Comparison of SABR with Other LDTs: History
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Hepatocellular carcinoma (HCC) is the most common liver tumor, with a continually rising incidence. The curative treatment for HCC is surgical resection or liver transplantation; however, only a small portion of patients are eligible due to local tumor burden or underlying liver dysfunction. Most HCC patients receive nonsurgical liver-directed therapies (LDTs), including thermal ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and external beam radiation therapy (EBRT). Stereotactic ablative body radiation (SABR) is a specific type of EBRT that can precisely deliver a high dose of radiation to ablate tumor cells using a small number of treatments (or fractions, typically 5 or less). With onboard MRI imaging, MRI-guided SABR can improve therapeutic dose while minimizing normal tissue exposure.

  • hepatocellular carcinoma (HCC)
  • liver-directed therapies (LDTs)
  • stereotactic ablative body radiation (SABR)

1. SABR vs. RFA

RFA is a practical approach to destroying inoperable primary or metastatic liver tumors by precisely delivering high-frequency alternating electrical current to the tumor site. It is recommended as the first treatment option for HCC patients with very early-stage or early-stage disease who are not candidates for transplant [1]. Microwave ablation is another ablation modality used in HCC management. Data has shown that microwave ablation is equivalent to RFA in terms of overall survival, local recurrence, and complication rates [2][3]. Besides RFA and microwave ablation, SABR has also been reported as an effective ablative option for patients with small HCC [4][5][6]. Park et al. followed 290 HCC patients with a median tumor size of 1.7 cm; their 5-year LC and overall survival (OS) rates were 91.3% and 44.9% after SABR treatment, respectively [4]. Mathew et al. published similar data in which patients with smaller HCC (<3 cm) had better LC after SABR compared to RFA [5]. In a single-arm phase II clinical trial, Yoon et al. demonstrated that SABR could be a good alternative for patients with small HCCs (<5 cm) with either curative or salvage intent [6].
Given that both RFA and RT have been proven effective for small HCCs, many studies have compared the efficacy of these treatment modalities. So far, the most robust evidence comes from a Korean phase III randomized control trial [7]. The study recruited 144 recurrent/residual HCC patients with less than 3 cm and 2 lesions. Participants were randomly assigned to either proton-beam RT (PBT) or RFA. Due to this unique depth-dose feature, the proton beam can spare adjacent normal tissue and allow dose escalation to the tumor target, similar to SABR. With the non-inferiority design margin at 15%, they found PBT has non-inferior local progression-free survival (PFS) at 2 years (primary endpoint, PBT vs. RFA: 92.8% vs. 83.2% in the ITT population, 94.8% vs. 83.9% in the PP population) [7]. Aside from this clinical trial, there are also multiple retrospective studies directly comparing RT and RFA. The University of Michigan analyzed data from 224 nonmetastatic HCC patients with a median size of 2 cm using either RFA or SABR [8]. Freedom from local progression for patients treated with RFA was 83.6% and 80.2% for 1- and 2-year, respectively, while the numbers for SABR were 97.4% and 83.8%, respectively. Tumor size was a significant prognostic factor for RFA but not for SABR. In patients with a tumor larger than 2 cm, there was a decreased LC for RFA compared with SABR (HR 3.35, p = 0.025). Hara et al. also found that SABR has a comparable outcome compared with RFA for small HCC (≤3 cm) after analyzing data from 695 HCC patients [9]. The 3-year local recurrence rate was 5.3% vs. 12.9% (SABR vs. RFA), and the 3-year OS rate was 70.4% vs. 69.1% [9]. Similar results were found in the Asian population [10]. Besides those single-institution studies, some research based on public databases have also compared SABR with RFA [11][12]. Parikh et al. analyzed 440 patients with stage I or II HCC from the SEER-Medicare database and found that SABR and RFA have similar 90-day hospitalization and 1-year mortality rates [11]. Meta-analyses based on retrospective studies have demonstrated that SABR is an effective alternative to RFA, if not better [13][14][15]. Several ongoing clinical trials are comparing RFA and SABR for HCC, including a phase III randomized trial for HCC ≤5 cm (NCT03898921), a randomized trial for recurrent small HCC ≤5 cm (NCT04047173), and a phase III randomized non-inferiority trial for unresectable small HCC ≤3 cm (NCT05433701). The results of those trials could help clarify SABR efficacy in small HCCs, compared with RFA.

2. SABR vs. TACE

SABR has been demonstrated as an alternative to TACE for treating HCC patients with specific conditions. However, high-quality data comparing these two modalities are lacking. A small pilot study by Nugent et al. of 29 patients randomized to either SABR or TACE demonstrated that SABR delivered to a mean dose of 45 Gy in 5 fractions had a re-treatment probability of 0% at 12 months versus 38.9% for TACE, favoring the ablative nature of external beam SABR [16], which was also supported by the updated data in 2020. In a single-institution retrospective study including 209 HCC patients, SABR was found to have better LC (1- and 2-year LC: SABR 97% and 91%; TACE 47% and 23%, p < 0.001) but similar OS (1- and 2-year OS: SABR 74.1% and 34.9%; TACE 75.3% and 54.9%, p = 0.21) [17]. Another single-center analysis revealed that SABR, even after prior HCC treatments, has equivalent 1-year LC and OS compared with TACE [18]. Similar results were presented in a multi-institutional retrospective propensity-matched analysis [19]. Su et al. analyzed data from 326 patients with inoperable BCLC-A HCC, of whom 167 patients had SABR with 28 to 50 Gy in 1 to 5 fractions and 159 patients underwent TACE [19]. The SABR group had improved LC (SABR vs. TACE, 1-, 3-, and 5-year: 86.8%, 62.5%, 56.9% vs. 69.3%, 53.3%, 36.6%, p = 0.0047), intrahepatic control (1-, 3-, and 5-year: 77.3%, 45.9%, 42.4% vs. 57.3%, 34.1%, 17.7%, p = 0.003), and PFS (1-, 3-, and 5-year: 63.4%, 35.9%, 27.5% vs. 53.5%, 27.4%, 14.2%, p = 0.049) [19]. The OS was comparable between two groups (1-, 3-, and 5-year: 85.7%, 65.1%, 62.8% vs. 83.6%, 61.0%, 50.4%, p = 0.29) [19]. SABR was associated with better local and intrahepatic control in multivariable analysis (HR = 1.59; 95% CI: 1.03–2.47; p = 0.04; HR = 1.61; 95% CI: 1.13–2.29; p = 0.009, respectively) [19].
Proton beam therapy is another external radiation modality being gradually tested in HCC management. As a charged particle, protons can penetrate a certain depth in tissues and deposit the majority of energy at the site of “Bragg Peak”. Due to this unique depth-dose feature, the proton beam can spare adjacent normal tissue and allow dose escalation to the tumor target, similar to SABR. A randomized clinical trial compared proton beam radiation therapy to TACE (NCT00857805) [20]. The interim analysis reported in 2016, including 69 available subjects, revealed similar OS rates on both arms (2-year OS 59%) [20]. The 2-year LC and PFS favor the proton beam group (LC: proton beam RT vs. TACE: 88% vs. 45%, p = 0.06, PFS: 48% vs. 31%, p = 0.06) [20]. The trial has completed enrollment, and the final results have not been published yet (NCT00857805).
Multiple clinical trials are directly comparing RT, mainly SABR, with TACE. Besides the aforementioned trials (NCT00857805, NCT02182687, NCT03960008), there is another trial comparing SABR to TACE (NCT03338647), and a trial for RT vs. TACE in postoperative HCC (NCT02125396). Moreover, trials are exploring the efficacy of the combination of TACE and RT (NCT03895359, NCT02513199, NCT02794337), and re-TACE vs. SABR in post-TACE HCC (NCT02921139, NCT02762266). The ongoing IAEA E33036 study by the International Atomic Energy Agency is a large prospective randomized multinational study seeking to evaluate the non-inferiority of SABR when compared to TACE [21]. Researchers will have better insights when making decisions between SABR and TACE with evidence from these trials.

3. SABR vs. TARE

TARE is another LDT by targeted delivery of high-dose radiation, Y90 microspheres, to the liver tumor via the hepatic artery. Growing evidence supports TARE efficacy in all stages of HCC. A prospective cohort study including 1000 HCC patients who underwent TARE over 15 years demonstrated favorable outcomes of TARE in all BCLC stages [22]. The censored OS was defined as from the first TARE until death, the last follow-up, or curative therapy. In CP A patients, the median censored OS for BCLC A, B, and C disease were 47.3, 25.0, and 15.0 months, respectively. The median censored OS for BCLC A, B, and C diseases in CP B patients was 27.0, 15.0, and 8.0 months, respectively [22]. Based on those results, Northwestern adopted TARE as the first-line transarterial LDT for HCC patients [22][23]. The following LEGACY study, published in 2021, further explored TARE efficacy in HCC patients. The study retrospectively analyzed data from 162 patients with tumors ≤8 cm from three medical centers [24]. TARE was used as neoadjuvant therapy for transplantation or resection (21% and 6.8%, respectively) or as primary treatment for others (72.2%). The objective response rate was 88.3%, with 62.2% of patients having a duration of response of at least 6 months. With a median follow-up of 29.9 months, the 3-year OS was 86.6% for all patients, and 92.8% for neoadjuvant patients who had subsequent resection or transplantation [24]. Higher-level evidence also supports TARE as an effective treatment for advanced HCC. In the randomized controlled phase III trial SARAH, Y90 was compared with sorafenib in locally advanced, inoperable HCC [25]. Here, 467 patients were randomly assigned. With a median follow-up of around 28 months (27.9 months in the Y90 group, 28.1 months in the sorafenib group), Y90-resin microsphere radioembolization demonstrated a comparable OS (median OS, Y90 vs. sorafenib: 8.0 vs. 9.9 months, p = 0.18) with fewer grade ≥3 treatment-related adverse events. Similar findings were presented in the SIRveNIB trial, a phase III open-label clinical trial comparing Y90 versus sorafenib for locally advanced HCC [26]. A total of 360 HCC patients from the Asia-Pacific region were enrolled. Y90-resin microsphere radioembolization has similar efficacy with no significant difference in OS (median OS, Y90 vs. sorafenib: 8.8 vs. 10.0 months, p = 0.36) [26]. Fewer patients in the Y90 group had severe adverse events (20.8% vs. 35.2%) [26]. Though SARAH and SIRveNIB did not prove that Y90 is superior to sorafenib, they did validate that TARE is a good treatment option for locally advanced HCC patients. The NRG/RTOG 1112 trial compares sorafenib versus SABR followed by sorafenib in new or recurrent HCC unsuitable for resection, transplant, ablation, or TACE. Of 85 patients had sorafenib with SABR, their median OS was improved to 15.8 months from 12.3 months in sorafenib only patients (HR=0.77, 1-sided p=0.0554). Median PFS was also improved from 5.5 months to 9.2 months (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). There is not observed increase in adverse events. Results were reported in ASCO GI 2023 and will be published soon. 
There is currently very limited data comparing Y90 TARE to other liver-directed therapies such as TACE, RFA, or SABR. In the only randomized controlled study of TARE versus TACE to date, albeit a small study of 45 patients [27], TARE was able to demonstrate a dramatic lengthening of time to progression (more than 26 months) versus TACE (6.8 months), with similar overall survival (~18 months) and highlights the relatively ablative nature of TARE when compared to chemoembolization. There are currently no additional published randomized controlled trials comparing the efficacy of TARE versus TACE in either the unresectable or resectable setting, though multiple meta-analyses have been performed, leading to varying and sometimes opposing conclusions [28][29][30]. As to data comparing TARE with SABR, a retrospective study including 87 patients reported comparable LC in the SABR and TARE groups (1-year LC, SABR vs. Y90, 87% vs. 89%, p = 0.76) [31]. Patients treated with SABR were more likely to have prior LDT, larger tumors, and higher tumor stages [31]. Some studies explored the role of SABR after extensive use of other local therapies, including Y90, and demonstrated that SABR could treat those patients safely with favorable outcomes (abstracts only) [32][33]. Though data is limited, evidence emerging in the near future might shine a light on the field. Two randomized clinical trials are ongoing. The first one is a single-site pilot study evaluating the efficacy of Y90 and SABR for solitary early-stage (≤3 cm) HCC (recruiting, NCT04235660). The other is a phase II trial exploring Y-90 segmentectomy versus SABR in treating inoperable liver cancer (not recruiting yet, NCT05157451). Besides those head-to-head comparison trials, one study is investigating the combination of Y90 followed by SABR in unresectable HCC (NCT04518748), which might offer a new pathway for selected HCC patients.

4. SABR in HCC with MVI

Advanced HCC is frequently associated with macrovascular invasion (MVI) of major vessels, including the portal vein and hepatic vein [33][34][35][36]. Among them, portal vein tumor thrombus (PVTT) is the most common pattern [33][34][37]. MVI is a significant negative prognostic factor, with a median OS of about 2–5 months without treatment and about 6 months with the best supportive care [36][38][39][40][41]. Treatment for patients with MVI is challenging due to the extent of disease and liver dysfunction, even decompensation. The extension of the tumor to the vasculature facilitates tumor spread both intrahepatically and extrahepatically. MVI could impair liver function by reducing liver perfusion, directly reducing inflow in PVTT, and/or elevating sinusoidal pressure in hepatic vein invasion [42]. Current guidelines recommend systematic therapy as the first-line treatment for patients with HCC and MVI [1][43][44][45]. However, several local treatment modalities have been tested in this clinical scenario, including surgical resection, TACE, TARE, SABR, RT, or combinations [26][46][47][48].
RT has been reported as an effective LDT for HCC with MVI. In a retrospective cohort including 128 HCC and MVI patients who underwent SABR, Munoz-Schuffenegger et al. found that SABR has excellent LC (1-year 87%) and OS (median OS 18.3 months) [49]. Significantly, for those who received sorafenib after SABR, the median OS could prolong to 37.9 months. Besides, 27% of patients had a more than 2-point decline in CP score 3 months after SABR [49]. Another cohort study with 70 HCC and PVTT patients reported similar results [50]. A randomized multicenter clinical trial compared the efficacy of neoadjuvant RT followed by surgery versus surgery alone for patients with resectable HCC and PVTT [51]. A total of 164 eligible patients were randomized to either RT (18 Gy in 6 fractions to PVTT using 3D-RT) with surgery 4 weeks later or surgery alone within 1 week after randomization. With a median follow-up of 15.2 months, OS was found to be significantly better in the RT group (1-year OS: RT + surgery vs. surgery: 75.2% vs. 43.1%), as well as disease-free survival (33.0% vs. 14.9%). Multivariable analyses showed that neoadjuvant RT could significantly reduce HCC-related mortality and recurrence rates (HR 0.35 and 0.45, respectively, both p < 0.001) [51]. Another single-center randomized trial was designed to test SABR in the adjuvant setting for HCC with MVI [52]. A total of 76 patients with MVI-positive disease who had marginal resection were randomly assigned to adjuvant SABR (35 Gy in 5 daily fractions) vs. observation. With a median follow-up of 55 months, patients in the adjuvant SABR group had better disease-free survival (1-, 3-, and 5-year SABR vs. observation, 92.1%, 65.8%, 56.1% vs. 76.3%, 36.8%, 26.3%, p = 0.005) but similar OS (1-, 3-, 5-year: 100%, 89.5%, 75.0% vs. 100.0%, 68.4%, 53.7%) [52]. No grade ≥3 adverse events were observed in the SABR group [52]. Of note, the aforesaid SIRveNIB and SARAH trials also included a portion of MVI patients (SIRveNIB: 30% of all participants; SARAH: 63% of patients in the TARE group, 58% in the sorafenib group) [25][26]. Both trials demonstrated that TARE is as effective as sorafenib for locally advanced HCC with or without MVI.
RT is also efficacious when combined with other LDT in treating HCC with MVI. One randomized clinical trial tested the efficacy of the combination of TACE and RT versus sorafenib in HCC patients with MVI [53]. Here, 90 patients with liver-confined disease were equally assigned to either the sorafenib group (receiving sorafenib 400 mg twice daily) or the TACE-RT group (TACE every 6 weeks with RT starting within 3 weeks after first TACE, maximum 45 Gy in 2.5–3 Gy per fraction). The TACE-RT group demonstrated a higher 12-week PFS (TACE-RT vs. sorafenib: 86.7% vs. 34.3%, p < 0.001) and prolonged median OS (55.0 vs. 43.0 weeks, p = 0.04) [53].

5. SABR as Bridge Therapy to Transplant

SABR is efficacious as a bridge therapy to transplant compared with other LDTs. Mohamed et al. reported retrospective data from 60 patients using SABR (n = 24), TACE (n = 37), RFA (n = 9), or Y90 (n = 9) as a bridge to transplant (79 bridge therapies in total) [54]. The median time to transplant after bridge therapy was 7.4 months. Pathologic complete response was 41%, 28.5%, 60%, and 75% for TACE, SABR, RFA, and Y90, respectively [54]. SABR and Y90 showed significantly less grade ≥3 acute toxicity [54]. Another retrospective study from the University of Toronto analyzed a cohort of 379 HCC patients who underwent bridge therapy (SABR 36 cases, TACE 99 cases, RFA 244 cases) [55]. Postoperative complications were similar and no significant survival difference among groups. Actuarial 1-, 3-, and 5-year survival after listing were 83%, 61%, and 61% for SABR, 86%, 61%, and 56% for TACE, and 86%, 72%, and 61% for RFA (p = 0.4), respectively [55]. The 1-, 3-, and 5-year OS from the time of transplant were 83%, 75%, and 75% for SABR, 96%, 75%, and 69% for TACE, and 95%, 81%, and 73% for RFA (p = 0.7), respectively [55]. Data from clinical trials, though limited, also supports RT (SABR) as a good bridge therapy modality. A phase II randomized clinical trial compared SABR with TACE as a bridging therapy for HCC patients undergoing transplants [56]. Preliminary analysis from 50 patients (21 patients in the SABR group, 29 patients in the TACE group) revealed that SABR is as effective as TACE with potentially less toxicity [56]. The trial has completed recruitment (a total of 60 patients, NCT02182687), and a following phase III multi-center clinical trial is ongoing (NCT03960008).

This entry is adapted from the peer-reviewed paper 10.3390/jcm12103517

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