remission (CR).

Statistical Analysis

The primary endpoint was progression-free survival (PFS), which was defined as the period from the date of commencement of the treatment to the time of disease progression, as per mRECIST, or death, whichever occurred earlier. The secondary endpoints included overall survival (OS), objective response rate (ORR), TRAEs, and liver function deterioration. OS was defined as the period from the date of commencement of the study treatment to the date of death or last follow-up, whichever occurred earlier. Radiological response was recorded per lesion according to the mRECIST. Disease control rate (DCR) was defined as percentage of patient attained radiological complete response (CR), partial response (PR) or stable disease for ≥ 6 months. Liver function deterioration was defined as progression of Child-Pugh score of ≥2. 

Continuous variables were presented as medians and ranges. Comparison between the groups was carried out using the Chi-squared or Mann-Whitney U test where appropriate. Survivals were studied with the Kaplan-Meier method. Cox proportional hazard regression model was used to determine independent prognostic factors. Statistical significance was defined as p < 0.05, and all the performed tests were two-tailed. Data was analysed using R version 3.25 (Vienna, Austria).

Results

Patients Population Between Tace And Sbrt-io

Among the 64 included patients after matching, the median size of tumour was 10 cm (range: 3.4–19.6 cm) and 20.3% of the patients had portal vein invasion. Among the 48 patients matched in the TACE arm, median 2 sessions of TACE (range: 1–16) were given. For the SBRT-IO arm, a median dose of 35 Gy (range: 27.5–37.5 Gy) was prescribed and median 10 cycles of nivolumab (range: 1–20 doses) were given. Total 24 lesions were irradiated in SBRT-IO arm. (N = 11, single lesion; N = 2, two lesions; N = 3, three lesions). One patient and six patients received post-progression therapies in the SBRT-IO and TACE arms, respectively. Neither patient in the TACE arm received SBRT or immunotherapy, nor patient in SBRT-IO arm received TACE after progression (refer to Table S1 for detailed information).

Overall Survival And Progression-free Survival Between Tace And Sbrt-io

The survival data was censored on December 31st, 2020. The median follow-up time of the SBRT-IO and matched TACE groups were 12.7 months (range: 2.5–36.1 months) and 7.4 months (range: 0.2–57.2 months), respectively. The 6-month, 12-month, and 24-month PFS were better in the SBRT-IO group (93.3% vs. 37.5%, 93.3% vs. 16.7%, and 77.8% vs. 2.1%, respectively, p < 0.001). The median PFS of the SBRT-IO group was not reached (range: 1.9–36.1 months) compared to 4.83 months (range: 0.2–42.2 months) of the TACE group. The 6-month, 12-month, and 24-month OS were also better in the SBRT-IO group (93.8% vs. 54.2%, 93.8% vs. 31.3%, and 80.4% vs. 8.3%, respectively, p < 0.001). The median OS of the SBRT-IO group was not reached (range: 2.5–36.1 months) compared to 7.44 months (range: 0.2–57.2 months) of the TACE group (as shown in Fig. 1).

At the time of analysis, there were three deaths out of 16 patients in the SBRT-IO arm, and all the 48 patients died in the matched TACE group. All the three patients that died in the SBRT-IO group showed no evidence of disease progression; two died of community-acquired pneumonia and one died of haemobilia. In the matched TACE group, 37 deaths (77.1%) were cancer related, four died of pulmonary causes, two died of intra-cranial haemorrhage, and one died of myocardial infarction, liver abscess, liver decompensation, intestinal obstruction, or unknown cause (each). Among patients in the matched TACE group, intra-hepatic progression (90.6%) represented the dominant mode of failure; there were no significant differences in the PFS or OS between the different treatment periods from 2010–2020 (as shown in Fig. S1).

Under the multi-variable analysis, SBRT-IO, was an independent predictor of better OS (hazard ratio [HR] = 0.14, range: 0.30–0.96, p = 0.036) and better PFS (HR = 0.1, range: 0.03–0.33, p < 0.001). Tumour number was another independent predictor of OS (HR = 0.54, range: 0.30–0.96, p = 0.036) and PFS (HR = 0.38, range 0.21–0.72, p = 0.003) (Table 2).

Radiological Objective Response Rate Between Tace And Sbrt-io

Figure 2 depicts the best objective response of 16 patients in SBRT-IO arm and 42 evaluable patients in matched-TACE arm. Six patients of TACE arm did not have reassessment scan due to rapid deterioration. The ORR was significantly higher in the SBRT-IO group (87.5% vs. 16.7%, p < 0.001). DCR was also significantly better in the SBRT-IO group (81.3% vs. 37.5%, p = 0.002). In the matched TACE group, 24 patients (50%) never had radiological disease controlled. In contrast, only one patient (6.3%) developed progressive disease after SBRT-IO; this patient developed a new HCC focus outside the irradiated field and two SBRT-treated lesions had partial response (PR) and static disease (SD). Two patients of the SBRT-IO arm (12.5%) had radiofrequency ablation (RFA) performed after PR, with complete clearance of the tumour subsequently achieved. The waterfall plot of Fig. 3 illustrates the better tumour shrinkage of index lesion in the SBRT-IO and TACE group.

Of note, Nivolumab was stopped for eight patients who achieved CR after median 7.1 months of treatment (range: 2.1–15.6 months); none of them developed relapse in the median follow-up time of 5.7 months (range: 0.7–25.0 months).

Treatment related adverse events and liver function deterioration between TACE and SBRT-IO

Risk of ≥ grade 3 TRAEs and discontinuation of treatment due to toxicities were more common in patients who received TACE (60.4% vs. 18.8%, p = 0.004; 25% vs. 12.5%, respectively, p = 0.295). There was more elevated transaminase, anaemia, leukopenia, and fever in TACE group, while patients who received SBRT-IO had more fatigue, diarrhoea, and rash. Among patients treated with SBRT-IO, none developed classical radiation induced liver disease, and there were no treatment-related deaths reported. There were fewer patients who developed Child-Pugh score progression ≥ 2 at 3 months (6.7% vs. 20.9%, p = 0.008), 6 months (6.7% vs. 12.0%, p = 0.021), and 12 months (0% vs. 21.4%, p < 0.001) in the SBRT-IO arm compared to the TACE arm (Table 3).

Discussion/conclusion

To our knowledge, this is the first comparative study to evaluate the combined SBRT-IO in HCC population. Our findings clearly demonstrated the promising anti-tumour activity of combined SBRT-IO among patients with locally advanced HCC. This present analysis reported that patients who received SBRT-IO had statistically significant better PFS, OS, and ORR than those who received TACE. Around 90% of the patients treated with SBRT-IO survived without disease progression at 1 year and 50% had achieved CR. The high ORR of 88.8% was also superior over that of ICI reported in previous studies [1–6].

Remarkably, our patient cohort had extensive tumour load and/or vascular invasion, which were reflected by the poor outcome of patients treated with TACE (ORR of 16.7%, median PFS of 4.83 months, and median OS of 7.44 months). Despite TACE is the standard of care in patients with unresectable HCC, previous studies suggested those with tumour burden beyond the up-to-seven criteria are unlikely to respond to TACE and patients’ hepatic reserve tends to deteriorate after the TACE treatment [13–14]. Our study had provided a novel therapeutic approach for HCC patients responded poorly to TACE.

There were several reasons accounted for the promising activity of SBRT-IO combination. First, previous studies had demonstrated that SBRT achieved excellent local control (1-year local control rate of 77–87%) in locally advanced HCC, but the competing risk of metastasis had resulted in later precipitous drop of OS (median OS of 9–17 months) [15–16]. Notably, only one patient (6.3%) treated with SBRT-IO in our study developed out-of-field failure. We postulated that the immune-modulatory effect of SBRT has augmented the effect of ICI in eradicating the occult metastasis; this phenomenon, known as ‘systemic therapy augmented by radiotherapy (STAR)’, has also been reported in NSCLC [17]. Second, because of the extensive tumour load in our patient cohort, we were only allowed to prescribe non-ablative dose of radiation (5.5–7.5 Gy x 5) to respect the radiation tolerance of liver. Nevertheless, excellent local tumour response (ORR: 87.5%, CR rate: 50%) was achieved. A study by Vanpouille-Box et al provided an important mechanistic clue regarding the modulation of the immunogenic effect by different radiation dose/fractionation schemes. They showed that modest dose radiation (8 Gy × 3) achieved similar local control as single ablative dose (30 Gy) in the concurrent use of ICI, but better systemic responses are achieved with increased IFN-β production via the cGAS/STING pathway. Our findings are consistent with the pre-clinical data suggesting that ICI can lower the radiation dose required to induce the same tumour response [18]. Lastly, we stopped anti-PD-1 therapy in eight patients once they attained radiological CR; the decisions were made at the discretion of clinicians in agreement with the patients. Interestingly, none of them relapsed after discontinuation of therapy for up to 2 years. The optimal duration of ICI remains unknown; yet a previous study has also suggested that the risk of progression or death is low among patients who achieved radiological CR [19]. Longer follow-up is needed in our cohort to ascertain the durability of response; nevertheless, the encouraging CR rate and the durable response experienced with SBRT-IO provide hope for a cure for unresectable HCC patients without the need for additional therapy, a goal that previously seemed unachievable.

There was no abnormal safety signal observed in combined SBRT and ICI. Patients treated with SBRT-IO had better safety profile and tolerance. More importantly, treatment of TACE often leads to the deterioration of liver function that robs the patients of the opportunity of subsequent systemic therapy [13–14]. Our data suggested that SBRT-IO might better preserve the liver function of patients compared with TACE.

Our data supported the benefit of SBRT-IO in HCC patients. Prospective studies are required to validate our findings in a broader population and compare its efficacy with SBRT alone or ICI alone; future studies should also be prioritised to define the optimal timing, dosing, and treatment volume of radiotherapy and the role of PD-L1 status. Correlative studies are needed to define the mechanistic rationale behind the synergy of SBRT-IO. Lastly, recent data suggested TACE may also favourably modulate the tumour microenvironment and potentially can effectively combine with ICI; a number of trials are now on-going to evaluate the synergy of this combination [20]; comparative study of SBRT-IO vs. TACE-IO is warranted when more data become available in the future.

There were several limitations of this study. First, it was a retrospective and single-centre study with a small sample size; therefore, the selection bias could not be entirely eliminated. However, we had followed the patients in both arms under an unified protocol with regular imaging schedule so that the biases of PFS assessment were minimized, thus the reliability of the superior results of OS and ORR of SBRT-IO. Second, the relatively short duration of follow-up rendered the assessment of late toxicity and long-term survival not feasible. Also, the difference in treatment period may introduce bias in favour of the survival outcome in the SBRT-IO arm, in which majority of the patients were treated in recent years with expanding therapeutic options. Nonetheless, our findings clearly demonstrated the superiority of SBRT-IO over TACE in terms of PFS and tumour response; additionally, the survival of the TACE arm has been fairly consistent over the years. Finally, the PD-L1 status and its impact on the treatment outcome were not evaluated in the present study; however, the high ORR of SBRT-IO suggested the combination worked regardless of the PD-L1 status.

In conclusion, our findings provide a strong rationale to study the SBRT-IO treatment among locally advanced HCC patients in prospective randomised studies.

Abbreviations

CR Complete remission

DCR Disease control rate

ECOG Eastern Cooperative Oncology Group

HCC Hepatocellular carcinoma

HR Hazard ratio

ICI Immune checkpoint Inhibitor

IRB Institutional review board

mRECIST Modified Response Evaluation Criteria in Solid Tumours

ORR Objective response rate

OS Overall survival

PD-1 Program cell death protein 1

PD-L1 Programmed death-ligand 1

PFS Progression-free survival

PR Partial remission

RTOG Radiation Therapy Oncology Group

SBRT-IO Combined stereotactic body radiotherapy and immunotherapy

TACE Transarterial chemoembolisation

TRAE Treatment-related adverse event

Declarations

Acknowledgement

We appreciate and acknowledge the efforts of Mr. Fong KS and Miss LY Kwan for data collection and Mr. Chan SK for statistical support.

Statement of Ethics

Study approval and consent to participate statement This study was approved by The University of Hong Kong/Hospital Authority Hong Kong West Cluster Institutional Review Board (IRB number: UW-20-674).

Conflict of Interest Statement

CL Chiang reports receiving research funding of AstraZeneca, Merck Kgga, and Taiho. He had a consulting or advisory role at AstraZeneca and Eiasi.

Funding Sources

Not applicable.

Author Contributions

Conception and design: CL Chiang, ACY Chan, KWH Chiu

Collection and assembly of data: CL Chiang, ACY Chan

Data analysis and interpretation: CL Chiang, ACY Chan

Manuscript writing: All authors

Final approval of the manuscript: All authors

Accountable for all aspects of the work: All authors

Data Availability Statement

All data relevant to the study are included in the article or uploaded as supplementary information. The study only utilized de-identified patient data collected from the authors’ own institution.

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