Palliative radiotherapy for hepatic tumors: a narrative review of indications and recommendations^※

Introduction

Background

Primary and secondary liver cancer carries a poor prognosis, so there is active investigation to identify better management options. Modalities such as chemotherapy, immunotherapy, ablation, and radiation have shown rapid advances recently. Much of this work has focused on patients in the curative setting. Despite these significant advances, most patients will succumb to disease or are not eligible for curative treatment. Here, we provide a review of the evidence focusing on palliative radiotherapy.

The liver is a common site of metastases, especially via portal venous drainage from the gastrointestinal tract. Approximately 20% of patients with colorectal cancer (CRC) present with liver metastasis at diagnosis, with 70% of recurrences found in the liver (1-3). Resection is feasible in patients with good liver function, adequate platelet count (>100 bil/L), good performance status (PS), no portal venous thrombosis (PVT), no portal hypertension, normal bilirubin, and no extra-hepatic disease with liver remnant of >40% of total liver volume. Unfortunately, 85–95% of patients with liver metastases (4) cannot undergo curative resection, and up to 50% cannot undergo palliative resection (4). Median survival (MS) for patients with liver metastases is 2–6 months (1), or 6–20 weeks if left untreated (1,3), so additional treatment options are needed (1,5-7).

Rationale and knowledge gap

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a leading global cause of death. A total of 80–90% of HCC patients (8,9) cannot undergo curative resection. Risk factors include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol abuse, non-alcoholic steatohepatitis, and cirrhosis. Patients are often asymptomatic at diagnosis, with disease found incidentally and at advanced stages. Classic imaging findings of arterial-phase enhancement and venous-phase “washout” in patients with lesions >2 cm are diagnostic for HCC without biopsy (2). HCC tends to remain in the liver, but multi-focality and macrovascular invasion (MVI) commonly develop (2). The American Association for the Study of Liver Disease guidelines suggest 6-month ultrasound screening for patients at-risk for HCC, with 3-month ultrasound screening for lesions <1 cm, and multi-phasic computed tomography (CT) scan and/or magnetic resonance imaging (MRI) for lesions >1 cm (10,11).

Standard curative-intent treatment modalities for non-metastatic primary liver cancers include resection, orthotopic liver transplantation (OLT), thermal ablation (radiofrequency or microwave), or catheter-based therapies (transarterial bland embolization or chemoembolization) (12-15). Effective palliation remains an unmet need in liver cancer patients, as one-third of patients report inadequate symptom control at presentation (16), including abdominal pain, night sweats, and nausea (17). Common medications, like opioids, may present excessive sedation risk due to reduced liver clearance, and may even exacerbate symptoms (18). Published guidelines, such as Barcelona Clinic Liver Cancer (BCLC) system for HCC, can help select appropriate management although it has primarily been applied to earlier-stage disease rather than palliative or emergent care settings (10,11). There are no classification systems for liver metastases.

Early treatment, even for asymptomatic patients, should be considered since progression can rapidly lead to organ failure, deleterious symptoms, and death. Advances in radiotherapy (RT), including stereotactic body radiotherapy (SBRT), have improved local control (LC) and reduced RT-induced liver toxicity (19). Recent American Society of Radiation Oncology (ASTRO) guidelines recommended first-line RT for all patients with liver-confined HCC who are not curative-treatment candidates, with conditional recommendations for RT alone or combined with catheter-based or systemic therapy as palliation for HCC with MVI, symptomatic lesions, or metastases (20,21). Dose-escalation for all liver-confined tumors was recommended via SBRT, hypofractionation with intensity-modulated radiotherapy (IMRT), or heavy-particle techniques combined with respiratory management and daily image-guidance (20-25). Recently, the RTOG 1112 randomized clinical trial compared the combination of SBRT and sorafenib, a multi-kinase inhibitor, to sorafenib alone for patients with advanced HCC. This multi-center trial demonstrated improved overall survival (OS) and progression-free survival (PFS) by adding SBRT to sorafenib with no difference in toxicity (26), providing level I evidence that SBRT can significantly improve clinical outcomes and palliation in advanced liver cancer.

Objective

The role of liver RT is rapidly evolving, with multiple guidelines and options published in parallel that include definitive and palliative patients. We present a narrative review synthesizing available literature focusing on palliative liver RT and provide evidence-based recommendations for RT to improve quality of life (QOL) and clinical outcomes in liver cancer patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-965/rc).

Methods

Search methods are summarized in Table 1. We searched PubMed, Ovid Medline, Embase, Cochrane Central, and Web of Science from inception to December 28th, 2022. Included reports studied adults who received RT (any technique) or other anti-cancer therapy for primary or secondary liver cancer. Recorded data includes disease factors (histology, tumor number, tumor size), patient factors [cirrhosis, Child-Pugh (CP) score, hepatitis], and treatment factors (modalities, RT technique, RT dose/fractionation). Case reports, studies of <10 patients, abstract-only publications, and commentaries that did not present new data were excluded. Outcomes of interest were LC, mortality, toxicity, progression, symptom control, response rates, patient reported outcomes (e.g., QOL), and survival.

Discussion

Literature review results

We found nine phase III randomized controlled trials (26-34). The remainder were retrospective, quality or committee recommendations, feasibility, phase I or II studies. We also identified nomograms for identifying which patients may benefit from radiotherapy.

Non-radiation local and regional therapy options

Techniques such as radiofrequency ablation (RFA), electroporation, light-activated drug therapy, and Yttrium-90 (Y-90) radioembolization are recommended for patients with potentially-curable early-stage HCC and liver metastases who cannot undergo surgical resection (35). Intrahepatic Y-90 also provides effective palliation, with symptomatic improvement demonstrated in 54% of patients and mean survival 5–14 months in mixed HCC and liver metastasis populations (36-38). RFA is commonly used for tumors <3 cm and far from large vessels with mostly retrospective or small prospective data suggesting LC up to 90% for HCC (39); decreasing LC is suggested for larger tumors or those close to large vessels (40). Variable 5-year survival (15–55%) and complication outcomes (6–9%, including mortality up to 2%) may limit its applicability, particularly in the palliative setting (2,35,41).

Transarterial chemoinfusion (TAI), image-targeted delivery of chemotherapy directly to the tumor (42), may act as an effective bridge to liver transplantation for HCC (43). Transarterial chemoembolization (TACE) combines chemoembolization with drug-eluting beads (42) and may improve survival for HCC and liver metastases (44,45). Usually, TACE is recommended for intermediate-stage primary HCC (BCLC-B), but guidelines vary, including the “up to seven” criteria (45) or BCLC-B3/B4 patients with good PS and low tumor burden (e.g., solitary nodule, or ≤3 nodules that measure ≤3 cm). Only 10% of HCC patients meet accepted TACE guidelines (46) so many TACE treatments are applied to patients outside of established criteria (46). TACE is less effective for large HCC (>10 cm) or with major PVT and is not recommended for extra-hepatic or metastatic disease (15). Despite evidence of OS improvement, death from liver failure remains frequent (30). Given limitations of TACE and other treatments, investigation of new techniques is a priority.

RT

Toxicity considerations

Given poor prognosis of liver cancers, selecting patients and appropriate treatment intent is critical (47). Factors to consider include liver function, PS, tumor histology, size, stage, local invasion (e.g., PVT), underlying liver disease, comorbidities, potential RT interactions with other therapies or anatomical structures (e.g., nearby gastrointestinal tissues), and patient’s goals of care (48). The multi-disciplinary team, along with the patient and their loved ones, should develop a comprehensive therapeutic approach. Patients often present with advanced disease and significant comorbidities, so early treatment is critical to avoid future problems, as well as improve chances of effective palliation. Even with low expectation of cure, aggressive pre-emptive treatment can provide significant palliative benefit by preventing symptoms like pain, nausea, night sweats, jaundice, or bleeding to improve or maintain patient QOL (17).

Historically, liver RT was avoided due to perceived risk of RT-induced toxicity, as fatal hepatitis can result from whole-liver radiotherapy (WLRT) of 30–36 Gray (Gy) in daily 2 Gy fractions. Classic radiation-induced liver disease (RILD) is a clinical syndrome of anicteric hepatomegaly, elevated liver enzymes, and ascites occurring 2 weeks to 3 months after RT (48-50). Classic RILD may cause tissue damage, cytotoxic chemical and antigen release, inflammation, and eventual fibrosis (51). However, patients with poorer baseline liver function and underlying liver disease usually develop non-classical RILD which includes any other liver toxicity, including hepatitis reactivation (52), elevation of liver enzymes, or decline in liver function (49). Acute toxicity from liver RT includes nausea and vomiting, usually well-managed with anti-emetics such as prochlorperazine (53), or serotonin antagonists like ondansetron (50). Antiretroviral therapy is recommended before initiating RT for patients with HBV due to risk of reactivation (52). Nearby non-hepatic normal structures (such as duodenum and bowel) also need to be protected to avoid toxicity (54).

Selecting patients for radiotherapy

Several systems may help select patients for RT and estimate outcomes, including Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) staging, the Okuda staging system for HCC (55), and others. The CP classification stratifies HCC patients with liver cirrhosis by perioperative mortality risk. Scores (1–3 points per category, depending on severity) are based on: ascites, bilirubin, serum albumin, international normalized ratio (INR), and encephalopathy. In total, 5–6 points (CP-A) suggests 2-year OS of 85%; score 7–9 (CP-B) yields 2-year OS of 60%; and ≥10 points (CP-C) yields 2-year OS of 35%. CP score is prognostic for survival in patients with cirrhosis from chronic liver diseases (56), but has variable reliability due to subjectivity of ascites and encephalopathy (57). Both TACE and SBRT can be pursued in HCC patients with CP-A status, CP-B status with caution, lesions <10 cm, no metastases or extra-hepatic sites, and no MVI. Because CP score correlates with toxicity from RT (58), CP ≤7 points has been recommended for RT in current ASTRO guidelines (20). For liver-directed therapy, including RT for cure or palliation, CP score is an important decision factor.

The Model for End-Stage Liver Disease (MELD) score can predict 3-month mortality in HCC or metastatic patients considered for liver transplant or trans-jugular intrahepatic portosystemic shunt (TIPS). It uses serum bilirubin, creatinine, sodium, and INR, while the updated MELD-Plus adds additional serum markers (59). Using a cut-off of 7.5, MELD may be more effective than CP in predicting toxicities for patients receiving RT (60).

The albumin-bilirubin (ALBI) grade, based on serum albumin and bilirubin, is the only score validated for predicting RILD. It may predict survival better than MELD in HCC patients (61-63), but has not been evaluated in the setting of liver metastases. Adding platelet count produces the platelet-ALBI (PALBI) score (64), which may be more prognostic, but requires validation. Volume of irradiated liver (to equivalent dose of 40 Gy) may predict post-RT decline in liver function as measured by ALBI or CP score (61). The CRAFITY score, based on serum C-reactive protein and alpha-fetoprotein (AFP), was studied in several HCC cohorts receiving PD-L1 immunotherapy, but not RT. The score was associated with radiological response and OS, and was validated among subgroups divided by CP score and PS (65).

Practical nomograms are being developed for prognostic and predictive information, and to select patients who may benefit from treatments like liver RT. One model has accurately predicted 3-month mortality [area under the curve (AUC), 0.961]: CP score and tumor size (>5 cm) predicted survival for HCC patients; serum albumin, extra-hepatic disease, and colorectal primary were predictive for metastatic patients; and CP score, Eastern Cooperative Oncology Group (ECOG) PS, ascites, serum albumin, previous resection, and presence of extrahepatic disease were predictive for the combined HCC and metastatic cohort (66,67). Another system for patients treated with SBRT uses number of lesions (0–1 or >1), active systemic disease, and PS (Karnofsky >80). Allocating 1 point for each factor, scores of 0, 1, 2, and 3 yielded median MS of 34, 12.5, 7.6, and 2.8 months, respectively (68). Another nomogram based on age, normal-liver volume, cancer stage, cirrhosis, hemoglobin, and AFP level also demonstrated favorable (AUC, 0.74) survival prediction (69). Further validation of these techniques is required. No single nomogram has been uniformly accepted as best in liver RT patients.

Another promising approach is a normal-tissue complication probability (NTCP) model incorporating dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) changes before and after RT along with cytokine biomarkers, CP score, ALBI score, and liver enzyme changes for patients with HCC and cirrhosis undergoing RT (70). Technetium-99m galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) imaging may also be able to assess extent of functional liver tissue; a small feasibility study observed correlation between SPECT-detected functional liver volume, lesion size, and risk of RILD, but needs further validation (71).

SBRT

Sometimes referred to as stereotactic ablative radiotherapy (SABR), SBRT is delivered in few (usually 5 or fewer) relatively-large doses of highly-conformal RT using advanced techniques like strict immobilization (e.g., via Vac-lock device) and daily cone-beam computed tomography (CBCT) for image-guidance to reduce setup variation between fractions (72); four-dimensional computed tomography (4DCT) (73) or tumor tracking via implanted fiducial markers (74,75) to evaluate physiological tumor motion; and multiple beams (including non-co-planar beams) to achieve steep dose gradients and minimize dose to normal tissues (76,77). Planning for SBRT generally uses CT with intravenous contrast, positron emission tomography (PET) and/or contrast-enhanced MRI to precisely define targets (78,79). To undergo liver SBRT, patients must be able to lie comfortably on their back for at least 30–40 min and produce consistent breathing patterns or breath-holds.

Proper SBRT allows safe delivery of ablative RT for liver cancer, previously contraindicated due to toxicity risk. Prospective data suggest significant OS advantage for SBRT over conventional RT for patients with HCC and liver metastases, with SBRT improving 2-year OS to 42% from 27% in one large study, with no difference by tumor histology (80). Different strategies have been developed to select SBRT doses while sparing normal liver such as individualizing RT doses based on maintaining the same predicted RILD risk (81) or using NTCP models and ensuring ≥700 cc of uninvolved liver is spared (20,23,82,83). Given the excellent safety profile of SBRT protocols, which resemble curative-intent plans, they can also be used effectively for palliative treatment. Table 2 lists studies of SBRT for both primary liver cancer and metastases. These studies suggest excellent LC rates of 57–100% at 1 year, up to 95% at 5 years, and 2-year OS from 30–83% (81,89,94,95,97,99,105-109,113,114). However, critical appraisal is needed since most used retrospective or early-phase prospective designs, aside from one phase III trial (26). Many of these pioneering SBRT studies had radical treatment intent, but most patients were end-stage and not eligible for interventions such as surgery or TACE.

SBRT allows treatment for patients who experience disease recurrence after loco-regional therapies like TACE or RFA (2,15,30,35-41,43-46,115), whereas previously only supportive care was available. HCC patients treated with SBRT after TACE have seen response rates of 67% with 14 months median OS (116). Patients with liver metastases, including many who received prior treatment, have also shown good outcomes using a range of SBRT doses (36–60 Gy in 1–6 fractions), with higher doses associated with improved LC (2-year LC 75–95% vs. 38% for lower doses) as long as ≥700 cc of normal liver was preserved for non-cirrhotic patients (81,87,91,94,96,98,101,103,106,110). Higher LC was also observed with higher doses in HCC, leading to the most recent ASTRO guidelines recommending a biologically effective dose (BED) of 65 Gy (20,21,117).

For patients with many prior treatments (91), advanced comorbidities, or liver disease (e.g., BCLC-B/C, CP-B, or vascular invasion), durable LC (up to 74% at 1 year) and effective palliation may still be achieved with lower SBRT doses (93). For example, CP-B patients (107) have seen tumor responses with SBRT doses of 24–28 Gy in 5 fractions (24,86).

The recent randomized RTOG 1112 trial evaluated the addition of SBRT (27.5–50 Gy in 5 fractions, individualized by normal-liver dose) to sorafenib for patients with BCLC-B (intermediate) or C (advanced) HCC, with 82% categorized as BCLC-C, and 4% having metastases outside the liver. In the trial, OS (median 16 months SBRT and sorafenib vs. 12 months sorafenib) and PFS (median 9 months SBRT and sorafenib vs. 5 months sorafenib) was improved by adding SBRT to sorafenib with no difference in toxicity (3.5% vs. 5% sorafenib alone), with particular benefit noted in patients with more advanced disease, suggesting SBRT can be considered for advanced or poor-prognosis HCC patients (26). Combining RT or SBRT with other therapies may be more effective than either treatment alone and aggressive treatments may improve palliation and survival in this population.

Studies of QOL also suggest that liver SBRT is well-tolerated. Common effects included temporary worsening of appetite and fatigue, with symptom severity generally recovering to baseline levels within 3 months after SBRT completion (112). Other potential adverse effects of SBRT can include nausea and vomiting, decline in liver function, esophagitis (16–18%), and gastroesophageal bleeding or ulceration (10,81,89,118).

Based on available evidence, SBRT can be considered primarily in settings of good liver function (CP ≤ B7) with up to 3 lesions with the sum of diameters ≤6 cm. This recommendation reflects the recent ASTRO guidelines which recommend selecting SBRT regimens for HCC patients based on CP score: CP-A patients should receive 40–50 Gy in 3–5 fractions, while 30–40 Gy in 5 fractions is recommended for CP-B7 patients (20,22,24). Given the increased risks from SBRT for patients with poor liver function or other risk factors, de-intensification modifications like longer fractionations, different dosing, or non-stereotactic techniques (discussed further below) may be considered.

SBRT and PVT

Vascular tumor invasion (also known as MVI), such as PVT or into the inferior vena cava, is common with HCC (10–40% at initial diagnosis) (12,20,34,119,120). Invasion may cause portal hypertension, ascites, tumor spread, reduced liver function, and destruction of collateral circulation, thereby limiting local therapies like TACE, TAI, Y-90, or surgery, precluding patients from lying flat for any RT. Some affected patients may require diuretics, drainage, or shunt before they can be considered for RT (121-123). Prognosis with PVT or MVI is poor, with MS <4 months without treatment (92,124-127), and systemic therapies are currently considered standard of care (12,20,34,119,120).

SBRT has shown good outcomes for HCC patients with PVT, with LC rates >80% and 1-year OS 43–50% with rates of grade 3 toxicity <10% (mostly bilirubin elevation or bone marrow suppression) (69,83,87,90,126). Another analysis suggested BED >65 Gy, AFP <200 ng/mL, single tumors, and ECOG PS predicted for OS, so these factors may be used to help select treatment for patients (92).

Given the severity of symptoms from PVT (large vascular tumor thrombi block portal blood flow and cause progression of liver dysfunction and ascites), recanalization and LC are important palliative outcomes in these patients. Studies suggest significant improvement in portal vein recanalization with SBRT compared with conventionally-fractionated RT (33% vs. 15%), as well as improved MS (11 vs. 5 months), and 2-year OS (15% vs. 8%) (92). Higher dose and better thrombus targeting may further improve survival rates (128), as may combining therapies like TACE and hypofractionated RT, which significantly improved median PFS (12 vs. 31 weeks) and OS (43 vs. 55 weeks) when compared with sorafenib alone in a randomized trial (27).

As mentioned previously, 74% of HCC patients in the RTOG 1112 randomized trial had MVI, and OS, PFS, and time to progression (TTP) were significantly improved by adding SBRT to sorafenib with no difference in toxicity. Patients with PVT saw an estimated 24-month OS rate of 28% [95% confidence interval (CI): 16–41%] when receiving sorafenib plus SBRT (vs. 9% when receiving sorafenib alone). This provides compelling evidence that incorporating SBRT into therapy for patients with advanced liver cancer not only provides effective LC, but also extends survival (26). Other combination therapies, such as RT with catheter-based therapies, are being investigated for patients with poor-prognosis or palliative-intent treatments, leading to conditional recommendations in recent ASTRO guidelines (20,27,129). Goals of care and willingness to risk potential toxicity (e.g., gastrointestinal) should inform any consideration of SBRT in combination with other treatments (130,131).

SBRT and large lesions

Larger liver tumors (e.g., ≥10 cm) present challenges in all pathologies for minimizing dose to normal liver and adjacent structures. Large lesions may also be RT-resistant due to hypoxia and therapy-resistant clonogens (82,102,111,132). Nevertheless, as shown in Table 2, good outcomes have been reported treating large lesions with SBRT doses of 26–54 Gy in 5–6 fractions: 1-year LC up to 90%, 1-year OS up to 50%, and grade 3 toxicity around 12%. Local and regional recurrence remain the major failure patterns, however, SBRT remains a palliative and definitive option for select patients with large liver tumors as long as sufficient liver volumes (≥700 cc) are spared (66,84,88,100,104,133).

SBRT recommendations

Although not currently endorsed by multi-disciplinary guidelines such as the National Comprehensive Cancer Network (NCCN), we believe that SBRT can be considered as a treatment option alongside RFA, systemic therapy, and TACE for definitive or palliative HCC patients with unresectable disease who are not candidates for liver transplantation. For HCC patients with intra-hepatic tumors <3 cm and away from large vessels, SBRT and RFA have demonstrated similar outcomes. However, with larger or multiple lesions, or those close to blood vessels, we recommend SBRT due to higher LC and lower toxicity (134,135). Surgery, RFA, or SBRT may be considered for smaller lesions. TACE may be considered for HCC patients with CP-A or CP-B liver function without metastases, extra-hepatic disease, or vascular invasion.

SBRT can also be considered for patients with recurrence after TACE (20), and represents the best palliative option for larger lesions that are still amenable to SBRT (20,22). As lesions become larger, more numerous, involve MVI, or as prognosis or liver function worsens, SBRT can still be considered for definitive or palliative treatment, as this is a spectrum of disease in which the improved control and survival benefits of SBRT can benefit the patient.

When treating with SBRT, doses should be individualized with a total dose of 30–50 Gy given in 3–5 fractions for HCC (20-22,24,25,117), and up to 60 Gy in 3-5 fractions for liver metastases. These doses should be considered for maximum benefit in palliative or symptomatic patients if they can tolerate it and normal-tissue liver constraints are met. Single-fraction SBRT (18–30 Gy) may be considered for lesions ≤5 cm if patients cannot tolerate a multi-fraction course. SBRT should be considered on a cautionary basis for patients with poor liver function, such as CP-B in HCC. These patients may still benefit from lower doses, such as 25 Gy in 5 fractions or 30–35 Gy in 3 fractions.

For patients with multiple (>5) or large volume (>10 cm) lesions, SBRT may still be considered for palliative treatment if liver function is adequate (e.g., CP-A). Tumor size >60 cc may be associated with worse LC. In these cases, systemic therapy may be preferred, such as atezolizumab [anti-programmed death ligand 1 (PD-L1) agents], bevacizumab [anti-vascular endothelial growth factor (VEGF) agents], or sorafenib for HCC, or other appropriate systemic therapy depending on cancer histology for metastatic disease. TACE is not recommended for HCC >10 cm or with PVT; SBRT can be considered in these conditions, but with potentially increased toxicity and lower LC rates. Conditional ASTRO recommendations suggest combination therapy with TACE. Combining SBRT and systemic therapy may improve outcomes for this relatively-common, high-risk subgroup.

Respiratory-motion management and image-guided daily treatment should be used (20), and understanding these set-up requirements is crucial for selecting appropriate SBRT patients. Regardless of indication, when planning liver SBRT, care must be taken to spare sufficient normal liver from radiation exposure. One popular method is to ensure that least 700 cc of normal-liver tissue, sometimes called “liver minus gross tumor volume (GTV)”, receives a maximum BED of 30–32 Gy in 2 Gy fractions (20,23). Alternatively, radiobiology-guided dose escalation based on mean liver dose may be used, as pioneered by Dawson et al. and used in RTOG 1112 (136).

Treatment as part of clinical trials should be encouraged where possible. Multi-disciplinary decision making is key when attempting to utilize definitive techniques to maximize palliation and clinical outcomes in palliative or poor-prognosis patients.

Charged particle radiotherapy (CPRT)

CPRT, such as protons or carbon ions, may improve liver sparing compared with photon SBRT techniques, permitting dose escalation. These techniques employ the Bragg peak, a phenomenon whereby dose is deposited within a narrow range and specific depth based on initial energy, with minimal dose deposited beyond the target (137). This phenomenon can allow better sparing of uninvolved liver and nearby critical organs (138). Given potential for improved normal-liver sparing, CPRT may also allow safer treatment of patients with compromised liver function (e.g., CP-B or CP-C).

Prospective CPRT trials have suggested favorable outcomes with 5-year OS approximately 50% for one HCC cohort treated with conventional-fractionation proton therapy, including around 25% for poor-prognosis CP-B and CP-C patients (139,140). Another study of poor-prognosis HCC patients (47% CP-B; 24% CP-C) treated with hypofractionated proton therapy demonstrated median PFS and OS of 36 and 18 months, respectively (141).

Proton therapy has demonstrated efficacy in HCC patients with large tumors >5 cm or multiple tumors >3 cm each, with prospective data suggesting median PFS 36 months without grade ≥3 toxicities (141). Randomized data comparing hypofractionated proton therapy (70.2 Gy in 15 fractions) to TACE alone in HCC patients showed fewer hospitalizations and re-treatments, and trends to better LC (88% vs. 35%, P=0.06) and PFS (48% vs. 31%, P=0.06) without significant difference in OS for proton therapy (142). Across a variety of fractionation schemes, including SBRT, similar outcomes have been shown with proton therapy and carbon-ion therapy for CP-B and CP-C HCC patients, with 5-year LC of 90–93% and OS 36–38% (143).

As with photon RT, dose and fractionation for CPRT must be tailored based on goals of care and proximity to normal structures and uninvolved liver-tissue volume. A phase II multi-institutional trial delivered hypofractionated proton therapy to doses of 67.5 Gray equivalents (GyE) in 15 fractions for peripheral tumors and 58.05 GyE in 15 fractions for central tumors, while keeping mean liver dose ≤24 GyE. Treatment was well tolerated with this risk-adjusted dosing approach in a population of patients with large primary liver tumors (diameter range, 2–12 cm) and PVT in 30% of patients. Two-year OS rates were 63% for HCC, and 2-year LC 95%. Only 4% of patients saw a decline in liver function from CP-A to CP-B, and only 5% of patients experienced grade ≥3 toxicity (144). More randomized trials and cost-effectiveness data are needed before further recommendations can be made regarding CPRT for palliative patients.

Partial-liver and WLRT

Some patients who may benefit from dose-escalated tumor RT are not good candidates for SBRT. These include patients with guarded prognosis, poor PS, extensive disease, small normal-liver volumes, need for urgent RT start, or inability to tolerate SBRT setup requirements. Partial-liver RT with conventional fractionation (i.e., smaller daily fraction-sizes that allow normal-tissue recovery, usually 1.8–2 Gy, delivered over a longer treatment course to a total dose that provides tumor control) may be a better option for these patients.

Table 3 summarizes studies that suggest reasonable rates of portal-vein recanalization for conventional RT, although worse than with SBRT (92). These studies employed either hypofractionated RT (2–5 Gy per fraction to balance patient convenience, more dose per fraction, and normal-tissue healing) or conventional (1.8–2 Gy per fraction) planning techniques and fractionations. Using a range of total doses (35.4–71.5 Gy), most studies suggest radiologic response and 1-year LC rates up to 90% and 1- and 2-year OS rates around 50% and 25%, with low toxicity (grade ≥3 1–10%). These are favorable results for a population that historically has been without good treatment options due to poor prognosis from factors including CP-B liver function, limited liver reserve, elevated AFP (≥400 µg/L), multiple tumors, distant metastases, severe symptoms, poor PS, or other factors (117,153,156). Studies support better responses using higher doses for HCC patients treated with partial-liver 3DCRT with 2-year OS rates of 31% for doses >53.1 Gy vs. 22% for lower doses (47,145,149-151,154). Palliative 3DCRT to symptomatic primary HCC tumors and/or symptomatic MVI is now conditionally recommended by ASTRO “alone or sequenced with systemic therapy or catheter-based therapies in the setting of locally advanced and metastatic HCC” (20,117,153,156).

Some advanced or poor-prognosis patients may be better served by low-dose WLRT (51), a palliative-intent regimen that can lead to symptom relief and tumor debulking, and has rapid planning and treatment times (136,157-159). These considerations must be balanced with sufficient RT dose for durable disease or symptom control, since mean liver doses (in 2 Gy fractions) of 28 Gy for primary liver cancer and 32 Gy for metastases are associated with 5% classic RILD risk (136,158-162). Table 4 summarizes WLRT studies, which suggest effective palliation for primary and metastatic liver tumors (55–95% at 2 weeks post-treatment) and 3–9 months response durations using a range of doses (e.g., 10 Gy in 2 fractions, 8 Gy in 1 fraction, or 20–33 Gy in 1.5–3 Gy fractions) (17,28,29,158,159,161,163-168,171-174). A dose-response relationship has been suggested with lower rates (~50%) of symptom improvement reported with doses 8–10 Gy and up to 90% for higher doses. Better response to RT may also predict longer response duration and clinical outcomes (161). Treatment with 33 Gy was associated with a 10% rate of late liver injury (171).

Combining WLRT with radiosensitizing agents to sensitize hypoxic cancer cells to radiation has been hypothesized to improve palliation. A phase I trial evaluating dose-escalated sorafenib combined with SBRT (30–60 Gy in 6 fractions) and WLRT (21.6 Gy in 6 fractions) for extensive liver metastases suggested that full-dose sorafenib can sometimes be combined safely with SBRT, but not with WLRT (175). A large, multi-institutional, prospective study assessing WLRT (21 Gy in 7 fractions) with or without the radiosensitizer misonidazole found no differences in clinical outcomes, with misonidazole significantly increasing nephropathy rates (29). Another phase I trial for patients with advanced cancer treated with WLRT found that intravenous amifostine increased liver tolerance, suggesting utility but future trials are needed to confirm these findings (176).

Partial-liver and WLRT recommendations

Palliative patients of any liver pathology who cannot undergo SBRT may be considered for 3DCRT or WLRT for symptomatic or local disease control. Multi-disciplinary discussion is critical to determine appropriate treatment, goals of care, and patient tolerance for RT setup requirements. Partial-liver 3DCRT attempts tumor dose-escalation and normal-tissue sparing via fractionation and planning techniques for advanced patients with large or multiple tumors or poor-prognosis features, but who can still tolerate extended treatment courses. Conversely, WLRT is reserved for patients with more advanced disease, significantly reduced PS, pain from liver-capsule stretch or rupture, emergency symptom relief, extensive and diffuse liver involvement, wish to minimize treatment time, diffuse infiltration of the liver refractory to systemic treatment, or extremely-guarded prognosis (e.g., <3 months) (177).

WLRT and partial-liver techniques may be faster to initiate than SBRT due to less intense dosimetry requirements and require less treatment time (<20 min), as they do not require breath-hold or motion management. Minimal immobilization and slight head elevation further improve palliative patient comfort. For partial-liver 3DCRT, mean dose to the liver outside the tumor should be kept <28 Gy with ≤30% liver volume exceeding 35 Gy. WLRT is simple to plan (usually 2 RT fields) and generally provides durable pain relief over several weeks. Recommended doses include 8 Gy in 1 fraction, 10 Gy in 2 fractions, or 20–30 Gy in 2–3 Gy per fraction (17,28,29,136,158,159,161,163-168,171-174,178). Recently, ASTRO guidelines conditionally endorsed palliative WLRT to 8 Gy in 1 fraction for pain alleviation and symptom improvement for HCC (20,158).

CPRT is promising but requires further evidence, given relative lack of availability and direct evidence comparing the modalities. If no RT techniques are tolerable or consistent with goals of care, alternatives include systemic therapy (with possible RT later, if disease responds), regional therapies, or hospice/supportive care alone.

Combination therapy with RT

Combining RT with regional or systemic therapy may provide synergy, which has been demonstrated in metastatic renal-cell carcinoma (179). Phase III trials support combining RT with TACE for MVI in HCC (27) and systemic treatments with palliative WLRT (28,29), but evidence should be interpreted with caution and decisions adapted to patient goals and treatment tolerability.

Combining therapies like TACE with SBRT (30–60 Gy in 5–15 fractions) has demonstrated excellent results and favorable toxicity (<10% grade ≥3 toxicity rates) (20,58,85,123,124,152). These studies suggest that combining TACE and partial-liver 3DCRT holds promise for patients with good PS and liver function who are ineligible for SBRT; studies for HCC patients suggest response rates up to 90%, 1-year OS 47–72%, 2-year OS 25–62%, and <20% grade ≥3 toxicity rates (47,117,145-148,150-153,155). Patients with liver metastases treated with partial-liver 3DCRT combined with TACE or chemotherapy have seen response rates of 50–60%, 1-year OS 55–60%, 2-year OS 30–35%, and <13% grade 3 toxicity (145,147,148,150,151,154,155,180). RTOG 1112 demonstrated improved OS, PFS, and TTP by combining SBRT with sorafenib with no toxicity difference, with particular benefit noted in more advanced disease (26).

Studies of chemotherapy and WLRT are generally small and non-randomized, reporting good results for CRT using different systemic therapies combined with a range of doses and fractionations, but with increased toxicity, as seen in Table 4 (29,154,155,164-167,169,170,181,182). Most studies of WLRT and systemic therapy report generally favorable results (165-167,170,182). However, one small randomized trial found that adding chemotherapy to WLRT did not improve outcomes (28). Improvements in LC or palliation may still be achievable with radiosensitization, as suggested in a study of NTCP-based RT for large tumors with concurrent hepatic arterial floxuridine (60% response and 17 months MS for metastatic patients) (155). Further data is required to fully evaluate the role of combined RT and systemic therapy in the palliative setting for liver RT.

Conclusions

Prevalence of primary and secondary liver cancer is growing, both of which carry a poor prognosis. Many patients present asymptomatically but may have advanced and/or rapidly progressing disease. Effective treatment is often indicated for symptomatic control or to prevent future symptoms.

New modalities like SBRT allow ablative doses to be safely delivered, including for palliation. Favorable outcomes have been demonstrated for patients with limited tumor burden, good PS, and adequate liver function. The randomized RTOG 1112 trial recently reported significant improvements in clinical outcomes with SBRT and sorafenib for patients with advanced HCC. As prognosis worsens with more advanced disease or if goals of care are palliative or less-intensive treatment modalities, partial-liver or WLRT techniques can be considered for rapid response and symptom relief.

In order to better optimize patient selection, RT techniques, and integration with other therapies, treatment as part of clinical trials, especially randomized studies, should be prioritized. However, the current body of evidence is robust enough to recommend RT alongside other established therapies for primary and secondary liver cancer in palliative settings.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Isabella Choi, Stephanie Schaub, Simon S. Lo, and Charles Simone) for the series “Radiotherapy for Oncologic Emergencies” published in Annals of Palliative Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-965/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-965/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-965/coif). The series “Radiotherapy for Oncologic Emergencies” was commissioned by the editorial office without any funding or sponsorship. M.L. has received honoraria for lectures by Eisai, a research pharmaceutical company. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

^※Special series on Radiotherapy for Oncologic Emergencies.

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